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Victoria University of Wellington
1.
George, Philip.
A Phase 1 Dose Escalation Trial of Third Generation Chimeric Antigen Receptor (CAR) T-Cell Therapy for Relapsed and Refractory B-Cell Non Hodgkin Lymphoma.
Degree: 2020, Victoria University of Wellington
URL: http://hdl.handle.net/10063/9103 
► Anti-CD19 Chimeric Antigen Receptor (CAR) T-cell therapy is shifting the treatment paradigm internationally for selected patients with relapsed and refractory B-cell Non- Hodgkin Lymphoma. Despite…
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▼ Anti-CD19
Chimeric Antigen Receptor (CAR) T-cell therapy is shifting the treatment paradigm internationally for selected patients with relapsed and refractory B-cell Non- Hodgkin Lymphoma. Despite high response rates with durable responses achieved in a significant proportion of patients, over 50% of patients will have progressed at one year following treatment with the currently licensed anti-CD19 CAR T-cell therapies. This modality of therapy is also associated with acute and potentially life-threatening toxicities, requiring strict risk mitigation strategies.
In this thesis, the design, preparation and implementation of a new third generation anti-CD19 CAR T-cell Phase 1 trial entitled ENABLE, for patients with relapsed and refractory B-cell Non-Hodgkin Lymphoma, is described in detail. Following a literature review of CAR T-cell therapy in patients with B-cell Non-Hodgkin Lymphoma, the rationale for the ENABLE trial design is discussed, along with regulatory and clinical requirements for setting up CAR T-cell therapy in New Zealand. The importance of international collaboration to inform aspects of study design, CAR T-cell product manufacturing and developing CAR T-cell toxicity management protocols, has been demonstrated.
The early clinical experience on the ENABLE trial is presented along with provisional safety, pharmacokinetic and efficacy data from the first participant treated. This is the first time that CAR T-cell therapy has been administered in New Zealand, demonstrating CAR T-cell expansion in vivo; but also highlighting the complexities of the CAR T-cell product manufacturing process and the importance of evaluating feasibility of CAR T-cell manufacturing, as a key secondary endpoint of the study. Further clinical experience on the ENABLE trial is crucial to develop the potential for CAR T-Cell therapy to be a safe, feasible and effective option for selected New Zealand patients in the future.
Advisors/Committee Members: Weinkove, Robert.
Subjects/Keywords: Lymphoma; Chimeric Antigen Receptor; Immunotherapy
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APA (6th Edition):
George, P. (2020). A Phase 1 Dose Escalation Trial of Third Generation Chimeric Antigen Receptor (CAR) T-Cell Therapy for Relapsed and Refractory B-Cell Non Hodgkin Lymphoma. (Masters Thesis). Victoria University of Wellington. Retrieved from http://hdl.handle.net/10063/9103
Chicago Manual of Style (16th Edition):
George, Philip. “A Phase 1 Dose Escalation Trial of Third Generation Chimeric Antigen Receptor (CAR) T-Cell Therapy for Relapsed and Refractory B-Cell Non Hodgkin Lymphoma.” 2020. Masters Thesis, Victoria University of Wellington. Accessed March 07, 2021.
http://hdl.handle.net/10063/9103.
MLA Handbook (7th Edition):
George, Philip. “A Phase 1 Dose Escalation Trial of Third Generation Chimeric Antigen Receptor (CAR) T-Cell Therapy for Relapsed and Refractory B-Cell Non Hodgkin Lymphoma.” 2020. Web. 07 Mar 2021.
Vancouver:
George P. A Phase 1 Dose Escalation Trial of Third Generation Chimeric Antigen Receptor (CAR) T-Cell Therapy for Relapsed and Refractory B-Cell Non Hodgkin Lymphoma. [Internet] [Masters thesis]. Victoria University of Wellington; 2020. [cited 2021 Mar 07].
Available from: http://hdl.handle.net/10063/9103.
Council of Science Editors:
George P. A Phase 1 Dose Escalation Trial of Third Generation Chimeric Antigen Receptor (CAR) T-Cell Therapy for Relapsed and Refractory B-Cell Non Hodgkin Lymphoma. [Masters Thesis]. Victoria University of Wellington; 2020. Available from: http://hdl.handle.net/10063/9103
Brigham Young University
2.
Ollerton, Matthew T.
Capacity of Human Immunodeficiency Virus Targeting Chimeric Antigen Receptor T Cells to Eliminate Follicular Dendritic Cells Bearing Human Immunodeficiency Virus Immune Complexes.
Degree: PhD, 2017, Brigham Young University
URL: https://scholarsarchive.byu.edu/cgi/viewcontent.cgi?article=8240&context=etd
► An important obstacle to a functional cure for HIV/AIDS is the persistence of viral reservoirs found throughout the body in various cells and tissues. Reservoirs…
(more)
▼ An important obstacle to a functional cure for HIV/AIDS is the persistence of viral reservoirs found throughout the body in various cells and tissues. Reservoirs can be latently infected cells, or in the case of follicular dendritic cells (FDC), non-infected cells that trap infectious virus on their surface through immune complexes (HIV-IC). Although several strategies have been employed to target and eliminate viral reservoirs, they are short-lived and ineffective. In an attempt to provide a long-term approach, chimeric antigen receptor T (CAR-T) cells were designed to eliminate native HIV on FDCs. Although effective at eliminating HIV-infected cells, and halting spreading infection, their ability to eliminate the viral reservoir found on (FDCs) remains unclear. We used a novel second-generation CAR-T cell expressing domains 1 and 2 of CD4 followed by the mannose binding lectin (MBL) to allow recognition of native HIV envelope (Env) to determine the capacity to respond to the viral reservoir found on FDCs. We employed a novel fluorescent lysis assay, the Carboxyfluorescein succinimidyl ester (CFSE) release assay, as well as flow cytometric based assays to detect functional CAR-T activation through IFN-γ production and CD107a (i.e., LAMP1) membrane accumulation to test cytolytic capacity and functional activation of CD4-MBL CAR-T cells, respectively. We demonstrated their efficacy at eliminating HIV-infected cells or cells expressing gp160. However, these CAR-T cells were unable to lyse cells bearing surface bound HIV-IC. We found that failed lysis was not a unique feature of a resistant target, but a limitation in the CAR-T recognition elements. CAR-T cells were inactive in the presence of free HIV or in the presence of concentrated, immobilized virus. Further experiments determined that in addition to gp120 recognition by the CAR-T, the adhesion molecule ICAM-1 was necessary for efficient CAR-T cell killing of HIV-infected cells. CAR-T cell activity and killing were inhibited in the presence of ICAM-1 blocking antibody. These results suggest that other factors, such as adhesion molecules, play a vital role in CAR-T responses to HIV-infected cells. In addition, our findings highlighted the necessity to consider all models of HIV reservoirs, including FDCs, when evaluating therapeutic efficacy.
Subjects/Keywords: HIV; chimeric antigen receptor; follicular dendritic cells
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APA (6th Edition):
Ollerton, M. T. (2017). Capacity of Human Immunodeficiency Virus Targeting Chimeric Antigen Receptor T Cells to Eliminate Follicular Dendritic Cells Bearing Human Immunodeficiency Virus Immune Complexes. (Doctoral Dissertation). Brigham Young University. Retrieved from https://scholarsarchive.byu.edu/cgi/viewcontent.cgi?article=8240&context=etd
Chicago Manual of Style (16th Edition):
Ollerton, Matthew T. “Capacity of Human Immunodeficiency Virus Targeting Chimeric Antigen Receptor T Cells to Eliminate Follicular Dendritic Cells Bearing Human Immunodeficiency Virus Immune Complexes.” 2017. Doctoral Dissertation, Brigham Young University. Accessed March 07, 2021.
https://scholarsarchive.byu.edu/cgi/viewcontent.cgi?article=8240&context=etd.
MLA Handbook (7th Edition):
Ollerton, Matthew T. “Capacity of Human Immunodeficiency Virus Targeting Chimeric Antigen Receptor T Cells to Eliminate Follicular Dendritic Cells Bearing Human Immunodeficiency Virus Immune Complexes.” 2017. Web. 07 Mar 2021.
Vancouver:
Ollerton MT. Capacity of Human Immunodeficiency Virus Targeting Chimeric Antigen Receptor T Cells to Eliminate Follicular Dendritic Cells Bearing Human Immunodeficiency Virus Immune Complexes. [Internet] [Doctoral dissertation]. Brigham Young University; 2017. [cited 2021 Mar 07].
Available from: https://scholarsarchive.byu.edu/cgi/viewcontent.cgi?article=8240&context=etd.
Council of Science Editors:
Ollerton MT. Capacity of Human Immunodeficiency Virus Targeting Chimeric Antigen Receptor T Cells to Eliminate Follicular Dendritic Cells Bearing Human Immunodeficiency Virus Immune Complexes. [Doctoral Dissertation]. Brigham Young University; 2017. Available from: https://scholarsarchive.byu.edu/cgi/viewcontent.cgi?article=8240&context=etd
3.
Yong, Carmen.
Enhancing adoptive immunotherapy: redirecting immune subsets and metabolic pathways.
Degree: 2017, University of Melbourne
URL: http://hdl.handle.net/11343/194374
► The adoptive transfer of T cells expressing a chimeric antigen receptor (CAR) as a treatment for cancer has achieved impressive responses in haematological malignancies, but…
(more)
▼ The adoptive transfer of T cells expressing a chimeric antigen receptor (CAR) as a treatment for cancer has achieved impressive responses in haematological malignancies, but has been less successful in the treatment of solid tumors. The tumor microenvironment of solid tumors presents multiple forms of immunosuppression, inhibiting the efficient effector function of infiltrating anti-tumor T cells. During my PhD, we assessed the potential of two strategies to enhance the anti-tumor function of CAR T cells. The first focuses on the potential of other CAR-expressing immune subsets to stimulate CAR T cell function and persistence in the tumor microenvironment. To elucidate the function of CAR-expressing non-T lymphocytes, we generated a transgenic mouse model (vav-CAR) in which immune cells express a CAR against the Her2 (ErbB2) tumor antigen. As expected, CAR T cells harboured anti-tumor function but we also found that CAR-modified macrophages and natural killer cells (NKs) exhibited significant antigen specific cytokine secretion, cytotoxicity and phagocytosis. Moreover, using the vav-CAR model, we demonstrated the potential of CAR immune cells to mediate tumor rejection independently of CD8+ T cells. CD4+ T cells were critical for this response as their deletion severely abrogated the anti-tumor responses in our vav-CAR model. Distinct T helper subsets have been shown to participate to anti-tumor responses, with Th1 and Th17 cells demonstrating a more robust efficacy as compared to other T helper subsets. Our second strategy was focused on the impact of metabolism in the polarisation of CD4+ T cells, in particular the differentiation of CAR T cells to Th1 lineage. T cell activation and polarisation is highly associated with increased metabolic needs. Given that nutrient deprivation in the tumor microenvironment, due to a high demand of the tumor for resources, can limit the nutrients available for other cell types, the fate and function of adoptively transferred immune cells may be altered upon entering the tumor. Therefore, modifying CAR immune cells to resist metabolic suppression in the tumor microenvironment may help retain their effector functions. Upon assessing the effects of nutrient deprivation on T cell differentiation, we previously found that limiting concentrations of glutamine, the most abundant amino acid in the plasma, inhibited the potential of T cells to undergo Th1 differentiation with associated IFNγ secretion. Rather, this condition resulted in the conversion of naïve CD4+ T cells into suppressive FOXP3+ regulatory T cells (Tregs). Here, we determined that a single glutamine-derived metabolite, α-ketoglutarate (αKG), enhanced the anti-tumor effector functions of multiple CAR T helper subsets, increasing the production of IFNγ and reducing FOXP3 expression.
Thus, during my PhD, I generated a vav-CAR model, providing a platform in which the function of multiple CAR-bearing immune subsets can be studied and manipulated. This model will promote the utilisation of optimized CAR-bearing immune cells…
Subjects/Keywords: cancer immunotherapy; metabolism; chimeric antigen receptor
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APA (6th Edition):
Yong, C. (2017). Enhancing adoptive immunotherapy: redirecting immune subsets and metabolic pathways. (Doctoral Dissertation). University of Melbourne. Retrieved from http://hdl.handle.net/11343/194374
Chicago Manual of Style (16th Edition):
Yong, Carmen. “Enhancing adoptive immunotherapy: redirecting immune subsets and metabolic pathways.” 2017. Doctoral Dissertation, University of Melbourne. Accessed March 07, 2021.
http://hdl.handle.net/11343/194374.
MLA Handbook (7th Edition):
Yong, Carmen. “Enhancing adoptive immunotherapy: redirecting immune subsets and metabolic pathways.” 2017. Web. 07 Mar 2021.
Vancouver:
Yong C. Enhancing adoptive immunotherapy: redirecting immune subsets and metabolic pathways. [Internet] [Doctoral dissertation]. University of Melbourne; 2017. [cited 2021 Mar 07].
Available from: http://hdl.handle.net/11343/194374.
Council of Science Editors:
Yong C. Enhancing adoptive immunotherapy: redirecting immune subsets and metabolic pathways. [Doctoral Dissertation]. University of Melbourne; 2017. Available from: http://hdl.handle.net/11343/194374
University of Pennsylvania
4.
Klichinsky, Michael.
Human Chimeric Antigen Receptor Macrophages For Cancer Immunotherapy.
Degree: 2018, University of Pennsylvania
URL: https://repository.upenn.edu/edissertations/3137
► Despite recent landmark advances in chimeric antigen receptor (CAR) T cell immunotherapy for the treatment of human cancer, metastatic solid tumors remain an intractable challenge.…
(more)
▼ Despite recent landmark advances in chimeric antigen receptor (CAR) T cell immunotherapy for the treatment of human cancer, metastatic solid tumors remain an intractable challenge. Myeloid cells are actively recruited to the tumor microenvironment (TME), where tumor associated macrophages (TAMs) are often the most abundant infiltrating immune cell. Currently, macrophage orientated immunotherapeutic approaches under clinical development in oncology seek to reduce TAM infiltration or enhance TAM phagocytosis. We hypothesized that genetically engineering human macrophages with CARs against tumor-associated antigens could redirect their phagocytic activity and lead to therapeutic efficacy with the potential for the induction of an anti-tumor T cell response.
In this thesis, we demonstrate that CD3-zeta based CARs are capable of inducing phagocytosis by human macrophages. Notably, an active intracellular CAR signaling domain was required for activity. Targeted phagocytosis and clearance of CD19+, mesothelin+, and HER2+ cells by CARs targeted against each respective antigen was significantly superior to that by control untransduced (UTD) macrophages. Importantly, CAR macrophages were capable of polyphagocytosis and serial phagocytosis of tumor cells.
We demonstrate that primary human monocyte derived macrophages, which are resistant to most viral vectors, are efficiently transduced by the chimeric-fiber adenoviral vector Ad5f35. Ad5f35 transduced primary human CAR macrophages demonstrated targeted phagocytosis, with phagocytic activity dependent on both the CAR and antigen densities. CAR, but not UTD, macrophages led to potent dose-dependent killing of tumor cells in vitro and led to tumor regression and improved overall survival in murine xenograft models of human cancer.
Macrophage transduction with Ad5f35 leads to a broad gene expression change, an interferon signaling signature, and induction of a classically activated M1 phenotype. CAR macrophages upregulated co-stimulatory ligand and antigen processing/presentation genes and led to enhanced T cell stimulation in vitro and in vivo. Lastly, CAR, but not UTD, macrophages showed a broad resistance for M2 conversion in response to immunosuppressive cytokines.
In conclusion, human CAR macrophages display targeted tumor phagocytosis, lead to improved overall survival in xenograft models, and demonstrate enhanced T cell stimulation. Taken together, these data show that CAR macrophages are a novel cell therapy platform for the treatment of human cancer.
Subjects/Keywords: car macrophage; chimeric antigen receptor; chimeric antigen receptor macrophage; macrophage; Allergy and Immunology; Immunology and Infectious Disease; Medical Immunology; Pharmacology
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APA (6th Edition):
Klichinsky, M. (2018). Human Chimeric Antigen Receptor Macrophages For Cancer Immunotherapy. (Thesis). University of Pennsylvania. Retrieved from https://repository.upenn.edu/edissertations/3137
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Klichinsky, Michael. “Human Chimeric Antigen Receptor Macrophages For Cancer Immunotherapy.” 2018. Thesis, University of Pennsylvania. Accessed March 07, 2021.
https://repository.upenn.edu/edissertations/3137.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Klichinsky, Michael. “Human Chimeric Antigen Receptor Macrophages For Cancer Immunotherapy.” 2018. Web. 07 Mar 2021.
Vancouver:
Klichinsky M. Human Chimeric Antigen Receptor Macrophages For Cancer Immunotherapy. [Internet] [Thesis]. University of Pennsylvania; 2018. [cited 2021 Mar 07].
Available from: https://repository.upenn.edu/edissertations/3137.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Klichinsky M. Human Chimeric Antigen Receptor Macrophages For Cancer Immunotherapy. [Thesis]. University of Pennsylvania; 2018. Available from: https://repository.upenn.edu/edissertations/3137
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
McMaster University
5.
Hammill, Joanne.
PRE-CLINICAL DEVELOPMENT OF SYNTHETIC RECEPTOR-ENGINEERED T LYMPHOCYTES FOR THE TREATMENT OF CANCER: NOVEL RECEPTORS AND UNDERSTANDING TOXICITY.
Degree: PhD, 2018, McMaster University
URL: http://hdl.handle.net/11375/22904
► Advances in our understanding of the molecular events leading to cancer have facilitated the development of next-generation targeted therapies. Among the most promising new approaches…
(more)
▼ Advances in our understanding of the molecular events leading to cancer have facilitated the development of next-generation targeted therapies. Among the most promising new approaches is immuno-oncology, where therapeutic agents engage the immune system to fight cancer. One exciting strategy therein is the adoptive transfer of ex vivo cultivated tumor-specific T lymphocytes into a cancer patient. Tumor-specific T cells can be produced by engineering a patient’s own T cells with synthetic receptors (e.g. chimeric antigen receptors (CARs)) designed to redirect T cell cytotoxicity against a tumor target. CAR-engineered T cells (CAR-T cells) were expected to be a non-toxic cellular therapy which would seek out and specifically eliminate disseminated tumors. The clinical experience supports the promise of CAR-T cell therapy (striking efficacy has been observed in the treatment of hematological malignancies), while highlighting areas for improvement; CAR-T cell use has been associated with a host of toxicities and robust clinical efficacy has yet to be replicated in solid tumors.
This thesis uses pre-clinical models to describe previously unappreciated aspects of CAR-T cell-associated toxicity and novel synthetic receptor strategies, including:
i. The capacity of NKG2D-based CAR-T cells to mediate toxicity.
ii. The utility of designed ankyrin repeat proteins as CAR antigen-binding domains.
iii. The discovery that variables intrinsic to human CAR-T cell products contribute to toxicity.
iv. A novel synthetic receptor capable of redirecting T cell specificity against a tumor target – the T cell antigen coupler (TAC). Unlike equivalent CAR-T cells, TAC-T cells are capable of mediating efficacy against a solid tumor in the absence of toxicity.
We anticipate that these results will contribute towards the development of next-generation synthetic receptor-engineered T cell products that can deliver upon the promise of safe, systemic cancer therapeutics.
Thesis
Doctor of Philosophy (PhD)
The human immune system has the unique capacity to “seek and destroy” tumor cells throughout the body. A novel class of drugs, immuno-oncology agents, harness this ability to fight cancer. Within this class is a new cellular drug where genetic engineering is used to create killer immune cells (called T cells) capable of recognizing and eliminating tumors. Two of these cellular drugs have recently received FDA approval, supporting the feasibility of this approach. However, further research is needed to improve the safety of engineered-T cells and increase the number of patients whom can benefit from their use. This thesis uses laboratory investigations to better understand the side-effects associated with anti-cancer engineered-T cells and evaluate new engineering strategies. We anticipate that these results will contribute towards the development of next-generation engineered-T cell drugs which retain the ability to function systemically against cancer but offer an enhanced safety profile.
Advisors/Committee Members: Bramson, Jonathan, Medical Sciences.
Subjects/Keywords: Immunology; Immuno-oncology; Chimeric antigen receptor; CAR-T cells
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APA ·
Chicago ·
MLA ·
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CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Hammill, J. (2018). PRE-CLINICAL DEVELOPMENT OF SYNTHETIC RECEPTOR-ENGINEERED T LYMPHOCYTES FOR THE TREATMENT OF CANCER: NOVEL RECEPTORS AND UNDERSTANDING TOXICITY. (Doctoral Dissertation). McMaster University. Retrieved from http://hdl.handle.net/11375/22904
Chicago Manual of Style (16th Edition):
Hammill, Joanne. “PRE-CLINICAL DEVELOPMENT OF SYNTHETIC RECEPTOR-ENGINEERED T LYMPHOCYTES FOR THE TREATMENT OF CANCER: NOVEL RECEPTORS AND UNDERSTANDING TOXICITY.” 2018. Doctoral Dissertation, McMaster University. Accessed March 07, 2021.
http://hdl.handle.net/11375/22904.
MLA Handbook (7th Edition):
Hammill, Joanne. “PRE-CLINICAL DEVELOPMENT OF SYNTHETIC RECEPTOR-ENGINEERED T LYMPHOCYTES FOR THE TREATMENT OF CANCER: NOVEL RECEPTORS AND UNDERSTANDING TOXICITY.” 2018. Web. 07 Mar 2021.
Vancouver:
Hammill J. PRE-CLINICAL DEVELOPMENT OF SYNTHETIC RECEPTOR-ENGINEERED T LYMPHOCYTES FOR THE TREATMENT OF CANCER: NOVEL RECEPTORS AND UNDERSTANDING TOXICITY. [Internet] [Doctoral dissertation]. McMaster University; 2018. [cited 2021 Mar 07].
Available from: http://hdl.handle.net/11375/22904.
Council of Science Editors:
Hammill J. PRE-CLINICAL DEVELOPMENT OF SYNTHETIC RECEPTOR-ENGINEERED T LYMPHOCYTES FOR THE TREATMENT OF CANCER: NOVEL RECEPTORS AND UNDERSTANDING TOXICITY. [Doctoral Dissertation]. McMaster University; 2018. Available from: http://hdl.handle.net/11375/22904
University of California – San Diego
6.
Huang, Peng Fei.
Immunotherapy Using Chimeric Antigen Receptor Macrophage.
Degree: Biology, 2019, University of California – San Diego
URL: http://www.escholarship.org/uc/item/2cx6x7vt
► Chimeric antigen receptor (CAR) T cell immunotherapy has become one of the most prominent and leading cancer therapies due to its remarkable success in targeting…
(more)
▼ Chimeric antigen receptor (CAR) T cell immunotherapy has become one of the most prominent and leading cancer therapies due to its remarkable success in targeting hematological malignancies. Unfortunately, CAR-T cell immunotherapy has not had the same amount of success in solid tumors due to the challenging tumor’s immunosuppressive microenvironment. Therefore, we hypothesize the use of macrophages as a vessel for CAR immunotherapy due to their associate with tumors as TAMs and also the tumors ability to secrete various chemokines that can attract myeloid cells to the tumor site. THP-1 a monocytic cell line that represents a monocyte/macrophage model was transduced with an anti-CD19 scFv CAR construct. K562 a leukemia cell line that represents hematological malignancies and H460 a lung cancer cell line that represents solid tumors were transduced to overexpress the surface marker CD19. THP-1 clones expressing the anti-CD19 CAR construct were cocultured with the two tumor cell lines, which demonstrated the ability of the THP-1 CARs to specifically targeted and lysis the tumor cells that overexpressed the CD19 surface marker. Upon CAR activation, THP-1 cells were polarized towards the M1 classical activated phenotype due to the increase in expression of TNF-α, IL-1β, IL-6, IL-12β, CXCl10, HLA-DR, and CD86. Additionally, THP-1 cells did not show any change in the M2 alternative activated markers of IL10, TFGβ, CCL18, CCL22, CD206, and CD204 to suggest polarization towards the M2 phenotype. As a result, this study validates the proof of concept that macrophages could potentially be a vessel for CAR immunotherapy.
Subjects/Keywords: Biology; Chimeric Antigen Receptor; Immunotherapy; Macrophages; Solid Tumors; Tumor Microenvironment
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APA ·
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to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Huang, P. F. (2019). Immunotherapy Using Chimeric Antigen Receptor Macrophage. (Thesis). University of California – San Diego. Retrieved from http://www.escholarship.org/uc/item/2cx6x7vt
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Huang, Peng Fei. “Immunotherapy Using Chimeric Antigen Receptor Macrophage.” 2019. Thesis, University of California – San Diego. Accessed March 07, 2021.
http://www.escholarship.org/uc/item/2cx6x7vt.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Huang, Peng Fei. “Immunotherapy Using Chimeric Antigen Receptor Macrophage.” 2019. Web. 07 Mar 2021.
Vancouver:
Huang PF. Immunotherapy Using Chimeric Antigen Receptor Macrophage. [Internet] [Thesis]. University of California – San Diego; 2019. [cited 2021 Mar 07].
Available from: http://www.escholarship.org/uc/item/2cx6x7vt.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Huang PF. Immunotherapy Using Chimeric Antigen Receptor Macrophage. [Thesis]. University of California – San Diego; 2019. Available from: http://www.escholarship.org/uc/item/2cx6x7vt
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Melbourne
7.
DUONG, CONNIE.
Generation of novel chimeric antigen receptors to enhance the specificity and activity of T cells for the adoptive immunotherapy for cancer.
Degree: 2014, University of Melbourne
URL: http://hdl.handle.net/11343/44219
► Adoptive immunotherapy is a promising treatment for cancer, with response rates of up to 70% in metastatic melanoma. To broaden this approach, T cells have…
(more)
▼ Adoptive immunotherapy is a promising treatment for cancer, with response rates of up to 70% in metastatic melanoma. To broaden this approach, T cells have been genetically modified to express chimeric antigen receptors (CARs) to endow T cells with anti-tumour activity capable of recognising a range of different cancer types. This approach has shown encouraging results in recent clinical trials for the treatment of haematological malignancies, however it has shown only moderate activity against solid cancers. To date, only a small number of molecules involved in T cell signaling have been incorporated into CARs, resulting in their suboptimal activity. Therefore improvements in CARs are needed in order to realise the full potential of adoptively transferred T cells. We proposed that using multiple or alternate signaling domains could enhance CAR-mediated T cell function. In this thesis, we describe the use of a DNA library of signaling molecules to investigate novel combinations of signaling molecules that could mediate enhanced CAR activity in the Jurkat T cell line and primary human T cells. A novel single-chain variable receptor was discovered comprising DAP10, CD3ζ and CD27 signaling domains that was able to trigger enhanced T cell activity in vitro and in an adoptive transfer mouse model. Clinical trials utilising CAR modified T cells have in some cases resulted in resulted in severe autoimmunity due to T cell recognition of tumour-associated antigens expressed on normal tissues. It is anticipated that as the application and efficacy of adoptive immunotherapy increases, toxicity against normal tissue will become increasingly common. To address this, we proposed that a T cell will respond less against normal tissue if endowed with a tumour-associated antigen-specific activating CAR co-localised with a chimeric inhibitory receptor (CIR) that is capable of turning off the T cell following engagement of antigen on normal tissue. We generated several novel chimeric inhibitory receptors and demonstrated expression of both CAR and CIR in T cells, which were then characterised for function against tumour-associated and normal tissue antigen expressing cell lines. In conclusion, the combination of these novel chimeric receptors may lead to a more efficacious but safer therapy for cancer.
Subjects/Keywords: adoptive immunotherapy; cancer; T cell; chimeric antigen receptor
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APA ·
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APA (6th Edition):
DUONG, C. (2014). Generation of novel chimeric antigen receptors to enhance the specificity and activity of T cells for the adoptive immunotherapy for cancer. (Doctoral Dissertation). University of Melbourne. Retrieved from http://hdl.handle.net/11343/44219
Chicago Manual of Style (16th Edition):
DUONG, CONNIE. “Generation of novel chimeric antigen receptors to enhance the specificity and activity of T cells for the adoptive immunotherapy for cancer.” 2014. Doctoral Dissertation, University of Melbourne. Accessed March 07, 2021.
http://hdl.handle.net/11343/44219.
MLA Handbook (7th Edition):
DUONG, CONNIE. “Generation of novel chimeric antigen receptors to enhance the specificity and activity of T cells for the adoptive immunotherapy for cancer.” 2014. Web. 07 Mar 2021.
Vancouver:
DUONG C. Generation of novel chimeric antigen receptors to enhance the specificity and activity of T cells for the adoptive immunotherapy for cancer. [Internet] [Doctoral dissertation]. University of Melbourne; 2014. [cited 2021 Mar 07].
Available from: http://hdl.handle.net/11343/44219.
Council of Science Editors:
DUONG C. Generation of novel chimeric antigen receptors to enhance the specificity and activity of T cells for the adoptive immunotherapy for cancer. [Doctoral Dissertation]. University of Melbourne; 2014. Available from: http://hdl.handle.net/11343/44219
University of Melbourne
8.
Mills, Jane Kathleen.
Combining TIL and CAR for adoptive cell therapy in metastatic melanoma.
Degree: 2019, University of Melbourne
URL: http://hdl.handle.net/11343/228933
► Background Metastatic melanoma is a highly lethal disease, and until recently patients had limited therapeutic options. Knowledge and understanding of the role the immune system…
(more)
▼ Background
Metastatic melanoma is a highly lethal disease, and until recently patients had limited therapeutic options. Knowledge and understanding of the role the immune system plays in tumour development and its therapeutic potential has recently gained momentum and immunotherapeutic agents have emerged as the gold standard of therapy in treating this cancer. Adoptive cell therapy (ACT) has been shown to have high rates of tumour regression with durable, complete responses and potential 'cure'. Tumour-infiltrating Lymphocytes (TIL) and Chimeric Antigen Receptor (CAR) therapies are examples of ACT. Each has their own advantages, limitations and toxicities. As the complexity of the immune system and its targets is increasingly appreciated, combining immunotherapies is emerging as a promising avenue for improving patient oncological outcomes. This project explores the efficacy of dual specific T cells by combining TIL and CAR therapies.
Aim
To establish a model system transducing TIL with anti-Her2 CAR (TIL-CAR) and assessing function against autologous melanoma tumour cells that express Her2 antigen.
Method
TIL were generated from patient derived metastatic melanoma tumours and tumour cell lines were established in a biobank. TIL were thawed and activated using CD3/28 beads and transduced with second generation anti-Her2 CAR (scFv-erbB2-CD28-zeta) using a retronectin protocol. Patient matched PBMCs were transduced for functional comparison. Melanoma tumour lines in the biobank were found to innately express Her2 antigen to varying degrees. Some melanoma tumour lines were transduced and sorted to create higher expressing Her2 antigen lines for functional comparison. Flow cytometry was used to confirm cell phenotype and antigen/CAR expression. Functional testing was performed using ELISA and chromium release assays. An in vivo ACT model in NSG mice was performed comparing TIL and TIL-CAR.
Results
TIL were successfully cultured from metastatic melanoma tumour pieces. Despite TIL proliferating at lower rates than PBMCs, both were successfully transduced to express anti-Her2 CAR. When TIL were transduced to express anti-Her2 CAR they were functionally active through both TCR and CAR and produced greater amounts of interferon gamma against Her2 expressing tumour lines. TIL-CAR had greater cytotoxic activity when cultured against autologous melanoma tumour lines, but the benefit transduced TIL over PBMCs varied in response between tested patients. The advantage of TIL-CAR over PBMC-CAR did not demonstrate consistent trends across this limited group of patients. The functional activity may be influenced by the level of Her2 expression in the co-cultured tumour cells as well as by the phenotype of T cell populations. Results of an in vivo pilot study in mice demonstrated reduction in tumour size when TIL-CAR were used in an ACT protocol. The primary limitation of this study was the low proliferation rate of TIL following transduction which required extended periods in culture.
…
Subjects/Keywords: melanoma; metastatic; adoptive cell therapy; ACT; chimeric antigen receptor; CAR; immunotherapy
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APA (6th Edition):
Mills, J. K. (2019). Combining TIL and CAR for adoptive cell therapy in metastatic melanoma. (Masters Thesis). University of Melbourne. Retrieved from http://hdl.handle.net/11343/228933
Chicago Manual of Style (16th Edition):
Mills, Jane Kathleen. “Combining TIL and CAR for adoptive cell therapy in metastatic melanoma.” 2019. Masters Thesis, University of Melbourne. Accessed March 07, 2021.
http://hdl.handle.net/11343/228933.
MLA Handbook (7th Edition):
Mills, Jane Kathleen. “Combining TIL and CAR for adoptive cell therapy in metastatic melanoma.” 2019. Web. 07 Mar 2021.
Vancouver:
Mills JK. Combining TIL and CAR for adoptive cell therapy in metastatic melanoma. [Internet] [Masters thesis]. University of Melbourne; 2019. [cited 2021 Mar 07].
Available from: http://hdl.handle.net/11343/228933.
Council of Science Editors:
Mills JK. Combining TIL and CAR for adoptive cell therapy in metastatic melanoma. [Masters Thesis]. University of Melbourne; 2019. Available from: http://hdl.handle.net/11343/228933
University of Southern California
9.
Gong, Songjie.
Construction and testing of chimeric antigen receptor
targeting CS1 for treatment of primary effusion lymphoma.
Degree: MS, Molecular Microbiology and Immunology, 2015, University of Southern California
URL: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/615523/rec/1608
► Currently, no effective therapies exist for human Primary effusion Lymphoma (PEL). Here we used a humanized CS1 monoclonal antibody (mAb) to target CS1, which is…
(more)
▼ Currently, no effective therapies exist for human
Primary effusion Lymphoma (PEL). Here we used a humanized CS1
monoclonal antibody (mAb) to target CS1, which is a cell surface
glycoprotein that selectively and consistently expressed on B-cell
cancer, while PEL is also kind of B-cell lymphoma, to treat PEL.
Chimeric antigen receptors (CARs), also known as artificial T cell
receptors, are a modification of extracted patient T-cells that
improve on human existing recognition abilities. We used CARs as
our CS1 mAb carrier which were then transfected to lentiviral
vectors and infected NK92-MI cells, which can be treated to PEL
cell lines. Administration of in vitro cytotoxicity assay showed
significantly inhibition of tumor expression. Our study suggests
that anti-CS1 CAR may represent a promising approach for the
treatment of PEL.
Advisors/Committee Members: Chaudhary, Preet M. (Committee Chair), Machida, Keigo (Committee Member), Zandi, Ebrahim (Committee Member).
Subjects/Keywords: primary effusion lymphoma; multiple myeloma; chimeric antigen receptor; CS1
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APA (6th Edition):
Gong, S. (2015). Construction and testing of chimeric antigen receptor
targeting CS1 for treatment of primary effusion lymphoma. (Masters Thesis). University of Southern California. Retrieved from http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/615523/rec/1608
Chicago Manual of Style (16th Edition):
Gong, Songjie. “Construction and testing of chimeric antigen receptor
targeting CS1 for treatment of primary effusion lymphoma.” 2015. Masters Thesis, University of Southern California. Accessed March 07, 2021.
http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/615523/rec/1608.
MLA Handbook (7th Edition):
Gong, Songjie. “Construction and testing of chimeric antigen receptor
targeting CS1 for treatment of primary effusion lymphoma.” 2015. Web. 07 Mar 2021.
Vancouver:
Gong S. Construction and testing of chimeric antigen receptor
targeting CS1 for treatment of primary effusion lymphoma. [Internet] [Masters thesis]. University of Southern California; 2015. [cited 2021 Mar 07].
Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/615523/rec/1608.
Council of Science Editors:
Gong S. Construction and testing of chimeric antigen receptor
targeting CS1 for treatment of primary effusion lymphoma. [Masters Thesis]. University of Southern California; 2015. Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/615523/rec/1608
University of New South Wales
10.
Chaudhry, Kajal.
The dynamics of anti-tumour responses generated by chimeric antigen receptor-modified immune effector cells.
Degree: Graduate School of Biomedical Engineering, 2018, University of New South Wales
URL: http://handle.unsw.edu.au/1959.4/61998
► A patient’s own T cells can be genetically modified and amplified in the laboratory to target antigens expressed ontumour cells through the introduction of chimeric…
(more)
▼ A patient’s own T cells can be genetically modified and amplified in the laboratory to target antigens expressed ontumour cells through the introduction of chimeric antigen receptor (CAR) genes. Despite considerable advances in the treatment of B cell leukaemia using chimeric antigen receptor T (CART) cells targeting the CD19 antigen, some patients have not responded well, particularly those with solid tumours. Understanding the biology of CART cell effector function may explain treatment failure, and lead to more effective cell therapy products. Population-based assays such as flow cytometry give a snapshot of these complex cellular systems, but do not allow one to study the fate of individual cells over time. Therefore, the aim of this thesis was to apply flow cytometry, time-lapse imaging and singlecell tracking to characterise the dynamics of CART and tumour cell interactions in vitro. The utility of time-lapse imaging and single-cell tracking was demonstrated by quantifying the cytotoxicity of CART cells targeting CD19+ leukaemia cell lines. This thesis also addresses the problem of minimal CART cell effector function against solid tumours by studying the potency of anti-GD2 re-directed Natural Killer (GD2NK) and T cells (GD2T) targeting neuroblastoma spheroids with time-lapse imaging. Flow cytometry studies show that at least 90% of CD19+ leukaemia cells were killed at high effector to target ratios (E:T=10:1), however only 10% killing was achieved at lower ratios (E:T=1:1). Cooperative killing by CART cells was observed by time-lapse imaging without serial killing. In the clinical context, localisation of effector cells through chemotaxis and proliferation at tumour sites may be required for tumour elimination. NK and GD2NK cell penetration of solid neuroblastoma spheroids was superior to T or CART cells. NK but not T cells were able to destroy tumour spheroids. However, coculture of neuroblastoma spheroids with NK and T cells resulted in loss of NK-mediated tumour killing. In conclusion, this thesis provides methodological advances to the study of anti-tumour response generated by innate and CAR-enhanced effector cells against haematological malignancy and solid tumours by application of time-lapse imaging. This thesis also provides insights into the detailed mechanism of effector cell killing by direct observation of the dynamics of effector cell migration, infiltration, conjugate formation and cytotoxicity using single-cell tracking.
Subjects/Keywords: T cells; Adoptive immunotherapy; Chimeric antigen receptor; NK cells
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APA ·
Chicago ·
MLA ·
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CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Chaudhry, K. (2018). The dynamics of anti-tumour responses generated by chimeric antigen receptor-modified immune effector cells. (Doctoral Dissertation). University of New South Wales. Retrieved from http://handle.unsw.edu.au/1959.4/61998
Chicago Manual of Style (16th Edition):
Chaudhry, Kajal. “The dynamics of anti-tumour responses generated by chimeric antigen receptor-modified immune effector cells.” 2018. Doctoral Dissertation, University of New South Wales. Accessed March 07, 2021.
http://handle.unsw.edu.au/1959.4/61998.
MLA Handbook (7th Edition):
Chaudhry, Kajal. “The dynamics of anti-tumour responses generated by chimeric antigen receptor-modified immune effector cells.” 2018. Web. 07 Mar 2021.
Vancouver:
Chaudhry K. The dynamics of anti-tumour responses generated by chimeric antigen receptor-modified immune effector cells. [Internet] [Doctoral dissertation]. University of New South Wales; 2018. [cited 2021 Mar 07].
Available from: http://handle.unsw.edu.au/1959.4/61998.
Council of Science Editors:
Chaudhry K. The dynamics of anti-tumour responses generated by chimeric antigen receptor-modified immune effector cells. [Doctoral Dissertation]. University of New South Wales; 2018. Available from: http://handle.unsw.edu.au/1959.4/61998
University of Toronto
11.
Oldham, Robyn Anne Alexa.
Development and Testing of Novel Cancer Immunotherapies for Hematological Malignancies.
Degree: PhD, 2020, University of Toronto
URL: http://hdl.handle.net/1807/103328
► Cancer immunotherapy – therapies that harness the human immune system to deliver personalized treatments – has become the subject of intensive study as multiple approaches…
(more)
▼ Cancer immunotherapy – therapies that harness the human immune system to deliver personalized treatments – has become the
subject of intensive study as multiple approaches have proven effective over the past years.
Chimeric antigen receptor (CAR) and other antibody-based therapies have demonstrated especially striking results, even in patients who have undergone many previous lines of therapy. The first stage of development for these immunotherapies requires selection of an appropriate tumor-associated
antigen (TAA) that optimizes tumor targeting while minimizing off-tumor effects. Suitable TAAs have not been identified for all malignancies and it is thought that, particularly for highly heterogeneous tumors, multiple TAAs may need to be targeted in order to maximize the anti-cancer effect. Following
antigen selection, antibody development and characterization are carried out, and an antibody candidate is selected based on a variety of factors. Finally, optimization of the therapeutic delivery method, in this case the effector cell, is required. The optimal effector cell may vary between tumor types, thus a thorough understanding of the available options is necessary in order to make informed decisions.
The purpose of this thesis was to approach each stage of immunotherapy development, from the identification of novel TAAs, through the design and testing of an antibody-based therapy, to the optimization of its delivery. We first identified novel TAAs in multiple myeloma (MM) using a combination of mass spectrometry and flow cytometry. Overall, 696 MM cell surface proteins were identified, and the presence of five antigens with increased abundance on MM was validated. Next, a bispecific antibody (biAb) therapy against the lymphoma
antigen CD30 was developed by conjugation of novel anti-CD30 antibodies with a CD3 antibody. Two biAbs were developed and characterized, and one lead candidate was selected for further development. Finally, we investigated T cells treated with rapamycin (T-Rapa cells) as a novel effector cell type for CAR therapy. CAR-T-Rapa cells were effective against tumors, and demonstrated a central memory (TCM) phenotype with reduced secretion of proinflammatory cytokines, suggesting they may be an ideal CAR effector cell. Overall, this research addresses three distinct facets of immunotherapy development, contributing to the knowledge and advancement of each stage.
Advisors/Committee Members: Medin, Jeffrey A, Medical Biophysics.
Subjects/Keywords: Antibody; Cancer; Chimeric antigen receptor; Immunotherapy; T-Rapa; Tumour-associated antigen; 0992
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APA ·
Chicago ·
MLA ·
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CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Oldham, R. A. A. (2020). Development and Testing of Novel Cancer Immunotherapies for Hematological Malignancies. (Doctoral Dissertation). University of Toronto. Retrieved from http://hdl.handle.net/1807/103328
Chicago Manual of Style (16th Edition):
Oldham, Robyn Anne Alexa. “Development and Testing of Novel Cancer Immunotherapies for Hematological Malignancies.” 2020. Doctoral Dissertation, University of Toronto. Accessed March 07, 2021.
http://hdl.handle.net/1807/103328.
MLA Handbook (7th Edition):
Oldham, Robyn Anne Alexa. “Development and Testing of Novel Cancer Immunotherapies for Hematological Malignancies.” 2020. Web. 07 Mar 2021.
Vancouver:
Oldham RAA. Development and Testing of Novel Cancer Immunotherapies for Hematological Malignancies. [Internet] [Doctoral dissertation]. University of Toronto; 2020. [cited 2021 Mar 07].
Available from: http://hdl.handle.net/1807/103328.
Council of Science Editors:
Oldham RAA. Development and Testing of Novel Cancer Immunotherapies for Hematological Malignancies. [Doctoral Dissertation]. University of Toronto; 2020. Available from: http://hdl.handle.net/1807/103328
UCLA
12.
Zah, Eugenia.
Engineering bispecific chimeric antigen receptors to improve the efficacy of adoptive T-cell therapy.
Degree: Chemical Engineering, 2018, UCLA
URL: http://www.escholarship.org/uc/item/019427pr
► The recent FDA approval of CD19 chimeric antigen receptor (CAR) adoptive T-cell therapy for B-cell leukemias serves to highlight CAR-T cell therapy as a promising…
(more)
▼ The recent FDA approval of CD19 chimeric antigen receptor (CAR) adoptive T-cell therapy for B-cell leukemias serves to highlight CAR-T cell therapy as a promising treatment approach for refractory cancers. More recently, adoptive transfer of T cells expressing CARs targeting B-cell maturation antigen (BCMA) has had numerous successes in clinical trial with 80-100% of multiple myeloma patients responding to treatment. However, CAR-T-cell therapy still faces several limitations including tumor antigen escape, a circumstance where tumor cells downregulate their surface antigen to avoid detection by CAR-T cells, and T-cell inhibition by cytokines such as transforming growth factor (TGF)-β in the solid tumor environment. These factors can significantly limit the efficacy of CAR-T-cell therapy. To overcome antigen escape, we designed single-chain bispecific CARs (OR-gate CARs) capable of signaling in the presence of two antigens instead of one. Using rational design principles, we constructed and evaluated CD19-OR-CD20 CARs that are able to prevent tumor antigen escape by CD19– leukemia. We further demonstrate that unlike single-input CD19 CARs, CD19-OR-CD20 CARs also prevent the emergence of spontaneous CD19-downregulated tumors in vivo. In a second study, we describe the rapid design and characterization of BCMA-OR-CS1 CARs and demonstrate that BCMA-OR-CS1 CARs can be rationally engineered to prevent antigen escape by BCMA– as well as CS1– myeloma cells. Finally, we explore the utility of the TGF-β CAR, a receptor capable of rewiring inhibitory TGF-β signaling to an activating response, in improving CD20 CAR function in TGF-β-rich environments. We evaluated three different bispecific targeting strategies, OR-gate CAR, DualCAR (co-expressing two receptors in one cells), and CARpool (pooling two different CAR-T cells), and demonstrate that TGF-β CAR-T cells are able to shield neighboring CD20 CAR-T cells from the inhibitory effects of TGF-β.
Subjects/Keywords: Chemical engineering; Immunology; Adoptive T-cell therapy; Cancer immunotherapy; Chimeric antigen receptor
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APA ·
Chicago ·
MLA ·
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CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Zah, E. (2018). Engineering bispecific chimeric antigen receptors to improve the efficacy of adoptive T-cell therapy. (Thesis). UCLA. Retrieved from http://www.escholarship.org/uc/item/019427pr
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Zah, Eugenia. “Engineering bispecific chimeric antigen receptors to improve the efficacy of adoptive T-cell therapy.” 2018. Thesis, UCLA. Accessed March 07, 2021.
http://www.escholarship.org/uc/item/019427pr.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Zah, Eugenia. “Engineering bispecific chimeric antigen receptors to improve the efficacy of adoptive T-cell therapy.” 2018. Web. 07 Mar 2021.
Vancouver:
Zah E. Engineering bispecific chimeric antigen receptors to improve the efficacy of adoptive T-cell therapy. [Internet] [Thesis]. UCLA; 2018. [cited 2021 Mar 07].
Available from: http://www.escholarship.org/uc/item/019427pr.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Zah E. Engineering bispecific chimeric antigen receptors to improve the efficacy of adoptive T-cell therapy. [Thesis]. UCLA; 2018. Available from: http://www.escholarship.org/uc/item/019427pr
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Debrecen
13.
Pham, Huynh Thuy An.
Characterization of chimeric antigen receptor (CAR) Modified T Cells specific for P97 and HMW-MAA human melanoma
.
Degree: DE – Gyógyszerésztudományi Kar, University of Debrecen
URL: http://hdl.handle.net/2437/267959
► Anti-p97 and HMW-MAA CAR T cells recognized Melur target cells in vitro. P97 CAR induced faster activation and better cytokine production of T cells, even…
(more)
▼ Anti-p97 and HMW-MAA CAR T cells recognized Melur target cells in vitro. P97 CAR induced faster activation and better cytokine production of T cells, even though the HMW-MAA
antigen is expressed to a similar extent on the target tumor cells and the HMW-MAA CAR is known to bind to its target with similar affinity as the p97 does. We hypothesize that a difference in the surface mobility of various melanoma associated antigens might have an impact on CAR T cell activation.
Advisors/Committee Members: Szöőr, Árpád (advisor), BIOPHYSICS AND CELL BIOLOGY (advisor).
Subjects/Keywords: Chimeric Antigen Receptor;
Melanoma;
Immunecell Therapy
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APA ·
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to Zotero / EndNote / Reference
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APA (6th Edition):
Pham, H. T. A. (n.d.). Characterization of chimeric antigen receptor (CAR) Modified T Cells specific for P97 and HMW-MAA human melanoma
. (Thesis). University of Debrecen. Retrieved from http://hdl.handle.net/2437/267959
Note: this citation may be lacking information needed for this citation format:
No year of publication.
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Pham, Huynh Thuy An. “Characterization of chimeric antigen receptor (CAR) Modified T Cells specific for P97 and HMW-MAA human melanoma
.” Thesis, University of Debrecen. Accessed March 07, 2021.
http://hdl.handle.net/2437/267959.
Note: this citation may be lacking information needed for this citation format:
No year of publication.
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Pham, Huynh Thuy An. “Characterization of chimeric antigen receptor (CAR) Modified T Cells specific for P97 and HMW-MAA human melanoma
.” Web. 07 Mar 2021.
Note: this citation may be lacking information needed for this citation format:
No year of publication.
Vancouver:
Pham HTA. Characterization of chimeric antigen receptor (CAR) Modified T Cells specific for P97 and HMW-MAA human melanoma
. [Internet] [Thesis]. University of Debrecen; [cited 2021 Mar 07].
Available from: http://hdl.handle.net/2437/267959.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
No year of publication.
Council of Science Editors:
Pham HTA. Characterization of chimeric antigen receptor (CAR) Modified T Cells specific for P97 and HMW-MAA human melanoma
. [Thesis]. University of Debrecen; Available from: http://hdl.handle.net/2437/267959
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
No year of publication.
University of Melbourne
14.
Davenport, Alexander.
Investigating the functional biology of chimeric antigen receptor T cells.
Degree: 2017, University of Melbourne
URL: http://hdl.handle.net/11343/137338
► Despite the success of autologous chimeric antigen receptor (CAR) T cells to treat patients with refractory B cell acute lymphoblastic leukaemia, (ALL) and lymphoma, there…
(more)
▼ Despite the success of autologous chimeric antigen receptor (CAR) T cells to treat patients with refractory B cell acute lymphoblastic leukaemia, (ALL) and lymphoma, there are many aspects of CAR T cell biology that remains unknown. For this reason, this thesis explored whether the recognition of antigen via either antigen receptor (CAR vs endogenous T cell receptor (TCR)) affected the CAR-T cell immune synapse, receptor signalling and tumour target killing kinetics. By addressing this issue we aim to translate this new knowledge to the clinic and broaden the CAR T therapy success to patients with a wider range of cancer subtypes. To explore the above questions, a novel transgenic mouse (designated CAR.OT-I) was developed, in which CD8+ T cells co-expressed the OVA257-specific T cell receptor (TCR) and a second generation CAR with an scFv specific for human HER2. Chapter 3 of this thesis validated the model system and compared CTL activation from CAR.OT-I and OT-I mice. Chapter 4 used time-lapse and confocal microscopy to explore whether the killing kinetics of CAR.OTI CTL was different when stimulated via with OVA257-pulsed (TCR) or HER2-expressing tumour cells (CAR). This thesis showed for the first time, individual CAR.OT-I CTL killed multiple tumour cells (‘serial killing’) and detached faster from dying targets after CAR ligation. Furthermore, in chapter 5, the CAR immune synapse gross molecular structure was described for the first time. This disrupted immune synapse had Lck micro-clusters, poor actin clearance and no peripheral LFA-1 clustering. Finally, phosphoprotein signalling and Ca2+ flux studies revealed faster, stronger signalling initiated via CAR compared to TCR ligation. This observation was also correlated with faster recruitment of cytotoxic granules to the target cell after CAR ligation. Taken together, the chapter 5 data reveals the mechanisms whereby CAR ligation initiates rapid tumour killing and detachment (Chapter 4). Information from this body of work can be used to inform on the next generation of CAR designs and provides a baseline for comparing CAR and TCR killing events.
Subjects/Keywords: immunology; cancer immunology; immunotherapy; cancer; CAR; chimeric antigen receptor; T cell; CAR T cell
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APA ·
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Manager
APA (6th Edition):
Davenport, A. (2017). Investigating the functional biology of chimeric antigen receptor T cells. (Doctoral Dissertation). University of Melbourne. Retrieved from http://hdl.handle.net/11343/137338
Chicago Manual of Style (16th Edition):
Davenport, Alexander. “Investigating the functional biology of chimeric antigen receptor T cells.” 2017. Doctoral Dissertation, University of Melbourne. Accessed March 07, 2021.
http://hdl.handle.net/11343/137338.
MLA Handbook (7th Edition):
Davenport, Alexander. “Investigating the functional biology of chimeric antigen receptor T cells.” 2017. Web. 07 Mar 2021.
Vancouver:
Davenport A. Investigating the functional biology of chimeric antigen receptor T cells. [Internet] [Doctoral dissertation]. University of Melbourne; 2017. [cited 2021 Mar 07].
Available from: http://hdl.handle.net/11343/137338.
Council of Science Editors:
Davenport A. Investigating the functional biology of chimeric antigen receptor T cells. [Doctoral Dissertation]. University of Melbourne; 2017. Available from: http://hdl.handle.net/11343/137338
Duke University
15.
Lin, Regina.
Targeting T Cells for the Immune-Modulation of Human Diseases
.
Degree: 2015, Duke University
URL: http://hdl.handle.net/10161/9824
► Dysregulated inflammation underlies the pathogenesis of a myriad of human diseases ranging from cancer to autoimmunity. As coordinators, executers and sentinels of host immunity,…
(more)
▼ Dysregulated inflammation underlies the pathogenesis of a myriad of human diseases ranging from cancer to autoimmunity. As coordinators, executers and sentinels of host immunity, T cells represent a compelling target population for immune-modulation. In fact, the
antigen-specificity, cytotoxicity and promise of long-lived of immune-protection make T cells ideal vehicles for cancer immunotherapy. Interventions for autoimmune disorders, on the other hand, aim to dampen T cell-mediated inflammation and promote their regulatory functions. Although significant strides have been made in targeting T cells for immune-modulation, current approaches remain less than ideal and leave room for improvement. In this dissertation, I seek to improve on current T cell-targeted immunotherapies, by identifying and preclinically characterizing their mechanisms of action and in vivo therapeutic efficacy. CD8+ cytotoxic T cells have potent antitumor activity and therefore are leading candidates for use in cancer immunotherapy. The application of CD8+ T cells for clinical use has been limited by the susceptibility of ex vivo-expanded CD8+ T cells to become dysfunctional in response to immunosuppressive microenvironments. To enhance the efficacy of adoptive cell transfer therapy (ACT), we established a novel microRNA-targeting approach that augments CTL cytotoxicity and preserves immunocompetence. Specifically, we screened for miRNAs that modulate cytotoxicity and identified miR-23a as a strong functional repressor of the transcription factor Blimp-1, which promotes CTL cytotoxicity and effector cell differentiation. In a cohort of advanced lung cancer patients, miR-23a was upregulated in tumor-infiltrating CD8+ T cells, and its expression correlated with impaired antitumor potential of patient CD8+ T cells. We determined that tumor-derived TGF-β directly suppresses CD8+ T cell immune function by elevating miR-23a and downregulating Blimp-1. Functional blockade of miR-23a in human CD8+ T cells enhanced granzyme B expression; and in mice with established tumors, immunotherapy with just a small number of tumor-specific CD8+ T cells in which miR-23a was inhibited robustly hindered tumor progression. Together, our findings provide a miRNA-based strategy that subverts the immunosuppression of CD8+ T cells that is often observed during adoptive cell transfer tumor immunotherapy and identify a TGFβ-mediated tumor immune-evasion pathway. Having established that miR-23a-inhibition can enhance the quality and functional-resilience of anti-tumor CD8+ T cells, especially within the immune-suppressive tumor microenvironment, we went on to interrogate the translational applicability of this strategy in the context of
chimeric antigen receptor (CAR)-modified CD8+ T cells. Although CAR T cells hold immense promise for ACT, CAR T cells are not completely curative due to their in vivo functional suppression by immune barriers ‒ such as TGFβ ‒ within the tumor microenvironment. Since TGFβ poses a substantial…
Advisors/Committee Members: Li, Qi-Jing (advisor).
Subjects/Keywords: Immunology;
Adoptive T cell transfer;
Autoimmune diseases;
Chimeric antigen receptor;
Immunotherapy;
microRNA
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APA ·
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Export
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Manager
APA (6th Edition):
Lin, R. (2015). Targeting T Cells for the Immune-Modulation of Human Diseases
. (Thesis). Duke University. Retrieved from http://hdl.handle.net/10161/9824
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Lin, Regina. “Targeting T Cells for the Immune-Modulation of Human Diseases
.” 2015. Thesis, Duke University. Accessed March 07, 2021.
http://hdl.handle.net/10161/9824.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Lin, Regina. “Targeting T Cells for the Immune-Modulation of Human Diseases
.” 2015. Web. 07 Mar 2021.
Vancouver:
Lin R. Targeting T Cells for the Immune-Modulation of Human Diseases
. [Internet] [Thesis]. Duke University; 2015. [cited 2021 Mar 07].
Available from: http://hdl.handle.net/10161/9824.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Lin R. Targeting T Cells for the Immune-Modulation of Human Diseases
. [Thesis]. Duke University; 2015. Available from: http://hdl.handle.net/10161/9824
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Pennsylvania
16.
Santoro, Stephen.
T Cells Bearing a Chimeric Antigen Receptor Against the Tumor Vasculature Destroy the Tumor Endothelium and Result in Tumor Regression.
Degree: 2014, University of Pennsylvania
URL: https://repository.upenn.edu/edissertations/1432
► Aberrant blood vessels enable tumor growth, provide a barrier to immune infiltration, and serve as a source of pro-tumorigenic signals. Targeting tumor blood vessels for…
(more)
▼ Aberrant blood vessels enable tumor growth, provide a barrier to immune infiltration, and serve as a source of pro-tumorigenic signals. Targeting tumor blood vessels for destruction, or tumor vascular disruption therapy, can therefore provide significant therapeutic benefit. Here I describe the development of two chimeric antigen receptors (CAR)s against the tumor vasculature, targeting either tumor endothelial marker 1 (TEM1) or prostate-specific membrane antigen (PSMA). CAR T cells incorporating scFv78, an scFv isolated against TEM1, were able to recognize immobilized plate-bound TEM1 protein, but were unable to recognize TEM1 on the surface of endothelial cell targets. In contrast, anti-PSMA CAR T cells, which incorporate the J591 scFv, were able to recognize human PSMA (hPSMA) both in vitro and in vivo. To elucidate the role of intracellular signaling domains on endothelial cell killing, a panel of the J591-based CAR T cells was characterized, each harboring a different combination of the intracellular signaling domains, CD3 zeta (z), CD28 (28), and CD137/4-1BB (BB). I found that all anti-hPSMA CAR T cells were able to recognize and eliminate PSMA+ endothelial targets in vitro, regardless of signaling domain. Furthermore, T cells bearing the 3rd generation anti-hPSMA CAR, P28BBz, were able to recognize and kill primary human endothelial cells isolated from gynecological cancers. In addition, the P28BBz CAR T cells were able to mediate regression of hPSMA-expressing vascular neoplasms in mice. Finally, in murine ovarian cancers models populated by murine vessels expressing hPSMA, the P28BBz CAR T cells were able to ablate PSMA+ vessels, cause secondary depletion of tumor cells, and reduce tumor burden. Taken together, these results provide strong rationale for the use of CAR T cells as agents of tumor vascular disruption, specifically those targeting PSMA.
Subjects/Keywords: Adoptive therapy; Chimeric antigen receptor; Endothelial cells; Prostate-specific membrane antigen; Vascular disruption; Biology; Cell Biology; Oncology
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APA (6th Edition):
Santoro, S. (2014). T Cells Bearing a Chimeric Antigen Receptor Against the Tumor Vasculature Destroy the Tumor Endothelium and Result in Tumor Regression. (Thesis). University of Pennsylvania. Retrieved from https://repository.upenn.edu/edissertations/1432
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Santoro, Stephen. “T Cells Bearing a Chimeric Antigen Receptor Against the Tumor Vasculature Destroy the Tumor Endothelium and Result in Tumor Regression.” 2014. Thesis, University of Pennsylvania. Accessed March 07, 2021.
https://repository.upenn.edu/edissertations/1432.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Santoro, Stephen. “T Cells Bearing a Chimeric Antigen Receptor Against the Tumor Vasculature Destroy the Tumor Endothelium and Result in Tumor Regression.” 2014. Web. 07 Mar 2021.
Vancouver:
Santoro S. T Cells Bearing a Chimeric Antigen Receptor Against the Tumor Vasculature Destroy the Tumor Endothelium and Result in Tumor Regression. [Internet] [Thesis]. University of Pennsylvania; 2014. [cited 2021 Mar 07].
Available from: https://repository.upenn.edu/edissertations/1432.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Santoro S. T Cells Bearing a Chimeric Antigen Receptor Against the Tumor Vasculature Destroy the Tumor Endothelium and Result in Tumor Regression. [Thesis]. University of Pennsylvania; 2014. Available from: https://repository.upenn.edu/edissertations/1432
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Boston University
17.
Pedro, Kyle D.
Cell-to-cell transmission and intrinsic mechanisms that influence human immunodeficiency virus infection.
Degree: PhD, Microbiology, 2020, Boston University
URL: http://hdl.handle.net/2144/42067
► Early in the course of human immunodeficiency virus (HIV) infection a population of latently infected cells is established which persists despite long-term anti-retroviral treatment. This…
(more)
▼ Early in the course of human immunodeficiency virus (HIV) infection a population of latently infected cells is established which persists despite long-term anti-retroviral treatment. This latent reservoir of HIV-infected cells, which reflects mechanisms of transcriptional repression, is the major barrier to cure. Efforts to target the latent reservoir have been inefficient, indicating a need for a more complete understanding of how HIV transcription is regulated.
The molecular networks involved in the regulation of HIV transcription remain incompletely defined. I hypothesized that utilization of a high throughput enhanced yeast one-hybrid assay would reveal novel host transcription factor-long terminal repeat (LTR) interactions and transcriptional networks that regulate HIV. The screen identified 42 human transcription factors and 85 total protein-DNA interactions with HIV LTRs. I investigated a subset of these factors for transcriptional activity in cell-based models of infection. Krüppel-like factors 2 and 3 (KLF2 and KLF3) are repressors of HIV-1 and HIV-2 transcription whereas PLAG1-like zinc finger 1 (PLAGL1) is an activator of HIV-2 transcription. These factors regulate HIV expression through direct protein-DNA interactions and correlate with epigenetic modifications of the HIV LTR.
Multiple signals converging from the cellular environment and cell-cell interactions converge at the HIV LTR to determine HIV replication and transcription. Previous work in our lab has shown that strong signaling through the T cell
receptor (TCR) was required to support HIV expression and the establishment of an inducible latent infection, whereas weak TCR signaling was insufficient for these outcomes. I hypothesized that dendritic cells-CD4+ T cell interactions provide signals that compensate for weak TCR signaling, supporting HIV-1 expression and generation of inducible latent infection. I used CD4+ T cells that express
chimeric antigen receptors in a dendritic cell coculture model to deliver differential signals to CD4+ T cells during cell-to-cell transmission of HIV. I found that signals from dendritic cells compensate for weak TCR signaling, facilitating cell activation, HIV expression and establishment of an inducible infection.
Advisors/Committee Members: Henderson, Andrew J. (advisor).
Subjects/Keywords: Microbiology; CD4+ T cell; Chimeric antigen receptor; Dendritic cell; HIV latency; HIV transcription; T cell receptor signaling
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APA ·
Chicago ·
MLA ·
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CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Pedro, K. D. (2020). Cell-to-cell transmission and intrinsic mechanisms that influence human immunodeficiency virus infection. (Doctoral Dissertation). Boston University. Retrieved from http://hdl.handle.net/2144/42067
Chicago Manual of Style (16th Edition):
Pedro, Kyle D. “Cell-to-cell transmission and intrinsic mechanisms that influence human immunodeficiency virus infection.” 2020. Doctoral Dissertation, Boston University. Accessed March 07, 2021.
http://hdl.handle.net/2144/42067.
MLA Handbook (7th Edition):
Pedro, Kyle D. “Cell-to-cell transmission and intrinsic mechanisms that influence human immunodeficiency virus infection.” 2020. Web. 07 Mar 2021.
Vancouver:
Pedro KD. Cell-to-cell transmission and intrinsic mechanisms that influence human immunodeficiency virus infection. [Internet] [Doctoral dissertation]. Boston University; 2020. [cited 2021 Mar 07].
Available from: http://hdl.handle.net/2144/42067.
Council of Science Editors:
Pedro KD. Cell-to-cell transmission and intrinsic mechanisms that influence human immunodeficiency virus infection. [Doctoral Dissertation]. Boston University; 2020. Available from: http://hdl.handle.net/2144/42067
UCLA
18.
Lorenzini, Michael Hideo.
Engineering Robust T-Cell Response Against Immunosuppressive Tumors.
Degree: Bioengineering, 2016, UCLA
URL: http://www.escholarship.org/uc/item/26h6c920
► With the establishment of clinically effective adoptive T-cell therapy for metastatic cancer, efforts are growing to advance T-cell therapy for new indications, especially solid tumors.…
(more)
▼ With the establishment of clinically effective adoptive T-cell therapy for metastatic cancer, efforts are growing to advance T-cell therapy for new indications, especially solid tumors. A major challenge, however, is that the antitumor activity of infused T cells can be suppressed by the cytokine transforming growth factor beta (TGFβ). To counteract TGFβ-mediated immunosuppression, a TGFβ-specific chimeric antigen receptor (TGFβ-CAR) was engineered and characterized in vitro. The TGFβ-CAR converted TGFβ from a suppressive signal to a stimulatory signal, enabling CD4+ and CD8+ T cells to overcome TGFβ-mediated dysfunction by blocking endogenous TGFβ signaling and triggering TGFβ-specific T-cell activation, Th1 cytokine production, and robust proliferation. These properties suggest the TGFβ-CAR could be incorporated into tumor-reactive T cells to boost antitumor activity. Alternatively, the TGFβ-CAR could be a tool for robust T-cell expansion ex vivo. To our knowledge, this is the first CAR specifically designed to respond to a soluble antigen.
Subjects/Keywords: Immunology; Biomedical engineering; Molecular biology; Adoptive cell therapy; Cancer immunosuppression; Cancer immunotherapy; CAR-T cells; Chimeric antigen receptor; TGF beta
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APA ·
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CSE |
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to Zotero / EndNote / Reference
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APA (6th Edition):
Lorenzini, M. H. (2016). Engineering Robust T-Cell Response Against Immunosuppressive Tumors. (Thesis). UCLA. Retrieved from http://www.escholarship.org/uc/item/26h6c920
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Lorenzini, Michael Hideo. “Engineering Robust T-Cell Response Against Immunosuppressive Tumors.” 2016. Thesis, UCLA. Accessed March 07, 2021.
http://www.escholarship.org/uc/item/26h6c920.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Lorenzini, Michael Hideo. “Engineering Robust T-Cell Response Against Immunosuppressive Tumors.” 2016. Web. 07 Mar 2021.
Vancouver:
Lorenzini MH. Engineering Robust T-Cell Response Against Immunosuppressive Tumors. [Internet] [Thesis]. UCLA; 2016. [cited 2021 Mar 07].
Available from: http://www.escholarship.org/uc/item/26h6c920.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Lorenzini MH. Engineering Robust T-Cell Response Against Immunosuppressive Tumors. [Thesis]. UCLA; 2016. Available from: http://www.escholarship.org/uc/item/26h6c920
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
UCLA
19.
Chang, ZeNan Li.
Rewiring signaling responses to soluble extracellular cues for T-cell therapies and beyond.
Degree: Molecular Biology, 2017, UCLA
URL: http://www.escholarship.org/uc/item/1gg9s6gk
► Soluble extracellular factors are a commonly used medium of communication between a cell and its environment. The ability to program the response of cell-based therapies…
(more)
▼ Soluble extracellular factors are a commonly used medium of communication between a cell and its environment. The ability to program the response of cell-based therapies to such cues will help realize the promise of cell therapies as a powerful strategy to treat a variety of diseases. Here, we report on a chimeric antigen receptor (CAR) that binds the cytokine TGF-β, an immunosuppressive factor commonly upregulated at solid tumors. The TGF-β CAR rewires T-cell responses to TGF-β, converting an immunosuppressant into an immunostimulatory molecule. Additionally, TGF-β CAR-T cells can protect surrounding T cells from TGF-β–induced functional defects and differentiation into the regulatory phenotype. Using lessons learned from the in-depth case-study of the TGF-β CAR, we next establish a framework for using CARs to engineer T cells to sense synthetic and natural extracellular soluble ligands of choice and with tunable sensitivity. Our work supports that the CAR is a mechanosensitive receptor, shows that the mechanosensative synthetic Notch receptors can be employed to rewire responses to soluble ligands in mammalian cells in general, and highlights that proteins that respond to mechanical forces serve as suitable chassis for establishing biochemically modular platforms in synthetic biology.
Subjects/Keywords: Molecular biology; Immunology; Chemical engineering; chimeric antigen receptor; immunotherapy; protein engineering; synthetic biology; T-cell therapy; TGF-β
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APA ·
Chicago ·
MLA ·
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CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Chang, Z. L. (2017). Rewiring signaling responses to soluble extracellular cues for T-cell therapies and beyond. (Thesis). UCLA. Retrieved from http://www.escholarship.org/uc/item/1gg9s6gk
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Chang, ZeNan Li. “Rewiring signaling responses to soluble extracellular cues for T-cell therapies and beyond.” 2017. Thesis, UCLA. Accessed March 07, 2021.
http://www.escholarship.org/uc/item/1gg9s6gk.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Chang, ZeNan Li. “Rewiring signaling responses to soluble extracellular cues for T-cell therapies and beyond.” 2017. Web. 07 Mar 2021.
Vancouver:
Chang ZL. Rewiring signaling responses to soluble extracellular cues for T-cell therapies and beyond. [Internet] [Thesis]. UCLA; 2017. [cited 2021 Mar 07].
Available from: http://www.escholarship.org/uc/item/1gg9s6gk.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Chang ZL. Rewiring signaling responses to soluble extracellular cues for T-cell therapies and beyond. [Thesis]. UCLA; 2017. Available from: http://www.escholarship.org/uc/item/1gg9s6gk
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of California – San Diego
20.
Allen, Molly Elizabeth.
Using Light to Improve CAR T Cell Immunotherapy Development and Applications.
Degree: Bioengineering, 2019, University of California – San Diego
URL: http://www.escholarship.org/uc/item/8bk4w5hc
► Cancer is the second-leading cause of death worldwide. Over the past two decades, chimeric antigen receptor (CAR) T cell therapy has emerged as a promising…
(more)
▼ Cancer is the second-leading cause of death worldwide. Over the past two decades, chimeric antigen receptor (CAR) T cell therapy has emerged as a promising alternative to traditional surgical, radiation and chemotherapy cancer treatments. Genetically engineered CAR T cells are designed to target and eradicate cancer cells in vivo. However, it remains difficult to identify a set of truly cancer-specific surface antigens to target—a critical requirement to prevent potentially fatal CAR T cell on-target off-tumor toxicity against other healthy tissues elsewhere in the body. I develop a variety of CARs and Receptors and assess their function using genetically encoded fluorescent protein-based biosensors to rapidly detect the pre-transcriptional molecular events leading to CAR-mediated T cell activation. I next propose the novel concept of using light to spatially and temporally limit CAR expression in T cells localized to the tumor site in order to limit on-target off-tumor toxicity in distant healthy tissues. After creating and evaluating a variety of light-sensitive protein-based optogenetic systems to control CAR expression, I uncover three limitations. First, even when kept in the dark, some light-sensitive engineered T cells prematurely express CAR. Second, engineered T cells stimulated with light only weakly upregulate CAR expression. Third, the amount of blue light exposure necessary to induce CAR expression is phototoxic to the T cells. To overcome these limitations, I create the first light-inducible optogenetic system capable of driving robust CAR expression in T cells only following stimulation with minimal, non-toxic amounts of blue light. To do so, I create and optimize a novel genetic AND-gate by integrating components of tamoxifen-inducible Cre recombinase systems with a blue light-inducible split Cre system driven by heterodimerization between the highly sensitive Magnet system protein domains, nMag and pMag. To prevent premature CAR expression, the cytosol-localizing mutant T2 estrogen receptor ligand binding domain (ERT2) is fused to the N-terminal half of the CreN-nMag fusion protein, thus physically separating it from its nuclear-localized binding partner NLS-pMag-CreC. Without tamoxifen to drive ERT2-CreN-nMag protein translocation into the nucleus, the high levels of spontaneous, premature Cre-loxP recombination native to the original photoactivatable split Cre system is significantly suppressed. Upon stimulation with both tamoxifen and blue light, T cells engineered with this novel optogenetic system undergo efficient Cre-loxP recombination to express CAR, with high sensitivity to low-intensity, short-duration blue light exposure. I demonstrate that the new tamoxifen- and photo-activatable split-Cre recombinase system, called TamPA-Cre, can be applied to strictly control localized CAR expression and subsequent T cell activation. The TamPA-Cre system has the potential to limit on-target off-tumor toxicity against distant healthy tissues in a way that was not previously possible.
Subjects/Keywords: Bioengineering; Molecular biology; Biomedical engineering; Biosensor; Chimeric Antigen Receptor (CAR); Immunotherapy; Optogenetics; Synthetic Biology; T cell
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APA ·
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CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Allen, M. E. (2019). Using Light to Improve CAR T Cell Immunotherapy Development and Applications. (Thesis). University of California – San Diego. Retrieved from http://www.escholarship.org/uc/item/8bk4w5hc
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Allen, Molly Elizabeth. “Using Light to Improve CAR T Cell Immunotherapy Development and Applications.” 2019. Thesis, University of California – San Diego. Accessed March 07, 2021.
http://www.escholarship.org/uc/item/8bk4w5hc.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Allen, Molly Elizabeth. “Using Light to Improve CAR T Cell Immunotherapy Development and Applications.” 2019. Web. 07 Mar 2021.
Vancouver:
Allen ME. Using Light to Improve CAR T Cell Immunotherapy Development and Applications. [Internet] [Thesis]. University of California – San Diego; 2019. [cited 2021 Mar 07].
Available from: http://www.escholarship.org/uc/item/8bk4w5hc.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Allen ME. Using Light to Improve CAR T Cell Immunotherapy Development and Applications. [Thesis]. University of California – San Diego; 2019. Available from: http://www.escholarship.org/uc/item/8bk4w5hc
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
21.
Jespersen, Henrik.
Translational studies of metastatic melanoma in the era of immunotherapy - from humanized mouse models to clinical trials.
Degree: 2020, University of Gothenburg / Göteborgs Universitet
URL: http://hdl.handle.net/2077/62684
► Immunotherapy with PD-1 inhibitors has transformed the treatment of met-astatic cutaneous mela- noma, and can lead to complete and durable responses in a proportion of…
(more)
▼ Immunotherapy with PD-1 inhibitors has transformed the treatment of met-astatic cutaneous mela- noma, and can lead to complete and durable responses in a proportion of patients. However, in around half of the patients, the treatment has little or no effect. In patients with metastatic uveal melanoma, a rare form of melanoma arising in the eye, effective treatments are lacking altogether. The overall aim of the research on which this thesis is based, is to develop and utilize mouse models to identify new immunotherapies for pa-tients with metastatic melanoma.
In paper I we describe the development of a novel immune humanized pa-tient derived xenograph (PDX) model. The PDX is based on sequential transplantation of ex vivo expanded, autologous tumor infiltrating lympho-cytes (TIL), and mirror the treatment effects seen in corresponding pa- tients. In paper II we evaluate the feasibility and preclinical efficacy of chimeric anti-gen receptor (CAR)-T cell therapy in melanoma and find that CAR T cells against HER2 are able to kill human cutaneous and uveal melanoma cells in vitro and in vivo. In paper III we first assess the rationale of combined epi-genetic modulation and PD-1 inhibition in experimental melanoma, and show that the histone deacetylase (HDAC) inhibitor entinostat increases expression of HLA-I and PD-1 on mela- noma cell lines and enhances the effect of a PD-1-inhibitor in vivo. Next, we describe the design and preliminary results of an ongoing phase II trial evaluating the effect of entinostat in combination with pembrolizumab (a PD-1 inhibitor) in patients with metastatic uveal mel-anoma.
In conclusion, this thesis shows that i) PDX models can be used to study key aspects of the human antitumoral immunity in melanoma; ii) that HER2 CAR-T cells represent a potential future treatment for metastatic melanoma refractory to other immunotherapies; and iii) that entinostat increases HLA- I expression and potentiates the effect of PD-1 inhibition in melanoma models, and that the same combination can result in clinical efficacy with manageable toxicity in patients with metastatic uveal melanoma.
Subjects/Keywords: Metastatic melanoma; Uveal melanoma; Humanized mouse models; Immunotherapy; Chimeric antigen receptor T cells; PD-1 inhibition; Epigenetics; Histone deacetylase inhibition
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APA (6th Edition):
Jespersen, H. (2020). Translational studies of metastatic melanoma in the era of immunotherapy - from humanized mouse models to clinical trials. (Thesis). University of Gothenburg / Göteborgs Universitet. Retrieved from http://hdl.handle.net/2077/62684
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Jespersen, Henrik. “Translational studies of metastatic melanoma in the era of immunotherapy - from humanized mouse models to clinical trials.” 2020. Thesis, University of Gothenburg / Göteborgs Universitet. Accessed March 07, 2021.
http://hdl.handle.net/2077/62684.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Jespersen, Henrik. “Translational studies of metastatic melanoma in the era of immunotherapy - from humanized mouse models to clinical trials.” 2020. Web. 07 Mar 2021.
Vancouver:
Jespersen H. Translational studies of metastatic melanoma in the era of immunotherapy - from humanized mouse models to clinical trials. [Internet] [Thesis]. University of Gothenburg / Göteborgs Universitet; 2020. [cited 2021 Mar 07].
Available from: http://hdl.handle.net/2077/62684.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Jespersen H. Translational studies of metastatic melanoma in the era of immunotherapy - from humanized mouse models to clinical trials. [Thesis]. University of Gothenburg / Göteborgs Universitet; 2020. Available from: http://hdl.handle.net/2077/62684
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
22.
Ollerton, Matthew T.
Capacity of Human Immunodeficiency Virus Targeting Chimeric Antigen Receptor T Cells to Eliminate Follicular Dendritic Cells Bearing Human Immunodeficiency Virus Immune Complexes.
Degree: PhD, 2017, Brigham Young University
URL: https://scholarsarchive.byu.edu/cgi/viewcontent.cgi?article=8292&context=etd
► An important obstacle to a functional cure for HIV/AIDS is the persistence of viral reservoirs found throughout the body in various cells and tissues. Reservoirs…
(more)
▼ An important obstacle to a functional cure for HIV/AIDS is the persistence of viral reservoirs found throughout the body in various cells and tissues. Reservoirs can be latently infected cells, or in the case of follicular dendritic cells (FDC), non-infected cells that trap infectious virus on their surface through immune complexes (HIV-IC). Although several strategies have been employed to target and eliminate viral reservoirs, they are short-lived and ineffective. In an attempt to provide a long-term approach, chimeric antigen receptor T (CAR-T) cells were designed to eliminate native HIV on FDCs. Although effective at eliminating HIV-infected cells, and halting spreading infection, their ability to eliminate the viral reservoir found on (FDCs) remains unclear. We used a novel second-generation CAR-T cell expressing domains 1 and 2 of CD4 followed by the mannose binding lectin (MBL) to allow recognition of native HIV envelope (Env) to determine the capacity to respond to the viral reservoir found on FDCs. We employed a novel fluorescent lysis assay, the Carboxyfluorescein succinimidyl ester (CFSE) release assay, as well as flow cytometric based assays to detect functional CAR-T activation through IFN-γ production and CD107a (i.e., LAMP1) membrane accumulation to test cytolytic capacity and functional activation of CD4-MBL CAR-T cells, respectively. We demonstrated their efficacy at eliminating HIV-infected cells or cells expressing gp160. However, these CAR-T cells were unable to lyse cells bearing surface bound HIV-IC. We found that failed lysis was not a unique feature of a resistant target, but a limitation in the CAR-T recognition elements. CAR-T cells were inactive in the presence of free HIV or in the presence of concentrated, immobilized virus. Further experiments determined that in addition to gp120 recognition by the CAR-T, the adhesion molecule ICAM-1 was necessary for efficient CAR-T cell killing of HIV-infected cells. CAR-T cell activity and killing were inhibited in the presence of ICAM-1 blocking antibody. These results suggest that other factors, such as adhesion molecules, play a vital role in CAR-T responses to HIV-infected cells. In addition, our findings highlighted the necessity to consider all models of HIV reservoirs, including FDCs, when evaluating therapeutic efficacy.
Subjects/Keywords: HIV; chimeric antigen receptor; follicular dendritic cells
…presenting cell
BCMA
B cell maturation antigen
CAR
Chimeric antigen receptor
CCR5
C-C motif… …1.3 Chimeric Antigen Receptor T cells
Chimeric Antigen Receptor T (CAR-T) cells… …trapping on FDCs.
Although CD32 is considered a low-affinity receptor for antigen binding, FDCs… …design of chimeric antigen receptors (CARs) on lymphocytes capable of
cytoxicity… …antigen. This was accomplished by replacing the variable region of the T cell
19
receptor…
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APA ·
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to Zotero / EndNote / Reference
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APA (6th Edition):
Ollerton, M. T. (2017). Capacity of Human Immunodeficiency Virus Targeting Chimeric Antigen Receptor T Cells to Eliminate Follicular Dendritic Cells Bearing Human Immunodeficiency Virus Immune Complexes. (Doctoral Dissertation). Brigham Young University. Retrieved from https://scholarsarchive.byu.edu/cgi/viewcontent.cgi?article=8292&context=etd
Chicago Manual of Style (16th Edition):
Ollerton, Matthew T. “Capacity of Human Immunodeficiency Virus Targeting Chimeric Antigen Receptor T Cells to Eliminate Follicular Dendritic Cells Bearing Human Immunodeficiency Virus Immune Complexes.” 2017. Doctoral Dissertation, Brigham Young University. Accessed March 07, 2021.
https://scholarsarchive.byu.edu/cgi/viewcontent.cgi?article=8292&context=etd.
MLA Handbook (7th Edition):
Ollerton, Matthew T. “Capacity of Human Immunodeficiency Virus Targeting Chimeric Antigen Receptor T Cells to Eliminate Follicular Dendritic Cells Bearing Human Immunodeficiency Virus Immune Complexes.” 2017. Web. 07 Mar 2021.
Vancouver:
Ollerton MT. Capacity of Human Immunodeficiency Virus Targeting Chimeric Antigen Receptor T Cells to Eliminate Follicular Dendritic Cells Bearing Human Immunodeficiency Virus Immune Complexes. [Internet] [Doctoral dissertation]. Brigham Young University; 2017. [cited 2021 Mar 07].
Available from: https://scholarsarchive.byu.edu/cgi/viewcontent.cgi?article=8292&context=etd.
Council of Science Editors:
Ollerton MT. Capacity of Human Immunodeficiency Virus Targeting Chimeric Antigen Receptor T Cells to Eliminate Follicular Dendritic Cells Bearing Human Immunodeficiency Virus Immune Complexes. [Doctoral Dissertation]. Brigham Young University; 2017. Available from: https://scholarsarchive.byu.edu/cgi/viewcontent.cgi?article=8292&context=etd
23.
Yong, Carmen.
Enhancing adoptive immunotherapy : redirecting immune subsets and metabolic pathways : Optimisation des immunothérapies : manipulation de sous populations immunitaires et exploitation du métabolisme.
Degree: Docteur es, Biologie Santé, 2017, Montpellier; University of Melbourne. The Sir Peter MacCallum Department of Oncology
URL: http://www.theses.fr/2017MONTT059
► Le transfert adoptif de cellules T exprimant un récepteur chimérique reconnaissant un antigène (CAR), est un traitement qui génère des réponses impressionnantes dans les cancers…
(more)
▼ Le transfert adoptif de cellules T exprimant un récepteur chimérique reconnaissant un antigène (CAR), est un traitement qui génère des réponses impressionnantes dans les cancers hématologiques mais est beaucoup moins efficace pour le traitement de tumeurs solides. Les tumeurs solides modulent leur microenvironnement induisant des formes multiples d’immunosuppression qui inhibent l’efficacité des fonctions effectrices des cellules T ayant infiltrées la tumeur. Au cours de ma thèse, j’ai évalué le potentiel de deux stratégies pour améliorer les réponses anti-tumorales des cellules T CAR. La première se focalise sur l’étude du rôle potentiel des cellules immunes non T, exprimant un CAR sur la stimulation des fonctions et de la persistance de cellules T CAR+ dans le microenvironnement tumoral. Afin d’étudier la fonction des cellules CAR non T, nous avons généré un modèle de souris transgénique (vav-CAR) dans lequel les cellules immunes expriment un CAR reconnaissant l’antigène tumoral Her2 (ErbB2). Comme attendu, les cellules T CAR+ possèdent des fonctions anti-tumorales, mais nous avons aussi mis en évidence que les macrophages et les cellules NK exprimant le CAR montraient une réponse cytokinique, cytotoxique et phagocytiques spécifiques de l’antigène. De plus, en utilisant le modèle vav-CAR, nous avons démontré le potentiel des cellules immunes CAR+ dans le rejet des tumeurs et cela indépendamment des cellules T CD8+. Les cellules T CD4+ sont essentielles puisque leur élimination réduit considérablement les réponses anti-tumorales dans notre modèle vav-CAR. Il a été démontré que certaines sous-populations de cellules T auxiliaires participent aux réponses anti-tumorales avec les cellules Th1 et Th17 démontrant une efficacité plus robuste que les autres sous-populations. Notre deuxième stratégie s’est focalisée sur l’étude de l’impact du métabolisme au cours de la polarisation des cellules T CD4+ et plus particulièrement lors de la différenciation des cellules T CAR+ en cellules Th1. En effet, l’activation et différenciation des cellules T sont fortement associées à une augmentation des besoins métaboliques. Dans le microenvironnement tumoral, en raison de la forte demande en ressources de la tumeur, la déprivation en nutriments ainsi générée peut limiter l’accès aux nutriments d’autres types cellulaires et ainsi altérer le devenir et les fonctions des cellules immunes greffés infiltrant la tumeur. En conséquence, modifier les cellules immunes CAR+ afin qu’elles puissent résister à la compétition métabolique du microenvironnement tumoral pourrait leur permettre de conserver leurs fonctions effectrices. En étudiant l’impact de la déprivation en nutriments sur la différenciation des cellules T, nous avons trouvé que des concentrations limitantes en glutamine, l’acide aminé le plus abondant du plasma, inhibaient le potentiel des cellules T à se différencier vers la voie Th1 associée à la production d’IFNγ. Au contraire, cette condition favorisait la conversion de cellules T CD4 naïves en cellules régulatrices Foxp3+ ayant…
Advisors/Committee Members: Taylor, Naomi (thesis director), Darcy, Phillip K. (thesis director), Kershaw, Michael H. (thesis director).
Subjects/Keywords: Immunothérapie; Cellules T; Differenciation; Anti-Tumoral; Récepteur chimérique; Metabolisme; Immunotherapy; T cells; Differentiation; Anti-Tumor; Chimeric antigen receptor; Metabolism
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APA (6th Edition):
Yong, C. (2017). Enhancing adoptive immunotherapy : redirecting immune subsets and metabolic pathways : Optimisation des immunothérapies : manipulation de sous populations immunitaires et exploitation du métabolisme. (Doctoral Dissertation). Montpellier; University of Melbourne. The Sir Peter MacCallum Department of Oncology. Retrieved from http://www.theses.fr/2017MONTT059
Chicago Manual of Style (16th Edition):
Yong, Carmen. “Enhancing adoptive immunotherapy : redirecting immune subsets and metabolic pathways : Optimisation des immunothérapies : manipulation de sous populations immunitaires et exploitation du métabolisme.” 2017. Doctoral Dissertation, Montpellier; University of Melbourne. The Sir Peter MacCallum Department of Oncology. Accessed March 07, 2021.
http://www.theses.fr/2017MONTT059.
MLA Handbook (7th Edition):
Yong, Carmen. “Enhancing adoptive immunotherapy : redirecting immune subsets and metabolic pathways : Optimisation des immunothérapies : manipulation de sous populations immunitaires et exploitation du métabolisme.” 2017. Web. 07 Mar 2021.
Vancouver:
Yong C. Enhancing adoptive immunotherapy : redirecting immune subsets and metabolic pathways : Optimisation des immunothérapies : manipulation de sous populations immunitaires et exploitation du métabolisme. [Internet] [Doctoral dissertation]. Montpellier; University of Melbourne. The Sir Peter MacCallum Department of Oncology; 2017. [cited 2021 Mar 07].
Available from: http://www.theses.fr/2017MONTT059.
Council of Science Editors:
Yong C. Enhancing adoptive immunotherapy : redirecting immune subsets and metabolic pathways : Optimisation des immunothérapies : manipulation de sous populations immunitaires et exploitation du métabolisme. [Doctoral Dissertation]. Montpellier; University of Melbourne. The Sir Peter MacCallum Department of Oncology; 2017. Available from: http://www.theses.fr/2017MONTT059
University of Pennsylvania
24.
Kawalekar, Omkar Uday.
Car Drivers and Fuel Sources: How Distinct Signaling Domains in Chimeric Antigen Receptors Reprogram T Cells.
Degree: 2016, University of Pennsylvania
URL: https://repository.upenn.edu/edissertations/1804
► With breakthroughs in synthetic biology, improved cell culture techniques and advanced genetic engineering, it has now become possible to generate bi-specific primary human T cells…
(more)
▼ With breakthroughs in synthetic biology, improved cell culture techniques and advanced genetic engineering, it has now become possible to generate bi-specific primary human T cells with desired specificities. One mode of redirecting specificity is the modification of T cells to express chimeric antigen receptors (CARs). Recent studies indicate that natural T cells have distinct biochemical and metabolic features that endow them with short lived effector or long lived memory fates. The central objective of this thesis was to investigate whether the signaling endodomain of CARs could reprogram T cells with pre-specified effector and memory fates. This thesis describes a novel technique that allows for detailed investigation of the impact of CAR design on the fate of T cells. Specifically, it compares the short-term and long-term signaling effects of CD28 and 4-1BB costimulatory domains in the CAR architecture. These two signaling domains have been most extensively employed in CAR therapy trials against a wide variety of malignancies. Incorporation of 4-1BB signaling domain imparts superior proliferative and survival benefits as compared to the CD28-containing CAR T cells. This increased persistence correlates with clinical observations. 4-1BB CARs T cells show an enrichment of central memory phenotype along with relative increase in fatty acid based metabolism. This is accompanied by a relative increase in mitochondrial mass, upregulation of key metabolic enzymes and increased spare respiratory capacity. Furthermore, stimulation of CD28-containing CARs promotes rapid induction of biochemical signaling events that are associated with T cell activation. Specifically, the phosphorylation of key proximal and distal signaling proteins between the two CAR models have been compared. Inclusion of CD28 domain in the CAR structure dramatically reduces activation threshold and leads to increased and sustained calcium flux. Taken together, this thesis work uncovers some key differences triggered by the different costimulatory domains. This thesis establishes that the choice of CAR signaling domain can be used to dictate the fate of engineered T cells. Moving forward, the ability of CARs to reprogram T cell metabolism and induce differential activation patterns will need to be considered when designing future CAR trials.
Subjects/Keywords: Chimeric Antigen Receptor; Immunotherapy; Metabolism; T cells; Allergy and Immunology; Cell Biology; Immunology and Infectious Disease; Medical Immunology; Molecular Biology
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APA ·
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APA (6th Edition):
Kawalekar, O. U. (2016). Car Drivers and Fuel Sources: How Distinct Signaling Domains in Chimeric Antigen Receptors Reprogram T Cells. (Thesis). University of Pennsylvania. Retrieved from https://repository.upenn.edu/edissertations/1804
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Kawalekar, Omkar Uday. “Car Drivers and Fuel Sources: How Distinct Signaling Domains in Chimeric Antigen Receptors Reprogram T Cells.” 2016. Thesis, University of Pennsylvania. Accessed March 07, 2021.
https://repository.upenn.edu/edissertations/1804.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Kawalekar, Omkar Uday. “Car Drivers and Fuel Sources: How Distinct Signaling Domains in Chimeric Antigen Receptors Reprogram T Cells.” 2016. Web. 07 Mar 2021.
Vancouver:
Kawalekar OU. Car Drivers and Fuel Sources: How Distinct Signaling Domains in Chimeric Antigen Receptors Reprogram T Cells. [Internet] [Thesis]. University of Pennsylvania; 2016. [cited 2021 Mar 07].
Available from: https://repository.upenn.edu/edissertations/1804.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Kawalekar OU. Car Drivers and Fuel Sources: How Distinct Signaling Domains in Chimeric Antigen Receptors Reprogram T Cells. [Thesis]. University of Pennsylvania; 2016. Available from: https://repository.upenn.edu/edissertations/1804
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Pennsylvania
25.
Lo, Albert.
Finding Common Ground to Treat Primary and Metastatic Cancer: The Potential of Targeting Tumor Stroma.
Degree: 2016, University of Pennsylvania
URL: https://repository.upenn.edu/edissertations/1862
► Primary carcinomas and metastases are complex organ-like structures composed of malignant parenchymal epithelial tissues and a desmoplastic stroma formed by accumulation of hematopoietic cells, mesenchymal…
(more)
▼ Primary carcinomas and metastases are complex organ-like structures composed of malignant parenchymal epithelial tissues and a desmoplastic stroma formed by accumulation of hematopoietic cells, mesenchymal stromal cells and extracellular matrix. The crosstalk between malignant epithelial cells and tumor stroma is becoming increasingly appreciated as a key determinant in tumor development, progression and metastasis, as well as inducing resistance to various cancer treatments including chemotherapy, radiotherapy and immunotherapy. Mechanistic understanding of how the tumor-stromal interaction contributes to tumor progression and therapeutic resistance will advance cancer therapies and improve clinical management, especially for patients with metastatic disease. Fibroblast activation protein (FAP) is a membrane surface protease found overexpressed in cancer-associated stromal cells. Overexpression of FAP is associated with tumor progression, metastasis and recurrence, and predicts a poorer prognosis in many types of human tumors. The central goal of my thesis project is to investigate whether FAP protease and/or FAP protease-expressing stromal cells play essential roles in tumor progression and metastasis. In collaboration with Drs. Steven Albelda and Carl June’s groups, we generated chimeric antigen receptor (CAR) T cells redirected against FAP+ stromal cells to study their impact on tumor progression. Conditional depletion of FAP+ stromal cells by FAP-CAR T cells restrains tumor progression without causing severe toxicity. Mechanistic investigations revealed that FAP+ stromal cells promote tumor growth via immune suppression and immune-independent remodeling of the stromal microenvironment. Additionally, using FAP-deficient mice, I found that FAP protease promotes early malignant cell seeding and pulmonary metastatic outgrowth, possibly through regulating coagulation pathways and the inflammatory response, respectively. Finally, I observed that FAP protease promotes pancreatic cancer development, as its deletion delays the progression of preneoplastic lesions and tumor formation in a genetically engineered mouse model of pancreatic ductal carcinoma. FAP protease is also essential for inducing pancreatic cancer resistance to necrotic cell death and promoting metastasis and outgrowth in multiple target organs. Together, these findings demonstrate that molecular and cellular targeting of FAP represents a promising therapeutic approach for a variety of solid tumors.
Subjects/Keywords: Cancer-associated fibroblasts (CAFs); Chimeric antigen receptor (CAR) T cells; Fibroblast activation protein (FAP); Tumor microenvironment; Oncology
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APA ·
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MLA ·
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CSE |
Export
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Manager
APA (6th Edition):
Lo, A. (2016). Finding Common Ground to Treat Primary and Metastatic Cancer: The Potential of Targeting Tumor Stroma. (Thesis). University of Pennsylvania. Retrieved from https://repository.upenn.edu/edissertations/1862
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Lo, Albert. “Finding Common Ground to Treat Primary and Metastatic Cancer: The Potential of Targeting Tumor Stroma.” 2016. Thesis, University of Pennsylvania. Accessed March 07, 2021.
https://repository.upenn.edu/edissertations/1862.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Lo, Albert. “Finding Common Ground to Treat Primary and Metastatic Cancer: The Potential of Targeting Tumor Stroma.” 2016. Web. 07 Mar 2021.
Vancouver:
Lo A. Finding Common Ground to Treat Primary and Metastatic Cancer: The Potential of Targeting Tumor Stroma. [Internet] [Thesis]. University of Pennsylvania; 2016. [cited 2021 Mar 07].
Available from: https://repository.upenn.edu/edissertations/1862.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Lo A. Finding Common Ground to Treat Primary and Metastatic Cancer: The Potential of Targeting Tumor Stroma. [Thesis]. University of Pennsylvania; 2016. Available from: https://repository.upenn.edu/edissertations/1862
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Pennsylvania
26.
Panjwani, Mohammed Kazim.
Development Of Canine Chimeric Antigen Receptor T Cell Therapy For Treatment & Translation.
Degree: 2017, University of Pennsylvania
URL: https://repository.upenn.edu/edissertations/2513
► Chimeric antigen receptor (CAR) T cell therapy has had remarkable success targeting B cell leukemias in human patients, but unexpected toxicities and failures in other…
(more)
▼ Chimeric antigen receptor (CAR) T cell therapy has had remarkable success targeting B cell leukemias in human patients, but unexpected toxicities and failures in other disease demonstrate the need for more predictive pre-clinical animal models than the murine ones currently used. Dogs develop spontaneous malignancies similar to humans in their tissues of origin, gene expression profiles, treatments, and disease courses, and have long been used as models for immunotherapy. I hypothesize that the development of CAR T cell therapy for dogs with spontaneous disease and that the treatment of these canine patients will recapitulate the observations found in human patients, and provide new insights into the safety and efficacy of this breakthrough therapy. To achieve this, I first established methods for growing primary canine T cells from healthy and disease-bearing donors to clinically relevant scale, developed RNA electroporation protocols to transiently express a CAR targeting the canine tumor-associated antigen CD20, demonstrated its function in vitro, and treated a relapsed canine B cell lymphoma patient with autologous CAR T cells as a proof of feasibility. I then developed methods to permanently express a second-generation cCD20-8-28-ζ CAR in canine T cells using lentiviral transduction, showed in vitro antigen-specific function and proliferation of CAR T cells, and treated four canine B cell lymphoma patients with CAR T cells. Based on my observations from those patients, I made iterative improvements to the T cell culture system and CAR construct, and treated a canine B cell lymphoma patient with cCD20-8-BB-ζ CAR T cells, whose tumor cells lost target antigen expression to avoid immune pressure. These results prove that it is not only possible to generate canine CAR T cell therapy, but that it recapitulates observations found until now only in human patients. In addition, novel findings regarding the recovery of T cells during ex vivo culture and the host immune response to the CAR demonstrate that this model can already inform human medicine.
Subjects/Keywords: chimeric antigen receptor; comparative oncology; immunotherapy; pre-clinical animal model; Allergy and Immunology; Immunology and Infectious Disease; Medical Immunology; Oncology
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APA ·
Chicago ·
MLA ·
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CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Panjwani, M. K. (2017). Development Of Canine Chimeric Antigen Receptor T Cell Therapy For Treatment & Translation. (Thesis). University of Pennsylvania. Retrieved from https://repository.upenn.edu/edissertations/2513
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Panjwani, Mohammed Kazim. “Development Of Canine Chimeric Antigen Receptor T Cell Therapy For Treatment & Translation.” 2017. Thesis, University of Pennsylvania. Accessed March 07, 2021.
https://repository.upenn.edu/edissertations/2513.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Panjwani, Mohammed Kazim. “Development Of Canine Chimeric Antigen Receptor T Cell Therapy For Treatment & Translation.” 2017. Web. 07 Mar 2021.
Vancouver:
Panjwani MK. Development Of Canine Chimeric Antigen Receptor T Cell Therapy For Treatment & Translation. [Internet] [Thesis]. University of Pennsylvania; 2017. [cited 2021 Mar 07].
Available from: https://repository.upenn.edu/edissertations/2513.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Panjwani MK. Development Of Canine Chimeric Antigen Receptor T Cell Therapy For Treatment & Translation. [Thesis]. University of Pennsylvania; 2017. Available from: https://repository.upenn.edu/edissertations/2513
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Pennsylvania
27.
Minutolo, Nicholas G.
Developing The Next Generation Of Universal Immune Receptors.
Degree: 2019, University of Pennsylvania
URL: https://repository.upenn.edu/edissertations/3605
► Chimeric antigen receptor (CAR) T cell therapy has produced impressive clinical results in the treatment of human cancers; however, their broad use is limited due…
(more)
▼ Chimeric antigen receptor (CAR) T cell therapy has produced impressive clinical results in the treatment of human cancers; however, their broad use is limited due to the restriction of targeting to a single tumor associated antigen (TAA), as well as the inability to control effector function post-infusion. We hypothesized that these limitations can be addressed through the development of a receptor system that dissociates TAA targeting and T cell signaling. These receptors, termed universal immune receptors (UIRs), function through the binding of an extracellular adapter domain which acts as a bridge between intracellular T cell signaling domains and a soluble TAA targeting ligand (TL). This modular receptor design allows for dose-control of effector function, as well as the ability to target multiple antigens with a single receptor.
In this thesis we describe the preclinical development of two novel UIRs, each designed with components that permit unique functionalities. First, we detail the development of a UIR based on the SpyCatcher/SpyTag protein bioconjugation system. We hypothesized that genetically engineering T cells to express an immune receptor containing the SpyCatcher protein as its extracellular domain would allow for covalent loading of SpyTag labeled TLs. We demonstrate that covalent loading of the receptor does occur with the addition of SpyTag-labeled TLs, and these new receptor architectures are capable of redirecting T cells against a range of TAAs, either individually or simultaneously, in a dose-dependent manner. Additionally, dose-controlled effector function was demonstrated in vivo.
Many UIRs are comprised of components derived from non-human proteins or use TL-tags that have never been clinically injected. To address these potential issues, we developed a UIR comprised of an extracellular humanized scFv that binds the clinically validated positron emission tomography (PET) imaging agent DOTA. Our preliminary data shows that T cells expressing the αDOTA receptor can be redirected against multiple TAAs through the use of DOTA-conjugated clinical grade antibodies. Additionally, potency of the T cell response can be titrated by alterations to the DOTA molecule or through chelation of various metals to DOTA. Our results suggest that with further assessment the DOTA UIR is uniquely poised for clinical translation.
Subjects/Keywords: Adoptive T cell Therapy; Chimeric Antigen Receptor; Immunotherapy; Universal Immune Receptor; Allergy and Immunology; Biology; Immunology and Infectious Disease; Medical Immunology; Pharmacology
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APA ·
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MLA ·
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CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Minutolo, N. G. (2019). Developing The Next Generation Of Universal Immune Receptors. (Thesis). University of Pennsylvania. Retrieved from https://repository.upenn.edu/edissertations/3605
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Minutolo, Nicholas G. “Developing The Next Generation Of Universal Immune Receptors.” 2019. Thesis, University of Pennsylvania. Accessed March 07, 2021.
https://repository.upenn.edu/edissertations/3605.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Minutolo, Nicholas G. “Developing The Next Generation Of Universal Immune Receptors.” 2019. Web. 07 Mar 2021.
Vancouver:
Minutolo NG. Developing The Next Generation Of Universal Immune Receptors. [Internet] [Thesis]. University of Pennsylvania; 2019. [cited 2021 Mar 07].
Available from: https://repository.upenn.edu/edissertations/3605.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Minutolo NG. Developing The Next Generation Of Universal Immune Receptors. [Thesis]. University of Pennsylvania; 2019. Available from: https://repository.upenn.edu/edissertations/3605
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
28.
NATASHA VINANICA.
IMPROVING THE EFFICACY OF CHIMERIC ANTIGEN RECEPTOR-T CELLS FOR CANCER THERAPY.
Degree: 2020, National University of Singapore
URL: https://scholarbank.nus.edu.sg/handle/10635/169796
Subjects/Keywords: chimeric antigen receptor; erythropoietin receptor; erythropoietin; IL-2; T cells; leukemia
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APA ·
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APA (6th Edition):
VINANICA, N. (2020). IMPROVING THE EFFICACY OF CHIMERIC ANTIGEN RECEPTOR-T CELLS FOR CANCER THERAPY. (Thesis). National University of Singapore. Retrieved from https://scholarbank.nus.edu.sg/handle/10635/169796
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
VINANICA, NATASHA. “IMPROVING THE EFFICACY OF CHIMERIC ANTIGEN RECEPTOR-T CELLS FOR CANCER THERAPY.” 2020. Thesis, National University of Singapore. Accessed March 07, 2021.
https://scholarbank.nus.edu.sg/handle/10635/169796.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
VINANICA, NATASHA. “IMPROVING THE EFFICACY OF CHIMERIC ANTIGEN RECEPTOR-T CELLS FOR CANCER THERAPY.” 2020. Web. 07 Mar 2021.
Vancouver:
VINANICA N. IMPROVING THE EFFICACY OF CHIMERIC ANTIGEN RECEPTOR-T CELLS FOR CANCER THERAPY. [Internet] [Thesis]. National University of Singapore; 2020. [cited 2021 Mar 07].
Available from: https://scholarbank.nus.edu.sg/handle/10635/169796.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
VINANICA N. IMPROVING THE EFFICACY OF CHIMERIC ANTIGEN RECEPTOR-T CELLS FOR CANCER THERAPY. [Thesis]. National University of Singapore; 2020. Available from: https://scholarbank.nus.edu.sg/handle/10635/169796
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Texas Medical Center
29.
Hurton, Lenka.
TETHERED IL-15 TO AUGMENT THE THERAPEUTIC POTENTIAL OF T CELLS EXPRESSING CHIMERIC ANTIGEN RECEPTOR: MAINTAINING MEMORY POTENTIAL, PERSISTENCE, AND ANTITUMOR ACTIVITY.
Degree: PhD, 2014, Texas Medical Center
URL: https://digitalcommons.library.tmc.edu/utgsbs_dissertations/421
► Tethered IL-15 to augment the therapeutic potential of T cells expressing chimeric antigen receptor: Maintaining memory potential, persistence, and antitumor activity Adoptive immunotherapy can…
(more)
▼ Tethered IL-15 to augment the therapeutic potential of T cells expressing
chimeric antigen receptor: Maintaining memory potential, persistence, and antitumor activity
Adoptive immunotherapy can retarget T cells to CD19, a tumor-associated
antigen (TAA) expressed on B-cell malignancies, by the expression of a
chimeric antigen receptor (CAR). Infusion of CAR-modified T cells for the treatment B-cell malignancies has demonstrated promise in preclinical and clinical trials. These data highlight the ability of infused CD19-specific T cells to be synchronously activated by large burdens of CD19
+ leukemia and lymphoma. This can lead to dramatic antitumor effects, but also exposes the recipient to toxicity associated with tumor-cell lysis and cytokine storm. Clinical trials will now be addressing the targeting of minimal burdens of CD19
+ malignancy as patients are enrolled earlier in their disease course and receive concomitant chemotherapy. It is likely that the existing populations of CAR T cells generated
ex vivo to address relapsed disease may not be able to address minimal residual disease (MRD). Therefore, we have developed a clinically appealing approach to sustaining the persistence of CAR T cells independent of TAA by providing signaling through the common gamma chain
receptor (gc). Administration of exogenous soluble recombinant cytokines that signal through the gc, such as interleukin (IL)-2, have been used clinically to sustain the persistence of adoptively transferred T cells. However, systemic high-dose administration has resulted in dose-limiting toxicities. Unlike IL-2, IL-15 possesses numerous attributes desirable for adoptive therapy and has been ranked among the most valuable immunotherapeutic agent for cancer treatment. It is a pro-survival cytokine that promotes the survival of long-lived T-cell memory subsets and
in vivo antitumor activity. Unlike other gc family cytokines, IL-15 is transpresented to responding T cells in the context of IL-15
receptor alpha (IL-15Ra). Therefore, we
hypothesized that a membrane-bound IL-15 fusion protein (mIL15) tethered to the cell surface would enhance T-cell costimulation to support persistence independent of CAR activation by preserving T-cell memory potential and maintain antitumor activity in the presence of low TAA. Using clinically compliant methods, the generated mIL15-CAR T cells mimicked the physiologic mechanism of transpresentation to sustain costimulation via phosphorylation of signal transducer and activator of transcription (pSTAT5). In contrast to conventional CD19-specific CAR T cells, mIL15-CAR T cells persisted in mice independent of the presence of TAA and mediated potent rejection of a systemically distributed CD19
+ leukemia. The potential for sustained immunity against B-cell malignancies was shown as, in the absence of
antigen, mIL15-CAR T cells were long-lived and adopted a desirable CD45RO
negCCR7
+ “low-differentiation” state with a…
Advisors/Committee Members: Laurence J.N. Cooper, M.D., Ph.D., Joya Chandra, Ph.D., Gianpietro Dotti, Ph.D..
Subjects/Keywords: immunotherapy; cytokines; IL-15; chimeric antigen receptor; T-cell persistence; memory; memory stem cell; leukemia; B-ALL; Medical Biotechnology; Medical Immunology; Medicine and Health Sciences; Other Immunology and Infectious Disease
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APA ·
Chicago ·
MLA ·
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CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Hurton, L. (2014). TETHERED IL-15 TO AUGMENT THE THERAPEUTIC POTENTIAL OF T CELLS EXPRESSING CHIMERIC ANTIGEN RECEPTOR: MAINTAINING MEMORY POTENTIAL, PERSISTENCE, AND ANTITUMOR ACTIVITY. (Doctoral Dissertation). Texas Medical Center. Retrieved from https://digitalcommons.library.tmc.edu/utgsbs_dissertations/421
Chicago Manual of Style (16th Edition):
Hurton, Lenka. “TETHERED IL-15 TO AUGMENT THE THERAPEUTIC POTENTIAL OF T CELLS EXPRESSING CHIMERIC ANTIGEN RECEPTOR: MAINTAINING MEMORY POTENTIAL, PERSISTENCE, AND ANTITUMOR ACTIVITY.” 2014. Doctoral Dissertation, Texas Medical Center. Accessed March 07, 2021.
https://digitalcommons.library.tmc.edu/utgsbs_dissertations/421.
MLA Handbook (7th Edition):
Hurton, Lenka. “TETHERED IL-15 TO AUGMENT THE THERAPEUTIC POTENTIAL OF T CELLS EXPRESSING CHIMERIC ANTIGEN RECEPTOR: MAINTAINING MEMORY POTENTIAL, PERSISTENCE, AND ANTITUMOR ACTIVITY.” 2014. Web. 07 Mar 2021.
Vancouver:
Hurton L. TETHERED IL-15 TO AUGMENT THE THERAPEUTIC POTENTIAL OF T CELLS EXPRESSING CHIMERIC ANTIGEN RECEPTOR: MAINTAINING MEMORY POTENTIAL, PERSISTENCE, AND ANTITUMOR ACTIVITY. [Internet] [Doctoral dissertation]. Texas Medical Center; 2014. [cited 2021 Mar 07].
Available from: https://digitalcommons.library.tmc.edu/utgsbs_dissertations/421.
Council of Science Editors:
Hurton L. TETHERED IL-15 TO AUGMENT THE THERAPEUTIC POTENTIAL OF T CELLS EXPRESSING CHIMERIC ANTIGEN RECEPTOR: MAINTAINING MEMORY POTENTIAL, PERSISTENCE, AND ANTITUMOR ACTIVITY. [Doctoral Dissertation]. Texas Medical Center; 2014. Available from: https://digitalcommons.library.tmc.edu/utgsbs_dissertations/421
Texas Medical Center
30.
Crossland, Denise L.
CD56-SPECIFIC T CELLS: USING GENETICALLY ENGINEERED T CELLS TO REDIRECT SPECIFICITY TO A T CELL EXPRESSED ANTIGEN.
Degree: PhD, 2014, Texas Medical Center
URL: https://digitalcommons.library.tmc.edu/utgsbs_dissertations/493
► The CD56 antigen is expressed on several deadly malignancies currently lacking long-term efficacious therapies. Chimeric antigen receptor (CAR) based immunotherapies have shown both safety…
(more)
▼ The CD56
antigen is expressed on several deadly malignancies currently lacking long-term efficacious therapies.
Chimeric antigen receptor (CAR) based immunotherapies have shown both safety and efficacy and even a curative ability in clinical trials, laying the foundation for applying CARs to new targets. Using T cells to target a T cell expressed
antigen, such as CD56, seems counterintuitive in that the T cells would be susceptible to self-targeting a.k.a. fratricide. However, we expand CD56-specific CAR
+ T cells that co-express the CD56
antigen. Since other CARs targeting T cell expressed antigens are hypothesized to be undergoing fratricide, such as the CD38-specific CAR, this unexpected observation of CD56
+CD56CAR
+ T cells infers that these cells are unique in their survival capacity in a self-targeting scenario. CD56CAR
+ T cells have redirected specificity to CD56
+ tumor cells and generate anti-tumor responses in neuroblastoma xenograft studies in mice. These CD56CAR
+ T cells expand similarly to CAR
+ T cells that do not target self-
antigen, CD19-specific CAR
+ T cells, and do not undergo fratricide. The CD56
antigen co-expressed by CD56CAR
+ T cells has diminished ability to stain with the CD56 monoclonal antibody clone N901, which is the epitope where the CAR binds, while the CD56
antigen on CD19CAR
+ T cells retains staining. Our data strongly suggest that this epitope loss is not a result of epitope escape of the CD56
antigen. Significant differences in the protein expression profiles of CD19CAR
+ and CD56CAR
+ T cells, which may be responsible for fratricide evasion of CD56
+CD56CAR
+ T cells, were observed. Further investigation into these protein differences could delineate a key pathway or responsible for fratricide evasion and be applied in the generation of other CAR based immunotherapies targeting T cell expressed tumor associated antigens. Targeting T cell expressed antigens not only has implications for cancer therapies, but also for treating autoimmune diseases, for the manipulation of transplants or to ablate existing immune cells in a patient as an alternative to chemotherapy.
Advisors/Committee Members: Laurence J.N. Cooper, M.D., Ph.D., Dean A. Lee, M.D., Ph.D., Bradley McIntyre, Ph.D..
Subjects/Keywords: Chimeric Antigen Receptor; CAR; Neural Cell Adhesion Molecule; NCAM; CD56; Fratricide; Autolysis; T cell immunotherapy; self-targeting; CD56CAR; Cancer Biology; Medicine and Health Sciences
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APA (6th Edition):
Crossland, D. L. (2014). CD56-SPECIFIC T CELLS: USING GENETICALLY ENGINEERED T CELLS TO REDIRECT SPECIFICITY TO A T CELL EXPRESSED ANTIGEN. (Doctoral Dissertation). Texas Medical Center. Retrieved from https://digitalcommons.library.tmc.edu/utgsbs_dissertations/493
Chicago Manual of Style (16th Edition):
Crossland, Denise L. “CD56-SPECIFIC T CELLS: USING GENETICALLY ENGINEERED T CELLS TO REDIRECT SPECIFICITY TO A T CELL EXPRESSED ANTIGEN.” 2014. Doctoral Dissertation, Texas Medical Center. Accessed March 07, 2021.
https://digitalcommons.library.tmc.edu/utgsbs_dissertations/493.
MLA Handbook (7th Edition):
Crossland, Denise L. “CD56-SPECIFIC T CELLS: USING GENETICALLY ENGINEERED T CELLS TO REDIRECT SPECIFICITY TO A T CELL EXPRESSED ANTIGEN.” 2014. Web. 07 Mar 2021.
Vancouver:
Crossland DL. CD56-SPECIFIC T CELLS: USING GENETICALLY ENGINEERED T CELLS TO REDIRECT SPECIFICITY TO A T CELL EXPRESSED ANTIGEN. [Internet] [Doctoral dissertation]. Texas Medical Center; 2014. [cited 2021 Mar 07].
Available from: https://digitalcommons.library.tmc.edu/utgsbs_dissertations/493.
Council of Science Editors:
Crossland DL. CD56-SPECIFIC T CELLS: USING GENETICALLY ENGINEERED T CELLS TO REDIRECT SPECIFICITY TO A T CELL EXPRESSED ANTIGEN. [Doctoral Dissertation]. Texas Medical Center; 2014. Available from: https://digitalcommons.library.tmc.edu/utgsbs_dissertations/493
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