You searched for subject:(immunotherapy).
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1.
Khare, Priyanka.
Attenuation of gonadotropin secreting tumors by
immunotherapy.
Degree: 2009, Jamia Hamdard University
URL: http://shodhganga.inflibnet.ac.in/handle/10603/37387 
Subjects/Keywords: Immunotherapy
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APA (6th Edition):
Khare, P. (2009). Attenuation of gonadotropin secreting tumors by
immunotherapy. (Thesis). Jamia Hamdard University. Retrieved from http://shodhganga.inflibnet.ac.in/handle/10603/37387
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):
Khare, Priyanka. “Attenuation of gonadotropin secreting tumors by
immunotherapy.” 2009. Thesis, Jamia Hamdard University. Accessed September 19, 2019.
http://shodhganga.inflibnet.ac.in/handle/10603/37387.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Khare, Priyanka. “Attenuation of gonadotropin secreting tumors by
immunotherapy.” 2009. Web. 19 Sep 2019.
Vancouver:
Khare P. Attenuation of gonadotropin secreting tumors by
immunotherapy. [Internet] [Thesis]. Jamia Hamdard University; 2009. [cited 2019 Sep 19].
Available from: http://shodhganga.inflibnet.ac.in/handle/10603/37387.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Khare P. Attenuation of gonadotropin secreting tumors by
immunotherapy. [Thesis]. Jamia Hamdard University; 2009. Available from: http://shodhganga.inflibnet.ac.in/handle/10603/37387
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
2.
Sunay, Melek ME.
Harnessing Mechanisms of Immune Modulation by Sorafenib to Augment the Efficacy of Cellular Immunotherapy.
Degree: 2015, Johns Hopkins University
URL: http://jhir.library.jhu.edu/handle/1774.2/38006
► The tumor microenvironment is established and maintained through the complex interactions of tumor cells with host stromal elements. Therefore, therapies that target multiple cellular components…
(more)
▼ The tumor microenvironment is established and maintained through the complex interactions of tumor cells with host stromal elements. Therefore, therapies that target multiple cellular components of the tumor may be most effective. Sorafenib, a multi-kinase inhibitor, alters signaling pathways in tumor cells and host stromal cells. Thus, we explored the potential immune-modulating effects of Sorafenib in a murine HER-2-(neu) overexpressing breast tumor model alone and in combination with a HER-2 targeted granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting vaccine. In vitro, Sorafenib inhibited the growth of HER-2 overexpressing NT2.5 tumor cells, inducing apoptosis. Western blot analysis revealed that Sorafenib interfered with ERK MAPK, p38 MAPK, and STAT3 signaling, but not HER-2 or Akt signaling. It also decreased D-type cyclin expression. In vivo, single agent Sorafenib disrupted the tumor-associated vasculature and induced tumor apoptosis,
effectively inducing the regression of established NT2.5 tumors in immune competent FVB/N mice. Immune depletion studies demonstrated that tumor rejection was mediated by both CD4+ and CD8+ T cells. Sorafenib treatment enhanced tumor clearance induced by vaccination with a GM-CSF-secreting, HER-2-expressing cellular vaccine in tumor-bearing FVB/N mice relative to either drug treatment or vaccination alone. Although the magnitude of the peripheral antigen-specific T cell response was unchanged, Sorafenib appeared to enhance antigen-specific T cell accumulation at the tumor site. Overall, these findings suggest that dendritic cell-based
immunotherapy can be integrated with Sorafenib, resulting in enhanced therapeutic response.
Advisors/Committee Members: Scott, Allan (advisor).
Subjects/Keywords: immunotherapy. cancer
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APA (6th Edition):
Sunay, M. M. (2015). Harnessing Mechanisms of Immune Modulation by Sorafenib to Augment the Efficacy of Cellular Immunotherapy. (Thesis). Johns Hopkins University. Retrieved from http://jhir.library.jhu.edu/handle/1774.2/38006
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):
Sunay, Melek ME. “Harnessing Mechanisms of Immune Modulation by Sorafenib to Augment the Efficacy of Cellular Immunotherapy.” 2015. Thesis, Johns Hopkins University. Accessed September 19, 2019.
http://jhir.library.jhu.edu/handle/1774.2/38006.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Sunay, Melek ME. “Harnessing Mechanisms of Immune Modulation by Sorafenib to Augment the Efficacy of Cellular Immunotherapy.” 2015. Web. 19 Sep 2019.
Vancouver:
Sunay MM. Harnessing Mechanisms of Immune Modulation by Sorafenib to Augment the Efficacy of Cellular Immunotherapy. [Internet] [Thesis]. Johns Hopkins University; 2015. [cited 2019 Sep 19].
Available from: http://jhir.library.jhu.edu/handle/1774.2/38006.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Sunay MM. Harnessing Mechanisms of Immune Modulation by Sorafenib to Augment the Efficacy of Cellular Immunotherapy. [Thesis]. Johns Hopkins University; 2015. Available from: http://jhir.library.jhu.edu/handle/1774.2/38006
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Hong Kong
3.
黃心龍; Wong, Sum-lung.
The use of immunotherapy in solid tumours : efficacy and
toxicity.
Degree: Master of Research in Medicine, Medicine, 2017, University of Hong Kong
URL: http://hdl.handle.net/10722/252496
► Immune checkpoint inhibitors are revolutionising cancer care worldwide. However, local data regarding the efficacy and toxicity of these agents is scarce. This is a single…
(more)
▼ Immune checkpoint inhibitors are revolutionising
cancer care worldwide.
However, local data regarding the efficacy
and toxicity of these agents is scarce.
This is a single centre,
retrospective study of the tumour response rate and toxicity of
Anti-programmed cell death protein 1 agents and Anti-Cytotoxic
T-lymphocyte-associated protein 4 agents for the treatment of 84
East Asian patients with various solid organ tumours. It was found
that the Objective Response Rate according to the Response
Evaluation Criteria in Solid Tumours (version 1.1) was 7.8% across
all tumour groups, and highest amongst Hepatocellular Carcinoma
patients at 15%. Within Sorafenib pre-treated Hepatitis B
Virus-associated Hepatocellular Carcinoma patients, the response
rate was 18.8%. A further 17.6% of patients had Stable Disease as
their best imaging response. 52% of patients suffered from clinical
progression. 16.7% of patients experienced Grade 3 or above
toxicity and 4.8% of patients terminated treatment due to toxicity.
In conclusion, immune checkpoint inhibitors were generally well
tolerated and effective against Sorafenib pre-treated Hepatitis B
Virus-associated Hepatocellular Carcinoma in this cohort of
patients. However, the response rate in other tumour groups was
inferior to those observed in published trials. This is possibly
due to a number of factors, including different tumour types, more
advanced disease and longer intervals of imaging
assessment.
published_or_final_version
Medicine
Master
Master of Research in Medicine
Subjects/Keywords: Immunotherapy - Tumors
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Chicago ·
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Manager
APA (6th Edition):
黃心龍; Wong, S. (2017). The use of immunotherapy in solid tumours : efficacy and
toxicity. (Masters Thesis). University of Hong Kong. Retrieved from http://hdl.handle.net/10722/252496
Chicago Manual of Style (16th Edition):
黃心龍; Wong, Sum-lung. “The use of immunotherapy in solid tumours : efficacy and
toxicity.” 2017. Masters Thesis, University of Hong Kong. Accessed September 19, 2019.
http://hdl.handle.net/10722/252496.
MLA Handbook (7th Edition):
黃心龍; Wong, Sum-lung. “The use of immunotherapy in solid tumours : efficacy and
toxicity.” 2017. Web. 19 Sep 2019.
Vancouver:
黃心龍; Wong S. The use of immunotherapy in solid tumours : efficacy and
toxicity. [Internet] [Masters thesis]. University of Hong Kong; 2017. [cited 2019 Sep 19].
Available from: http://hdl.handle.net/10722/252496.
Council of Science Editors:
黃心龍; Wong S. The use of immunotherapy in solid tumours : efficacy and
toxicity. [Masters Thesis]. University of Hong Kong; 2017. Available from: http://hdl.handle.net/10722/252496
University of Hong Kong
4.
Ho, Hoi-hang.
Study of fumagillin analogues on murine immune cells and
immunomodulatory effects in different cancer models.
Degree: PhD, 2012, University of Hong Kong
URL: Ho,
H.
[何凱恆].
(2012).
Study
of
fumagillin
analogues
on
murine
immune
cells
and
immunomodulatory
effects
in
different
cancer
models.
(Thesis).
University
of
Hong
Kong,
Pokfulam,
Hong
Kong
SAR.
Retrieved
from
http://dx.doi.org/10.5353/th_b5060560
;
http://dx.doi.org/10.5353/th_b5060560
;
http://hdl.handle.net/10722/198805
► Fumagillin is the natural product isolated from fungus Aspergillus fumigatus, and is recognized as a potent anti-angiogenic compound. Substantial investigation has been focused on the…
(more)
▼ Fumagillin is the natural product isolated from
fungus Aspergillus fumigatus, and is recognized as a potent
anti-angiogenic compound. Substantial investigation has been
focused on the anti-tumor activities of fumagillin and its
analogues, some of which have been adopted in pre-clinical and
clinical studies. However, investigation on the immunomodulating
activities of this class of compounds is limited and results have
been controversial. As there is intense interest in elucidating the
interrelation between immune modulation and tumor development,
novel immunopharmacological properties of chemotherapeutic agents
have recently been explored for their therapeutic potentials in
clinical applications. As a combination to both these research
topics, fumagillin and its synthetic analogues were firstly
investigated on different types of immune cells, such as T
lymphocytes, dendritic cells and macrophages. F23, a fumagillin
analogue with potent immunological activities, was further examined
in three different murine cancer models, EL4 lymphoma, CT26 colon
carcinoma and 4T1 mammary carcinoma, and their anti-tumor
activities and intrinsic immunomodulatory effects were explored.
Fumagillin and its analogues exert diversified functions in
different types of immune cells. For example, they showed
inhibitory effects on cell proliferation and cytokine production of
T lymphocytes upon polyclonal stimulation, stimulatory effects on
dendritic cells by inducing a highly-matured population, which
contributed to induction of syngeneic and allogeneic lymphocyte
proliferation and a preference to Th1 polarization, and multiple
effects on macrophages based on phenotypic and cytokine analyses.
Studies in murine cancer models showed that the fumagillin analogue
F23 caused substantial inhibition of tumor development in three
cancer models to different extents, with pronounced inhibitory
effects on the expansion and functions of myeloid-derived
suppressor cells (MDSCs), the signature cell population responsible
for tumor progression and refractoriness to chemotherapeutic and
immunotherapeutic agents, thereby suggesting the novel
immunopharmacological properties of fumagillin and its analogues
contributed to tumor suppression.
published_or_final_version
Chemistry
Doctoral
Doctor of Philosophy
Subjects/Keywords: Cancer - Immunotherapy
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APA ·
Chicago ·
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CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Ho, H. (2012). Study of fumagillin analogues on murine immune cells and
immunomodulatory effects in different cancer models. (Doctoral Dissertation). University of Hong Kong. Retrieved from Ho, H. [何凱恆]. (2012). Study of fumagillin analogues on murine immune cells and immunomodulatory effects in different cancer models. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5060560 ; http://dx.doi.org/10.5353/th_b5060560 ; http://hdl.handle.net/10722/198805
Chicago Manual of Style (16th Edition):
Ho, Hoi-hang. “Study of fumagillin analogues on murine immune cells and
immunomodulatory effects in different cancer models.” 2012. Doctoral Dissertation, University of Hong Kong. Accessed September 19, 2019.
Ho, H. [何凱恆]. (2012). Study of fumagillin analogues on murine immune cells and immunomodulatory effects in different cancer models. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5060560 ; http://dx.doi.org/10.5353/th_b5060560 ; http://hdl.handle.net/10722/198805.
MLA Handbook (7th Edition):
Ho, Hoi-hang. “Study of fumagillin analogues on murine immune cells and
immunomodulatory effects in different cancer models.” 2012. Web. 19 Sep 2019.
Vancouver:
Ho H. Study of fumagillin analogues on murine immune cells and
immunomodulatory effects in different cancer models. [Internet] [Doctoral dissertation]. University of Hong Kong; 2012. [cited 2019 Sep 19].
Available from: Ho, H. [何凱恆]. (2012). Study of fumagillin analogues on murine immune cells and immunomodulatory effects in different cancer models. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5060560 ; http://dx.doi.org/10.5353/th_b5060560 ; http://hdl.handle.net/10722/198805.
Council of Science Editors:
Ho H. Study of fumagillin analogues on murine immune cells and
immunomodulatory effects in different cancer models. [Doctoral Dissertation]. University of Hong Kong; 2012. Available from: Ho, H. [何凱恆]. (2012). Study of fumagillin analogues on murine immune cells and immunomodulatory effects in different cancer models. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5060560 ; http://dx.doi.org/10.5353/th_b5060560 ; http://hdl.handle.net/10722/198805
University of Hong Kong
5.
Tan, Zhiwu.
Vaccine-elicited CD8⁺ T cells overcome immune suppressive
environment to cure malignant mesothelioma in mice.
Degree: PhD, 2014, University of Hong Kong
URL: Tan,
Z.
[譚志武].
(2014).
Vaccine-elicited
CD8⁺
T
cells
overcome
immune
suppressive
environment
to
cure
malignant
mesothelioma
in
mice.
(Thesis).
University
of
Hong
Kong,
Pokfulam,
Hong
Kong
SAR.
Retrieved
from
http://dx.doi.org/10.5353/th_b5317026
;
http://dx.doi.org/10.5353/th_b5317026
;
http://hdl.handle.net/10722/206430
► Malignant mesothelioma is an aggressive cancer with increasing incidence worldwide. Exposure to asbestos is believed to be the main mechanistic basis of malignant transformation of…
(more)
▼ Malignant mesothelioma is an aggressive cancer with
increasing incidence worldwide. Exposure to asbestos is believed to
be the main mechanistic basis of malignant transformation of
mesothelial cells. Despite decades of efforts, treatment options
for this malignancy are still limited to traditional surgery and
chemotherapy, which do not provide significant survival benefits,
highlighting the importance of finding novel therapeutic and
preventive approaches to fight mesothelioma. For this reason, we
aimed to examine the efficacy of immunotherapy strategy using DNA
vaccines targeting tumor-expressing antigens. Immunotherapy
targeting tumor associated self-antigen WT1 with conventional and
PD1-based DNA vaccines was unable to induce tumor regression or
improved survival in a quantitative mouse malignant mesothelioma
model due to insufficient levels of antigen-specific immune
responses being elicited. While why PD1-based DNA vaccine does not
improve self-antigen WT1-specific immune responses remains to be
investigated, it becomes important to define the level of
vaccine-elicited immune responses for protection.
To date, the
immune correlates of vaccine-elicited immunity remains poorly
understood for the prevention and eradication of malignant
mesothelioma. With the development of a malignant mesothelioma
mouse model stably expressing HIV-1 GAG model antigen, we utilized
the remarkably enhanced antigen-specific T cell responses elicited
from our PD1-based HIV-1 GAG p24 vaccine to define antitumor
responses. It has been demonstrated in this study that
vaccine-elicited host immunity not only achieved complete and
long-lasting protection against murine mesothelioma cell challenges
but also resulted in therapeutic eradication of pre-existing
mesothelioma after four consecutive DNA vaccinations.
Vaccine-elicited 〖CD8〗^+ T cells attributed primarily and
dose-dependently to the protective efficacy in both preventive and
therapeutic settings. Moreover, the consecutive vaccinations
activated polyfunctional 〖CD8〗^+ T effector cells via T-bet and
Eomes-mediated pathways, leading to the rejection of mesothelioma
by releasing inflammatory IFN-γ and TNF-α in the vicinity of target
cells and by triggering the TRAIL induced apoptosis. Importantly,
the vaccination not only activated 〖CD8〗^+ T cells and maintained
their effector function but also overcame immunosuppressive
networks by downregulating inhibitory PD1 and Tim-3 molecule
expression on 〖CD8〗^+ cells and reducing suppressor cells such as
myeloid-derived suppressor cells (MDSCs) and Treg, leading to the
shift of tumor immune oediting from progression to elimination.
Taken together, the generation of malignant mesothelioma mouse
models in our study can enable targeting immunotherapy strategies
to be evaluated in a quantitative way. Our data suggested that high
frequency of vaccine-elicited 〖CD8〗^+ T cells could prevent and
eradicate malignant mesothelioma. The activation of quantitatively
and qualitatively enhanced CD8+ T cells caneliminate theimmune
suppressive network…
Subjects/Keywords: Mesothelioma - Immunotherapy
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APA ·
Chicago ·
MLA ·
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CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Tan, Z. (2014). Vaccine-elicited CD8⁺ T cells overcome immune suppressive
environment to cure malignant mesothelioma in mice. (Doctoral Dissertation). University of Hong Kong. Retrieved from Tan, Z. [譚志武]. (2014). Vaccine-elicited CD8⁺ T cells overcome immune suppressive environment to cure malignant mesothelioma in mice. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5317026 ; http://dx.doi.org/10.5353/th_b5317026 ; http://hdl.handle.net/10722/206430
Chicago Manual of Style (16th Edition):
Tan, Zhiwu. “Vaccine-elicited CD8⁺ T cells overcome immune suppressive
environment to cure malignant mesothelioma in mice.” 2014. Doctoral Dissertation, University of Hong Kong. Accessed September 19, 2019.
Tan, Z. [譚志武]. (2014). Vaccine-elicited CD8⁺ T cells overcome immune suppressive environment to cure malignant mesothelioma in mice. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5317026 ; http://dx.doi.org/10.5353/th_b5317026 ; http://hdl.handle.net/10722/206430.
MLA Handbook (7th Edition):
Tan, Zhiwu. “Vaccine-elicited CD8⁺ T cells overcome immune suppressive
environment to cure malignant mesothelioma in mice.” 2014. Web. 19 Sep 2019.
Vancouver:
Tan Z. Vaccine-elicited CD8⁺ T cells overcome immune suppressive
environment to cure malignant mesothelioma in mice. [Internet] [Doctoral dissertation]. University of Hong Kong; 2014. [cited 2019 Sep 19].
Available from: Tan, Z. [譚志武]. (2014). Vaccine-elicited CD8⁺ T cells overcome immune suppressive environment to cure malignant mesothelioma in mice. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5317026 ; http://dx.doi.org/10.5353/th_b5317026 ; http://hdl.handle.net/10722/206430.
Council of Science Editors:
Tan Z. Vaccine-elicited CD8⁺ T cells overcome immune suppressive
environment to cure malignant mesothelioma in mice. [Doctoral Dissertation]. University of Hong Kong; 2014. Available from: Tan, Z. [譚志武]. (2014). Vaccine-elicited CD8⁺ T cells overcome immune suppressive environment to cure malignant mesothelioma in mice. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5317026 ; http://dx.doi.org/10.5353/th_b5317026 ; http://hdl.handle.net/10722/206430
Vanderbilt University
6.
Shae, Daniel.
Design and Optimization of âSmartâ Nanoparticles for Targeting of the STING Pathway with Applications in Cancer Immunotherapy.
Degree: PhD, Chemical Engineering, 2019, Vanderbilt University
URL: http://etd.library.vanderbilt.edu/available/etd-03042019-120929/
;
► I detail the rational design and optimization of STING-NPs: a nanoparticle delivery platform that stimulates innate immunity and T cell activation through targeted activation of…
(more)
▼ I detail the rational design and optimization of STING-NPs: a nanoparticle delivery platform that stimulates innate immunity and T cell activation through targeted activation of the stimulator of interferon genes (STING) protein, a critical cytosolic immune sensor of oncogenesis that has historically been difficult to target due to the poor pharmacokinetic properties of its natural ligand, cGAMP. STING-NPs comprise self-assembling, pH responsive, and endosomolytic polymers and overcome delivery barriers associated with cGAMP delivery by facilitating the cellular uptake and endosomal escape of cGAMP, facilitating a 2-3 order of magnitude enhancement in drug potency.
Administration of STING-NPs in murine tumor models initiates a multifaceted pro-inflammatory program associated with type I interferon expression and recruitment of T cells into the tumor microenvironment, eliciting tumor suppression or complete rejection through both intratumoral and systemic administration routes. Strikingly, STING-NP treatment is capable of mediating rejection of primary tumor growth as well as generating systemic and long-lived antitumor immunity, manifesting in suppression of distal tumor growth and resistance to cancer cell rechallenge. Efficacy is improved with the addition of checkpoint blockade antibodies, demonstrating that STING-NP treatment can sensitize tumors to ICB. Finally, the activity of STING-NPs is validated in an ex vivo model of freshly resected human melanoma.
Advisors/Committee Members: Jeffrey C. Rathell (committee member), Scott A. Guelcher (committee member), Paul E. Laibinis (committee member), Justin M. Balko (committee member), John T. Wilson (chair).
Subjects/Keywords: Cancer Immunotherapy
Record Details
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APA ·
Chicago ·
MLA ·
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CSE |
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to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Shae, D. (2019). Design and Optimization of âSmartâ Nanoparticles for Targeting of the STING Pathway with Applications in Cancer Immunotherapy. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://etd.library.vanderbilt.edu/available/etd-03042019-120929/ ;
Chicago Manual of Style (16th Edition):
Shae, Daniel. “Design and Optimization of âSmartâ Nanoparticles for Targeting of the STING Pathway with Applications in Cancer Immunotherapy.” 2019. Doctoral Dissertation, Vanderbilt University. Accessed September 19, 2019.
http://etd.library.vanderbilt.edu/available/etd-03042019-120929/ ;.
MLA Handbook (7th Edition):
Shae, Daniel. “Design and Optimization of âSmartâ Nanoparticles for Targeting of the STING Pathway with Applications in Cancer Immunotherapy.” 2019. Web. 19 Sep 2019.
Vancouver:
Shae D. Design and Optimization of âSmartâ Nanoparticles for Targeting of the STING Pathway with Applications in Cancer Immunotherapy. [Internet] [Doctoral dissertation]. Vanderbilt University; 2019. [cited 2019 Sep 19].
Available from: http://etd.library.vanderbilt.edu/available/etd-03042019-120929/ ;.
Council of Science Editors:
Shae D. Design and Optimization of âSmartâ Nanoparticles for Targeting of the STING Pathway with Applications in Cancer Immunotherapy. [Doctoral Dissertation]. Vanderbilt University; 2019. Available from: http://etd.library.vanderbilt.edu/available/etd-03042019-120929/ ;
Rice University
7.
Evans, Emily Reiser.
Gold Nanovaccine Strategies for Cancer Immunotherapy.
Degree: PhD, Engineering, 2018, Rice University
URL: http://hdl.handle.net/1911/105658
► Gold nanoparticles have excellent properties for cancer therapeutics because their tunable size and surface chemistry make them customizable for many applications. For immunotherapy applications in…
(more)
▼ Gold nanoparticles have excellent properties for cancer therapeutics because their tunable size and surface chemistry make them customizable for many applications. For
immunotherapy applications in particular, we can leverage their natural biodistribution to the spleen and immune cells for delivering peptide antigen vaccines or tune their optical properties for photothermal therapy to ablate tumors, which results in tumor antigen circulation and an in situ vaccination effect. Our group has demonstrated the potential of gold nanoparticles to elicit systemic, anti-tumor immunity through several iterations of particle design, characterization, and in vivo testing. However, most of the animal testing was done using a B16-OVA model, which is less clinically relevant due to the transgene antigen inserted for vaccination and tumor detection. My work builds upon the strong foundation of proof-of-concept vaccination strategies and examines the use of these gold nanoparticle platforms for cancer
immunotherapy applications in a more clinically relevant tumor model. Though many hurdles remain for the first gold nanoparticles to reach FDA approval, this work demonstrates the progression of gold nanoparticle-enabled cancer
immunotherapy toward that end and illustrates novel immunotherapeutic outcomes and combinations that may inform future progress toward identifying a clinically viable gold nanoparticle cancer
immunotherapy strategy.
Advisors/Committee Members: Drezek, Rebekah (advisor).
Subjects/Keywords: nanoparticle; immunotherapy
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APA ·
Chicago ·
MLA ·
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CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Evans, E. R. (2018). Gold Nanovaccine Strategies for Cancer Immunotherapy. (Doctoral Dissertation). Rice University. Retrieved from http://hdl.handle.net/1911/105658
Chicago Manual of Style (16th Edition):
Evans, Emily Reiser. “Gold Nanovaccine Strategies for Cancer Immunotherapy.” 2018. Doctoral Dissertation, Rice University. Accessed September 19, 2019.
http://hdl.handle.net/1911/105658.
MLA Handbook (7th Edition):
Evans, Emily Reiser. “Gold Nanovaccine Strategies for Cancer Immunotherapy.” 2018. Web. 19 Sep 2019.
Vancouver:
Evans ER. Gold Nanovaccine Strategies for Cancer Immunotherapy. [Internet] [Doctoral dissertation]. Rice University; 2018. [cited 2019 Sep 19].
Available from: http://hdl.handle.net/1911/105658.
Council of Science Editors:
Evans ER. Gold Nanovaccine Strategies for Cancer Immunotherapy. [Doctoral Dissertation]. Rice University; 2018. Available from: http://hdl.handle.net/1911/105658
University of Minnesota
8.
Murphy, Katherine Anne.
Immune-based tumor regression induced by Fc-OX40L in a murine model of glioma.
Degree: PhD, Molecular, Cellular, Developmental Biology and Genetics, 2012, University of Minnesota
URL: http://purl.umn.edu/151476
► Glioblastoma multiforme, the most aggressive form of glioma, is a lethal brain tumor with a dismal median survival of 15-19 months. Immunotherapy is a promising…
(more)
▼ Glioblastoma multiforme, the most aggressive form of glioma, is a lethal brain tumor with a dismal median survival of 15-19 months. Immunotherapy is a promising adjuvant therapy for malignant brain tumors. Lack of adequate, endogenous antigen presentation and the immune suppressive nature of the tumor microenvironment present significant hurdles that need to be overcome in order to mount an effective immune response, capable of tumor elimination. Vaccination with tumor-derived antigen has sought to overcome inadequate antigen presentation, yet has shown to been inefficient at complete tumor elimination. Functionally unresponsiveness, anergy, can be induced in immune cells when antigen recognition occurs without proper costimulation. To test if additional costimulation was necessary to achieve a functional immune response, costimulatory molecules 41BBL, CD80, GITRL and OX40L, fused to the Fc portion of human immunoglobulin, were tested in combination with tumor vaccine. Vaccine/Fc-OX40L yielded the most potent response resulting in complete tumor regression in the majority of animals and the generation of immunological memory capable of rapidly clearing tumor upon tumor rechallenge. Additionally, combining vaccine/Fc-OX40L with the standard of care chemotherapy resulted in regression of 100% of glioma tumors, however 80% of these animals developed fatal secondary lymphoid malignancy. These data demonstrate Fc-OX40L has incredibly potent activity against experimental gliomas relative to the other molecules tested. In addition, it reveals a potential hazard in combining mutagenic chemotherapeutics with immunotherapy.
Lymphocytes isolated from vaccine/Fc-OX40L treated animals had enhanced cytolytic activity and increased proliferative capacity, compared to controls. Additional analysis demonstrated a CD4 T cell, NK, and B cell dependent, and CD8 T cell independent mechanism of action. The presence of tumor reactive antibody in the serum of treated mice and deposition of antibody at the tumor site, combined with the observation that loss of the Fc receptor negatively affected the ability of animals to control tumor growth generated interest in antibody-mediated mechanisms. Tumor infiltration of perforin expressing NK, NKT, and neutrophil-like cells in vaccine/Fc-OX40L treated animals may provide a possible mechanism of tumor killing. Further understanding the necessary effector cells and mechanisms involved in tumor elimination will aid in the design of future immunotherapy approaches.
Subjects/Keywords: Cancer; Immunotherapy
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APA (6th Edition):
Murphy, K. A. (2012). Immune-based tumor regression induced by Fc-OX40L in a murine model of glioma. (Doctoral Dissertation). University of Minnesota. Retrieved from http://purl.umn.edu/151476
Chicago Manual of Style (16th Edition):
Murphy, Katherine Anne. “Immune-based tumor regression induced by Fc-OX40L in a murine model of glioma.” 2012. Doctoral Dissertation, University of Minnesota. Accessed September 19, 2019.
http://purl.umn.edu/151476.
MLA Handbook (7th Edition):
Murphy, Katherine Anne. “Immune-based tumor regression induced by Fc-OX40L in a murine model of glioma.” 2012. Web. 19 Sep 2019.
Vancouver:
Murphy KA. Immune-based tumor regression induced by Fc-OX40L in a murine model of glioma. [Internet] [Doctoral dissertation]. University of Minnesota; 2012. [cited 2019 Sep 19].
Available from: http://purl.umn.edu/151476.
Council of Science Editors:
Murphy KA. Immune-based tumor regression induced by Fc-OX40L in a murine model of glioma. [Doctoral Dissertation]. University of Minnesota; 2012. Available from: http://purl.umn.edu/151476
University of Victoria
9.
Little, Nicole S.
Investigating the co-evolution of tumor antigens and the anti-tumor immune response.
Degree: Department of Biochemistry and Microbiology, 2017, University of Victoria
URL: https://dspace.library.uvic.ca//handle/1828/8503
► Background: High-grade serous carcinoma (HGSC) can exhibit high intratumoral heterogeneity (ITH). Despite a strong association between tumor-infiltrating lymphocytes (TIL) and survival in HGSC, ITH may…
(more)
▼ Background: High-grade serous carcinoma (HGSC) can exhibit high intratumoral heterogeneity (ITH). Despite a strong association between tumor-infiltrating lymphocytes (TIL) and survival in HGSC, ITH may have profound impacts on the anti-tumor T cell response. Yet, it is unknown how anti-tumor T cell responses contend with ITH over time in HGSC. Previous studies in melanoma and HGSC both showed tumor-reactive T cell clones emerge over time with their cognate tumor-antigens. Therefore, I hypothesized patients would share a common mechanism of T cell evolution to respond to ITH in HGSC. If so, I expect to see similar patterns of tumor recognition between primary and recurrent disease.
Methods: Tumor-associated lymphocytes (TAL) were expanded from primary and recurrent ascites samples using high-dose IL-2 and a rapid-expansion protocol (REP). Following expansion, TAL were assessed for recognition of autologous tumor by IFN-γ ELISPOT and flow cytometry for CD137. CD137+ tumor-reactive TAL were FACS-purified and the tumor-reactive T cell repertoire was profiled by deep sequencing of TCRβ chains (TCRseq). Tumor-reactive TCR clonotypes were compared between primary and recurrent disease to elucidate differences in tumor-reactive populations over time in HGSC.
Results: Patient TAL recognized tumor in two out of three cases. In patient IROC 060, the tumor became more immunogenic between primary and recurrent disease, which may reflect expression of new antigens and/or loss of an immunosuppressive phenotype. In patient IROC 106, the tumor remained immunogenic between primary and recurrent disease, which may reflect maintenance of stable antigen expression and an immune-sensitive phenotype. Patient IROC 034 did not exhibit any tumor-reactivity, suggesting tumor-reactivity is not ubiquitous in HGSC. FACS-purification of CD137+ T cells followed by TCRseq was successfully performed on T cell populations of both high- and low-abundance, suggesting TCRseq can be performed on populations containing very few T cells. TCRseq results that profiled the clonal repertoire of tumor-reactive TAL from primary and recurrent disease in two patients, IROC 060 and IROC 106, showed both patients had evidence of T cell loss and T cell emergence between primary and recurrent disease. Further, IROC 106 had evidence of T cell clones that were maintained between primary and recurrent disease.
Conclusions: Anti-tumor T cell responses from ascites are both diverse between patients and dynamic within a patient, suggesting various mechanisms of T cell evolution to contend with ITH in HGSC. I developed a pipeline for the identification of tumor-reactive TCR sequences without the need for a priori knowledge of specific antigens. Additionally, this pipeline is feasible for very low-abundance samples, such as tumor-reactive T cells.
Significance: This study provides early insights into how TAL contend with ITH in HGSC. Ultimately, these results will inform the design of adoptive T cell therapy for recurrent HGSC.
Advisors/Committee Members: Nelson, Brad H. (supervisor).
Subjects/Keywords: Cancer; Cancer Immunotherapy; Ovarian Cancer; Immunology; Immunotherapy
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Manager
APA (6th Edition):
Little, N. S. (2017). Investigating the co-evolution of tumor antigens and the anti-tumor immune response. (Masters Thesis). University of Victoria. Retrieved from https://dspace.library.uvic.ca//handle/1828/8503
Chicago Manual of Style (16th Edition):
Little, Nicole S. “Investigating the co-evolution of tumor antigens and the anti-tumor immune response.” 2017. Masters Thesis, University of Victoria. Accessed September 19, 2019.
https://dspace.library.uvic.ca//handle/1828/8503.
MLA Handbook (7th Edition):
Little, Nicole S. “Investigating the co-evolution of tumor antigens and the anti-tumor immune response.” 2017. Web. 19 Sep 2019.
Vancouver:
Little NS. Investigating the co-evolution of tumor antigens and the anti-tumor immune response. [Internet] [Masters thesis]. University of Victoria; 2017. [cited 2019 Sep 19].
Available from: https://dspace.library.uvic.ca//handle/1828/8503.
Council of Science Editors:
Little NS. Investigating the co-evolution of tumor antigens and the anti-tumor immune response. [Masters Thesis]. University of Victoria; 2017. Available from: https://dspace.library.uvic.ca//handle/1828/8503
Georgia Tech
10.
Campbell, Elizabeth.
Janus Particles Designed for Cancer Immunotherapy.
Degree: PhD, Biomedical Engineering (Joint GT/Emory Department), 2018, Georgia Tech
URL: http://hdl.handle.net/1853/61676
► Although CD8+ T cells commonly migrate to solid tumors, cancer cells suppress and evade these cells through a variety of intrinsic and extrinsic mechanisms. As…
(more)
▼ Although CD8+ T cells commonly migrate to solid tumors, cancer cells suppress and evade these cells through a variety of intrinsic and extrinsic mechanisms. As a result, recruited cytotoxic T cells are rendered anergic or apoptotic and are thus ineffective at killing cancer cells. Cancer is traditionally treated using chemotherapy, radiation, and surgery; however, these treatments are often unsuccessful alone and are usually used in some combination – resulting in numerous side effects. Bispecific antibody therapy, in which a fusion protein contains antibody regions that target cancer cells and activate immune cells, has shown great promise but only a subset of cancer patients respond to treatment due to lack of avidity and the inflexibility of the design. Our lab has pioneered the engineering and application of a novel particle platform, called Janus particles, in which each particle hemisphere is functionalized specifically such that the particle is capable of two distinct biological functions. Thus the objective of this thesis overall was to develop a Janus particle-based cancer immunotherapeutic strategy that is capable to binding and activating CD8+ T cells while simultaneously targeting cancer cells. We characterized our the ability to activate T cells via biological and mechanical behaviors exhibited by dosed T cells and investigated the effect Janus particles have on eliciting cytotoxicity using 2D and 3D ovarian cancer cultures.
Advisors/Committee Members: Sulchek, Todd (advisor), Botchwey, Edward (advisor), Kwong, Gabe (advisor), Roy, Krish (advisor), Waller, Edmund (advisor).
Subjects/Keywords: Particles; Janus particles; cancer immunotherapy; immunoengineering; immunotherapy
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APA (6th Edition):
Campbell, E. (2018). Janus Particles Designed for Cancer Immunotherapy. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/61676
Chicago Manual of Style (16th Edition):
Campbell, Elizabeth. “Janus Particles Designed for Cancer Immunotherapy.” 2018. Doctoral Dissertation, Georgia Tech. Accessed September 19, 2019.
http://hdl.handle.net/1853/61676.
MLA Handbook (7th Edition):
Campbell, Elizabeth. “Janus Particles Designed for Cancer Immunotherapy.” 2018. Web. 19 Sep 2019.
Vancouver:
Campbell E. Janus Particles Designed for Cancer Immunotherapy. [Internet] [Doctoral dissertation]. Georgia Tech; 2018. [cited 2019 Sep 19].
Available from: http://hdl.handle.net/1853/61676.
Council of Science Editors:
Campbell E. Janus Particles Designed for Cancer Immunotherapy. [Doctoral Dissertation]. Georgia Tech; 2018. Available from: http://hdl.handle.net/1853/61676
University of Hong Kong
11.
Kwok, Yim.
Is immunotherapy effective for asthma prevention? : a
systematic review.
Degree: MPH, 2016, University of Hong Kong
URL: http://hdl.handle.net/10722/237256
► Background: Asthma is a chronic allergic disease causing significant morbidity to patients. Recent studies showed that allergen immunotherapy may be an effective prevention measure for…
(more)
▼ Background: Asthma is a chronic allergic disease
causing significant morbidity to patients. Recent studies showed
that allergen immunotherapy may be an effective prevention measure
for asthma.
Objectives: To assess whether allergen immunotherapy
can effectively lower the incidence of asthma by systematic review
of existing randomized controlled trials
Data sources: A
systematic review of the literature was conducted via Pubmed,
Medline and Embase. Reference lists of related studies and review
articles were also reviewed.
Study eligibility criteria: Studies
were limited to randomized controlled trials conducted in humans,
published in English and whose full articles were accessible
Participants: Subjects without asthma
Intervention: Allergen
immunotherapy
Study appraisal and synthesis methods: The CONSORT
checklist 2010 was used to assess the quality of reporting of the
selected studies, and the Cochrane “Risk of Bias” assessment tool
was used to assess the risk of bias.
Result: Four studies were
included in the final review. The quality of reporting was
generally suboptimal and the assessment of risk of bias was limited
by inadequate information. Lower rates of asthma (0% to 24%) were
observed in the intervention groups compared to the control groups
(9% to 47%), although the results of two studies did not reach
statistical significance, possibly because of inadequate power.
Limitations: Only one reviewer conducted this systematic review.
The number of eligible studies was small. The generalization of the
result to the general population was low because the study
participants had underlying atopic disease.
Conclusion: The
allergen immunotherapy is effective in lowering the rate of asthma
in patients with underlying atopic disease but the strength of
evidence is fair in view of the small number of studies, poor
quality of reporting and unclear risk of bias. It may be considered
in those patients with underlying allergic rhinitis or
rhinoconjunctivitis, after detailed discussion with the patient
about the cost and potential benefit.
published_or_final_version
Public Health
Master
Master of Public Health
Subjects/Keywords: Asthma - Prevention; Immunotherapy
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Manager
APA (6th Edition):
Kwok, Y. (2016). Is immunotherapy effective for asthma prevention? : a
systematic review. (Masters Thesis). University of Hong Kong. Retrieved from http://hdl.handle.net/10722/237256
Chicago Manual of Style (16th Edition):
Kwok, Yim. “Is immunotherapy effective for asthma prevention? : a
systematic review.” 2016. Masters Thesis, University of Hong Kong. Accessed September 19, 2019.
http://hdl.handle.net/10722/237256.
MLA Handbook (7th Edition):
Kwok, Yim. “Is immunotherapy effective for asthma prevention? : a
systematic review.” 2016. Web. 19 Sep 2019.
Vancouver:
Kwok Y. Is immunotherapy effective for asthma prevention? : a
systematic review. [Internet] [Masters thesis]. University of Hong Kong; 2016. [cited 2019 Sep 19].
Available from: http://hdl.handle.net/10722/237256.
Council of Science Editors:
Kwok Y. Is immunotherapy effective for asthma prevention? : a
systematic review. [Masters Thesis]. University of Hong Kong; 2016. Available from: http://hdl.handle.net/10722/237256
University of Otago
12.
Bouwer, Anthea Lynne.
Role of NK cells in DC-based immunotherapy of melanoma
.
Degree: 2011, University of Otago
URL: http://hdl.handle.net/10523/1619
► Natural killer (NK) cells were first identified by their ability to kill tumour or virally infected cells without prior sensitization. In spite of this, the…
(more)
▼ Natural killer (NK) cells were first identified by their ability to kill tumour or virally infected cells without prior sensitization. In spite of this, the actual role of NK cells in tumour
immunotherapy remains controversial. This study therefore set out to investigate the potential of Streptococcus salivarius K12, a gram-positive bacterium that has a history of commercial application as a probiotic in New Zealand, for use as a NK cell adjuvant, applying the therapy using B16.OVA melanoma as a model. To confirm that S. salivarius K12 was able to induce efficient activation of NK cells, I first screened a number of gram-positive and gram-negative bacteria for their ability to induce IFNγ release from NK cells. Using ELISA and fluorescence activated cell sorting (FACS) I found that gram-positive bacteria stimulated a rapid release (<24 hours) of IFNγ from dendritic cell: NK cell co-cultures. Cytotoxicity assays showed that despite optimal activation of NK cells by S. salivarius K12, their cytotoxic activity was not enhanced above that of the naive NK cells. Dissecting NK cells into two subsets based on their CD27 expression using FACS, it was discovered that S. salivarius K12-NK activation was predominantly exerted on the mature CD27high NK cell subset and was dependent on membrane-contact with DC and IL-12/IL-18 expression. NK cell activation was found to be independent of Ly49A expression, a marker that can be used in C57BL/6 mice to discriminate between 'unlicensed' NK cells, and those that had been 'licensed' through interaction with self MHC during development. Therefore having a setting where the addition of S. salivarius K12 activates NK cells, I investigated whether these NK cells were recruited to the draining lymph nodes where they could potentially influence the adaptive immune response. A range of adjuvant-activated and S. salivarius K12-activated DC were injected subcutaneously into the flanks of mice and tested their ability to recruit NK cells to the draining lymph node. The adjuvants differed markedly in their ability to recruit NK cells with S. salivarius K12 being the most effective. To determine if activated NK cells would be of benefit in tumour
immunotherapy, I investigated the ability of bacterially activated DCs to elicit anti-tumour responses in a B16.OVA melanoma model. Utilizing a therapeutic tumour model where treatment was started three days following tumour inoculation, I found a significant delay of tumour growth in mice that were immunized with ovalbumin-pulsed DC that had been treated for 4 hours with S. salivarius K12 as opposed to other adjuvants tested. I also determined that in vivo depletion of NK cells completely abolished the benefit of DC
immunotherapy. A therapeutic tumour experiment where DC were primed in the presence or absence of tumour antigen showed that while NK cells were critical for the antigen-dependent anti-tumour response they did not appear to exert an effector function. To investigate the role of NK cells in priming the anti-tumour response I next utilized a…
Advisors/Committee Members: McLellan, Alexander Donald (advisor).
Subjects/Keywords: NK cells;
immunotherapy
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Manager
APA (6th Edition):
Bouwer, A. L. (2011). Role of NK cells in DC-based immunotherapy of melanoma
. (Doctoral Dissertation). University of Otago. Retrieved from http://hdl.handle.net/10523/1619
Chicago Manual of Style (16th Edition):
Bouwer, Anthea Lynne. “Role of NK cells in DC-based immunotherapy of melanoma
.” 2011. Doctoral Dissertation, University of Otago. Accessed September 19, 2019.
http://hdl.handle.net/10523/1619.
MLA Handbook (7th Edition):
Bouwer, Anthea Lynne. “Role of NK cells in DC-based immunotherapy of melanoma
.” 2011. Web. 19 Sep 2019.
Vancouver:
Bouwer AL. Role of NK cells in DC-based immunotherapy of melanoma
. [Internet] [Doctoral dissertation]. University of Otago; 2011. [cited 2019 Sep 19].
Available from: http://hdl.handle.net/10523/1619.
Council of Science Editors:
Bouwer AL. Role of NK cells in DC-based immunotherapy of melanoma
. [Doctoral Dissertation]. University of Otago; 2011. Available from: http://hdl.handle.net/10523/1619
Victoria University of Wellington
13.
Hunn, Martin Kent.
Improving immunotherapy for high grade glioma.
Degree: 2015, Victoria University of Wellington
URL: http://hdl.handle.net/10063/4869
► Glioblastoma multiforme (GBM) is a malignant primary brain tumour that is almost always fatal. Conventional treatment modalities are limited by toxicity. T cell-based immunotherapy is…
(more)
▼ Glioblastoma multiforme (GBM) is a malignant primary brain tumour that is almost always fatal. Conventional treatment modalities are limited by toxicity. T cell-based
immunotherapy is a promising alternative that has the potential to specifically target tumour cells.
The author of this thesis was a principal investigator for a recently completed Phase I clinical trial in which patients with recurrent GBM were treated with surgery, dendritic cell-based
immunotherapy and chemotherapy. In addition to conducting the trial in collaboration with others, the author used peripheral blood mononuclear cells from trial participants to assess anti-tumour immune responses before and after treatment. A broad correlation was observed between clinical outcome and anti-tumour immunity, with sustained progression-free survival occurring in two patients with baseline responses that persisted or increased after treatment. However, the overall clinical benefit was modest. For progress to be made, there is a need to develop a more potent vaccine.
With this in mind, a novel “Glioma-Gal” vaccine was devised and tested in an orthotopic mouse model of glioma, This simple vaccine consisted of irradiated autologous tumour cells pulsed with the glycolipid alpha-galactosylceramide, an immunoadjuvant that induces invariant Natural Killer T cells to licence endogenous dendritic cells. The vaccine was shown to be effective in a therapeutic setting when accompanied by depletion of regulatory T cells. Mechanistically, vaccine efficacy was dependent on CD4 T cells and the mediastinal lymph node was shown to be an important site of T cell priming. It was further shown that components of the immune system necessary for the vaccine to work were present and competent in a cohort of GBM patients.
The final chapters explore the idea of enhancing the therapeutic benefit of this vaccine by targeting certain tumour cell subsets or phenotypes. Cancer stem cells (CSC) are proposed to be a subset of tumour cells with a unique capacity for initiating and maintaining tumours. Eliminating these cells may therefore be both necessary and sufficient to achieve cure. Using the same mouse model, a variety of methods were assessed for their ability to isolate or enrich for a CSC subset. Of these, culture in serum-free medium in the presence of certain growth factors was shown to enrich for a more stem cell-like phenotype. However, a vaccine constructed from these stem cell-like cells was not more effective than the standard vaccine. Next, the author tested the hypothesis that a vaccine manipulated to target chemoresistant cells would be more effective than standard vaccine when used in combination with chemotherapy. However, the modified vaccine showed no advantage over standard vaccine in this model. In the course of these experiments, synergy was observed between the vaccine and the chemotherapy agent doxorubicin. The mechanism responsible for this supra-additive effect remains undetermined but is most likely due to an immunomodulatory effect of low dose doxorubicin.…
Advisors/Committee Members: Hermans, Ian.
Subjects/Keywords: Glioma; Immunotherapy; Vaccine
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Manager
APA (6th Edition):
Hunn, M. K. (2015). Improving immunotherapy for high grade glioma. (Doctoral Dissertation). Victoria University of Wellington. Retrieved from http://hdl.handle.net/10063/4869
Chicago Manual of Style (16th Edition):
Hunn, Martin Kent. “Improving immunotherapy for high grade glioma.” 2015. Doctoral Dissertation, Victoria University of Wellington. Accessed September 19, 2019.
http://hdl.handle.net/10063/4869.
MLA Handbook (7th Edition):
Hunn, Martin Kent. “Improving immunotherapy for high grade glioma.” 2015. Web. 19 Sep 2019.
Vancouver:
Hunn MK. Improving immunotherapy for high grade glioma. [Internet] [Doctoral dissertation]. Victoria University of Wellington; 2015. [cited 2019 Sep 19].
Available from: http://hdl.handle.net/10063/4869.
Council of Science Editors:
Hunn MK. Improving immunotherapy for high grade glioma. [Doctoral Dissertation]. Victoria University of Wellington; 2015. Available from: http://hdl.handle.net/10063/4869
University of Otago
14.
Win, Stephanie Joy.
Inducing Anti-Tumor Immune Responses with Antigen Conjugated Virus-Like Particles
.
Degree: 2011, University of Otago
URL: http://hdl.handle.net/10523/1733
► Virus-like particles (VLP) have been shown to be useful nanoscale platforms in a diverse range of applications including their use as vaccines. They can act…
(more)
▼ Virus-like particles (VLP) have been shown to be useful nanoscale platforms in a diverse range of applications including their use as vaccines. They can act as vehicles for the delivery of heterologous antigens to the immune system thereby initiating strong anti-tumor responses. Model tumor antigens chemically coupled to rabbit hemorrhagic disease virus VLP (RHDV VLP) have been shown to delay or prevent the development of tumors in vivo using an aggressive model of murine melanoma. RHDV VLP are amenable to conjugation with a range of peptide antigens, single proteins or complex tumor lysates, all of which are relevant for studying immune responses to tumors in mouse models or with human systems in vitro.
Dendritic cells (DC) play a key role in the development of anti-tumor T cell responses due to their ability to take up antigens, process them into peptides and present them to CD8+ T cells on MHC-I by cross-presentation. Inhibitor studies showed RHDV VLP are rapidly taken up by both mouse- and human-derived DC by macropinocytosis and phagocytosis and are subsequently prepared for presentation on MHC-I that has recycled from the cell surface within acidified lysosomal compartments. Additionally, the ability of murine DC to cross-present VLP does not seem to be confined to specific subsets as DC expressing CD8α were able to cross-present VLP-SIINFEKL in vivo, to equivalent levels as other populations of DC.
RHDV VLP conjugated to tumor peptides or lysates do not stimulate phenotypic maturation of the DC required for the cross-priming of naïve T cell responses. The addition of an adjuvant, either OK432 or oncolytic reovirus, to DC pulsed with VLP-MART1 or VLP-Lysates, resulted in phenotypic maturation of DC and enabled the priming of naïve T cells able to produce IFN-γ and directly lyse specific target cells. Furthermore, MART-1 specific MHC-I pentamer staining demonstrated the expansion of CD8+ T cells possessing a TCR specific for MART-1 while the T cells took on a more activated, effector memory phenotype through diminished expression of CD45RA and increased expression of CD45RO and CCR7. Importantly, T cell responses primed using VLP-MART1 or VLP-Lysate with either adjuvant were more pronounced than where MART1 peptide or Lysate was used with that same adjuvant indicating a significant benefit in delivery of antigen on VLP. Collectively, these results indicate that VLP-conjugates, together with adjuvant, have the ability to stimulate cytotoxic T cell responses specifically against tumor cells.
Production of a VLP able to induce DC maturation was attempted by conjugation of melanoma lysates infected previously with oncolytic reovirus to the VLP (VLP-ReoLysate). Results indicate that these VLP-ReoLysate are able to induce activation of innate NK and NKT cells as well as DC. Furthermore, DC pulsed with VLP-ReoLysate resulted in priming of naïve T cells with cytotoxic capabilities against melanoma cells in vitro, however minimal differences were seen where ReoLysates were delivered alone or conjugated to…
Advisors/Committee Members: Baird, Margaret (advisor).
Subjects/Keywords: Virus-Like Particles;
Immunotherapy
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APA ·
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MLA ·
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Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Win, S. J. (2011). Inducing Anti-Tumor Immune Responses with Antigen Conjugated Virus-Like Particles
. (Doctoral Dissertation). University of Otago. Retrieved from http://hdl.handle.net/10523/1733
Chicago Manual of Style (16th Edition):
Win, Stephanie Joy. “Inducing Anti-Tumor Immune Responses with Antigen Conjugated Virus-Like Particles
.” 2011. Doctoral Dissertation, University of Otago. Accessed September 19, 2019.
http://hdl.handle.net/10523/1733.
MLA Handbook (7th Edition):
Win, Stephanie Joy. “Inducing Anti-Tumor Immune Responses with Antigen Conjugated Virus-Like Particles
.” 2011. Web. 19 Sep 2019.
Vancouver:
Win SJ. Inducing Anti-Tumor Immune Responses with Antigen Conjugated Virus-Like Particles
. [Internet] [Doctoral dissertation]. University of Otago; 2011. [cited 2019 Sep 19].
Available from: http://hdl.handle.net/10523/1733.
Council of Science Editors:
Win SJ. Inducing Anti-Tumor Immune Responses with Antigen Conjugated Virus-Like Particles
. [Doctoral Dissertation]. University of Otago; 2011. Available from: http://hdl.handle.net/10523/1733
15.
Hu, Hong-Ming.
Priming of therapeutic T cells for adoptive immunotherapy.
Degree: PhD, 2003, Oregon Health Sciences University
URL: doi:10.6083/M4HX19ZF
;
http://digitalcommons.ohsu.edu/etd/3146
Subjects/Keywords: Immunotherapy; Adoptive
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APA ·
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MLA ·
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to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Hu, H. (2003). Priming of therapeutic T cells for adoptive immunotherapy. (Doctoral Dissertation). Oregon Health Sciences University. Retrieved from doi:10.6083/M4HX19ZF ; http://digitalcommons.ohsu.edu/etd/3146
Chicago Manual of Style (16th Edition):
Hu, Hong-Ming. “Priming of therapeutic T cells for adoptive immunotherapy.” 2003. Doctoral Dissertation, Oregon Health Sciences University. Accessed September 19, 2019.
doi:10.6083/M4HX19ZF ; http://digitalcommons.ohsu.edu/etd/3146.
MLA Handbook (7th Edition):
Hu, Hong-Ming. “Priming of therapeutic T cells for adoptive immunotherapy.” 2003. Web. 19 Sep 2019.
Vancouver:
Hu H. Priming of therapeutic T cells for adoptive immunotherapy. [Internet] [Doctoral dissertation]. Oregon Health Sciences University; 2003. [cited 2019 Sep 19].
Available from: doi:10.6083/M4HX19ZF ; http://digitalcommons.ohsu.edu/etd/3146.
Council of Science Editors:
Hu H. Priming of therapeutic T cells for adoptive immunotherapy. [Doctoral Dissertation]. Oregon Health Sciences University; 2003. Available from: doi:10.6083/M4HX19ZF ; http://digitalcommons.ohsu.edu/etd/3146
Georgia State University
16.
Cacan, Ercan.
Combating the Epigenome: Elucidation of Mechanisms Underlying Chemoresistance and Enhancing Tumor Immunogenicity.
Degree: PhD, Biology, 2015, Georgia State University
URL: https://scholarworks.gsu.edu/biology_diss/156
► Chemotherapy and radiation therapy remain the backbone of cancer treatments, and now cancer immunotherapy offers promising new approaches for the treatment of malignancies. One…
(more)
▼ Chemotherapy and radiation therapy remain the backbone of cancer treatments, and now cancer
immunotherapy offers promising new approaches for the treatment of malignancies. One of the major obstacles for chemo-based therapies is acquired chemoresistance. We find Regulator of G-protein signaling protein (RGS10) is an important regulator of cell survival and chemoresistance in ovarian cancer. Our findings further indicate RGS10 transcript expression is suppressed by DNA hypermethylation and histone deacetylation during acquired chemoresistance in ovarian cancer. We identify two important epigenetic regulators, HDAC1 and DNMT1, which exhibit aberrant association with RGS10 promoters in chemoresistant ovarian cancer cells. Inhibition of DNMT1 or HDAC1 significantly increases RGS10 expression and cisplatin-mediated cell death.
We further focus on modulation of death receptors in advanced colorectal cancer (CRC) cells. We use a combination treatment of irradiation and proteasome inhibition to further induce activation of tumor-specific immune responses. We investigate the effect of the 26S proteasome inhibitor bortezomib alone or in combination with radiotherapy, on the expression of death receptors in normal colon and in colorectal cancer cell lines. Our results indicate a combination of 26S proteasome inhibition and sub-lethal radiation significantly increases the sensitivity of carcinoma cells to apoptosis. Combination treatment up-regulates cell surface expression of DR4, DR5 and Fas by increasing their transcriptional activation. Thus, the combination treatment enhanced sensitivity to killing through FAS and TRAIL receptors by CD8
+ T cells. We further characterized the mechanisms by which radiation controls CRC expression of death receptors. We have shown that sub-lethal irradiation increases expression of our target molecules by enhancing histone acetylation at promoter regions through decreasing binding of HDAC2 and HDAC3, and by DNA hypomethylation, via decreasing binding of DNMT1. In sum, our studies provide insight into the alteration of molecular pathways involved in cancer cell death and survival.
Advisors/Committee Members: Susanna F. Greer, Charlie Garnett-Benson, Timothy L. Denning.
Subjects/Keywords: Chemoresistance; Immunotherapy; Epigenetics; Radiation; Proteasome
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APA (6th Edition):
Cacan, E. (2015). Combating the Epigenome: Elucidation of Mechanisms Underlying Chemoresistance and Enhancing Tumor Immunogenicity. (Doctoral Dissertation). Georgia State University. Retrieved from https://scholarworks.gsu.edu/biology_diss/156
Chicago Manual of Style (16th Edition):
Cacan, Ercan. “Combating the Epigenome: Elucidation of Mechanisms Underlying Chemoresistance and Enhancing Tumor Immunogenicity.” 2015. Doctoral Dissertation, Georgia State University. Accessed September 19, 2019.
https://scholarworks.gsu.edu/biology_diss/156.
MLA Handbook (7th Edition):
Cacan, Ercan. “Combating the Epigenome: Elucidation of Mechanisms Underlying Chemoresistance and Enhancing Tumor Immunogenicity.” 2015. Web. 19 Sep 2019.
Vancouver:
Cacan E. Combating the Epigenome: Elucidation of Mechanisms Underlying Chemoresistance and Enhancing Tumor Immunogenicity. [Internet] [Doctoral dissertation]. Georgia State University; 2015. [cited 2019 Sep 19].
Available from: https://scholarworks.gsu.edu/biology_diss/156.
Council of Science Editors:
Cacan E. Combating the Epigenome: Elucidation of Mechanisms Underlying Chemoresistance and Enhancing Tumor Immunogenicity. [Doctoral Dissertation]. Georgia State University; 2015. Available from: https://scholarworks.gsu.edu/biology_diss/156
University of Plymouth
17.
Goddard, Ruth Victoria.
Generation of in vitro B-cell chronic lymphocytic leukaemia-specific T cell responses using dendritic cells.
Degree: PhD, 2002, University of Plymouth
URL: http://hdl.handle.net/10026.1/2695
► Immunotherapy using dendritic cells has shown encouraging results in both haematological and non-haematological malignancies. In this study, monocyte-derived dendritic cells from patients with B-cell Chronic…
(more)
▼ Immunotherapy using dendritic cells has shown encouraging results in both haematological and non-haematological malignancies. In this study, monocyte-derived dendritic cells from patients with B-cell Chronic Lymphocytic Leukaemia were generated by culture in Interleukin-4 and Granulocyte Macrophage-Colony Stimulating Factor. Lysate-pulsed autologous dendritic cells were used as antigen presenting cells in co-culture with autologous B-cell Chronic Lymphocytic Leukaemia T-cells. B-cell Chronic Lymphocytic Leukaemia T-cells stimulated with B-cell Chronic Lymphocytic Leukaemia lysate-pulsed autologous dendritic cells showed a significant increase in cell surface expression of Interleukin-2 Receptor (CD25), Interferongamma secretion and cytotoxicity against autologous B-cell Chronic Lymphocytic Leukaemia B-cell targets hut not against targets from healthy volunteers. Responses were only stimulated by the B-cell Chronic Lymphocytic Leukaemia B cell lysate. Cytotoxicity was Major Histocompatibility Complex Class II restricted. The addition of maturation agents such as Lipopolysaccharide, Tumour Necrosis Factor-alpha and Polyriboinosinic Polyribocytidylic Acid to monocyte derived dendritic cells was unsuccessful at increasing anti-tumour responses. Pre-treatment of T cells with Interleukin-15 before stimulation by lysate pulsed autologous dendritic cells increased numbers of activated cells, cytokine secretion and specific cytotoxicity to B-cell Chronic Lymphocytic Leukaemia 8-cells. Fusion of monocyte derived dendritic cells and B-cell Chronic Lymphocytic Leukaemia B-cells generated both Major Histocompatibility Complex Class I and Class II restricted cytotoxicity to B-cell Chronic Lymphocytic Leukaemia B-cell targets. When B-cell lysates were analysed using reducing sodium dodecyl sulphate-polyacrylamide gel electrophoresis, a B-cell Chronic Lymphocytic Leukaemia specific hand at 42,000 Dalton and other patient specific bands were observed. Only the 65,000 Dalton and 42,000 Dalton hands were capable of stimulating comparable T cell responses as the whole lysate. The 65,000 Dalton band from normal healthy volunteers showed a dominant peptide that closely matched Human Serum Albumin. The 42,000 Dalton band from B-cell Chronic Lymphocytic Leukaemia patients showed a possible match with Human Actin.
Subjects/Keywords: 616; Immunotherapy
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APA (6th Edition):
Goddard, R. V. (2002). Generation of in vitro B-cell chronic lymphocytic leukaemia-specific T cell responses using dendritic cells. (Doctoral Dissertation). University of Plymouth. Retrieved from http://hdl.handle.net/10026.1/2695
Chicago Manual of Style (16th Edition):
Goddard, Ruth Victoria. “Generation of in vitro B-cell chronic lymphocytic leukaemia-specific T cell responses using dendritic cells.” 2002. Doctoral Dissertation, University of Plymouth. Accessed September 19, 2019.
http://hdl.handle.net/10026.1/2695.
MLA Handbook (7th Edition):
Goddard, Ruth Victoria. “Generation of in vitro B-cell chronic lymphocytic leukaemia-specific T cell responses using dendritic cells.” 2002. Web. 19 Sep 2019.
Vancouver:
Goddard RV. Generation of in vitro B-cell chronic lymphocytic leukaemia-specific T cell responses using dendritic cells. [Internet] [Doctoral dissertation]. University of Plymouth; 2002. [cited 2019 Sep 19].
Available from: http://hdl.handle.net/10026.1/2695.
Council of Science Editors:
Goddard RV. Generation of in vitro B-cell chronic lymphocytic leukaemia-specific T cell responses using dendritic cells. [Doctoral Dissertation]. University of Plymouth; 2002. Available from: http://hdl.handle.net/10026.1/2695
18.
Šilanskas, Mantas.
Oncolytic viruses armed with immunostimulatory genes for cancer treatment.
Degree: Biology Education Centre, 2018, Uppsala UniversityUppsala University
URL: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-353153
► Cancer is a major health burden in modern society, costing millions of lives worldwide and negatively impacting many more. With increasing rates of cancer,…
(more)
▼ Cancer is a major health burden in modern society, costing millions of lives worldwide and negatively impacting many more. With increasing rates of cancer, there is a need for new approaches to its treatment. This is where immunotherapies step in, this a relatively new approach to cancer treatment which caught public’s attention only in recent years. The main goal of these therapies is to enhance and help immune cells to identify and kill tumor cells, thereby initiating the cycle of cancer immunity. In this project LOAd platform viruses were evaluated and compared for their ability to induce oncolysis in cancer cells and ability to produce immunostimulatory molecules. Established LOAd703 virus armed with CD40L and 4-1BBL transgenes was compared to new constructs LOAd732, LOAd780 and LOAd786. All three new viruses are armed with CD40L and 4-1BBL, but also have additional transgenes X, Y and Z, respectively. Specific molecules coded by these transgenes cannot be disclosed at this moment. All viruses demonstrated high competence in oncolysis of A549-lung, T24-bladder and 526-mel melanoma cancer cell lines and were able to express transgenes coding for CD40L and 4-1BBL in all cell lines. New viruses were able to induce expression of new transgenes in infected cells, except for LOAd780 infected cell which had low concentration of protein Y in their supernatants. Also dendritic cells matured using LOAd viruses were able to induce expansion of CMV-specific T cells and a major expansion of natural killer cells.
Subjects/Keywords: Cancer; Virus; Immunotherapy; Immunology; Immunologi
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APA (6th Edition):
Šilanskas, M. (2018). Oncolytic viruses armed with immunostimulatory genes for cancer treatment. (Thesis). Uppsala UniversityUppsala University. Retrieved from http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-353153
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):
Šilanskas, Mantas. “Oncolytic viruses armed with immunostimulatory genes for cancer treatment.” 2018. Thesis, Uppsala UniversityUppsala University. Accessed September 19, 2019.
http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-353153.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Šilanskas, Mantas. “Oncolytic viruses armed with immunostimulatory genes for cancer treatment.” 2018. Web. 19 Sep 2019.
Vancouver:
Šilanskas M. Oncolytic viruses armed with immunostimulatory genes for cancer treatment. [Internet] [Thesis]. Uppsala UniversityUppsala University; 2018. [cited 2019 Sep 19].
Available from: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-353153.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Šilanskas M. Oncolytic viruses armed with immunostimulatory genes for cancer treatment. [Thesis]. Uppsala UniversityUppsala University; 2018. Available from: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-353153
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Saskatchewan
19.
Tomporowski, Jason Scott.
Improving the biological activity of CpG ODN by linking it to carbon nanotubes.
Degree: 2010, University of Saskatchewan
URL: http://hdl.handle.net/10388/etd-01142010-103203
► Preventative immunotherapeutic treatments have been an area of great interest to combat infectious disease because of the ability to stimulate the host’s immune system which…
(more)
▼ Preventative immunotherapeutic treatments have been an area of great interest to combat infectious disease because of the ability to stimulate the host’s immune system which prepares the host to fight pathogenic microbes. The immunotherapeutic approach requires the use of an immune stimulating molecule that is able to boost the host’s immune response. A major problem exists that these immune stimulating molecules are often very expensive and require a large dose to be effective. To reduce the cost of using these molecules, a delivery system can be used which is able to lower the effective dose of the immune stimulant while not causing any toxic effects towards the host’s health. In this study, the immune stimulating molecules synthetic unmethylated cytidine-phosphate-guanosine oligodeoxynucleotides were attached non-covalently to multi-walled carbon nanotubes. The use of carbon nanotubes as a delivery mechanism could result in a lower effective dose able to stimulate a protective immune response in a chicken model. In this study, we first assessed which of the non-covalant linkages was ideal for linking the immune stimulant to the carbon nanotubes. This was conducted by looking at which method of linkage would allow the best cellular proliferation and transcriptional activation of selected innate immune genes. Once an appropriate linkage method had been selected, cellular uptake studies were conducted to establish that cytidine-phosphate-guanosine oligodeoxynucleotides were delivered to intracellular target receptors. After cellular uptake was demonstrated, it was important that the carbon nanotubes linked to the immune stimulant do not cause toxicity towards the host. To measure toxicity, in vitro studies were conducted to observe cell viability post treatment with carbon nanotube linked immune stimulant. Further studies were conducted on any alterations to the immune stimulants’ ability to activate immune cells by studying the pathway of macrophage activation. The protective ability of the molecules was then measured by the ability to protect chickens from a lethal challenge with S. typhimurium. Once the protective nature of the molecules was established, the mechanism of immune stimulation was examined by in vivo cell recruitment and in vitro cytokine production. These studies indicate that linking cytidine-phosphate-guanosine oligodeoxynucleotides to carbon nanotubes can lower the effective dose of the immune stimulant without altering the biological function of the molecule.
Advisors/Committee Members: Aich, Palok, Warrington, Robert, Lee, Jeremy, Khandelwal, Ramji, Gerdts, Volker.
Subjects/Keywords: Carbon nanotube; CpG ODN; immunotherapy
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APA (6th Edition):
Tomporowski, J. S. (2010). Improving the biological activity of CpG ODN by linking it to carbon nanotubes. (Thesis). University of Saskatchewan. Retrieved from http://hdl.handle.net/10388/etd-01142010-103203
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):
Tomporowski, Jason Scott. “Improving the biological activity of CpG ODN by linking it to carbon nanotubes.” 2010. Thesis, University of Saskatchewan. Accessed September 19, 2019.
http://hdl.handle.net/10388/etd-01142010-103203.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Tomporowski, Jason Scott. “Improving the biological activity of CpG ODN by linking it to carbon nanotubes.” 2010. Web. 19 Sep 2019.
Vancouver:
Tomporowski JS. Improving the biological activity of CpG ODN by linking it to carbon nanotubes. [Internet] [Thesis]. University of Saskatchewan; 2010. [cited 2019 Sep 19].
Available from: http://hdl.handle.net/10388/etd-01142010-103203.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Tomporowski JS. Improving the biological activity of CpG ODN by linking it to carbon nanotubes. [Thesis]. University of Saskatchewan; 2010. Available from: http://hdl.handle.net/10388/etd-01142010-103203
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
McMaster University
20.
Afsahi, Arya.
Development of novel chimeric receptors for delivery of costimulation to tumor-reactive engineered T cells.
Degree: MSc, 2015, McMaster University
URL: http://hdl.handle.net/11375/18413
► Introduction: Manipulation of the immune system to eliminate cancer, known as cancer immunotherapy, is an emerging field that has shown impressive clinical success and promise.…
(more)
▼ Introduction: Manipulation of the immune system to eliminate cancer, known as cancer immunotherapy, is an emerging field that has shown impressive clinical success and promise. Adoptive transfer of T cells engineered for tumor reactivity is an avenue of therapy for patients with previously untreatable disease. Our lab has developed a novel chimeric receptor, called a T cell antigen coupler (TAC), which redirects T cell cytotoxicity towards a tumor target. Although considerably effective, this receptor does not provide T cell costimulation necessary for optimal anti-tumor effectiveness.
Methods: We explored two methods to deliver costimulation to TAC-engineered T cells. First, we designed a receptor to be utilized in conjunction with the TAC in a dual receptor system. This chimeric costimulatory receptor (CCR) was generated by fusion of the T cell TIGIT and CD28 receptors. In our second approach, we investigated direct incorporation of costimulatory domains into the TAC design. To do so, we substituted in regions from the CD28 or 4-1BB costimulatory receptors.
Results: Three TIGIT/CD28 chimeras were successfully generated. Of these, two were well surface-expressed on primary human T cells. Despite testing of these receptors in several biological assays, we were unable to confirm functionality of these receptors in transmitting CD28 signals. We next generated the 4-1BB and CD28TAC variants. The 4-1BBTAC was poorly surface-expressed
M.Sc Thesis – Arya Afsahi McMaster University – Medical Sciences
iv
and was difficult to introduce into T cells at high efficiency. The CD28TAC-variant was virtually absent from the T cell surface membrane. Further analysis indicated that the CD28TAC was retained in the endoplasmic reticulum (ER) and the 4-1BBTAC was produced at an extremely low amount.
Conclusions: Our investigation into delivery of costimulation through a novel CCR or TAC receptor was inconclusive. We recommend several optimizations to both receptor design and experimental analysis to further elucidate the potential of these receptors.
Thesis
Master of Science (MSc)
Advisors/Committee Members: Bramson, Jonathan, Medical Sciences (Molecular Virology and Immunology Program).
Subjects/Keywords: Immunology; T cell; Cancer; Immunotherapy
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APA (6th Edition):
Afsahi, A. (2015). Development of novel chimeric receptors for delivery of costimulation to tumor-reactive engineered T cells. (Masters Thesis). McMaster University. Retrieved from http://hdl.handle.net/11375/18413
Chicago Manual of Style (16th Edition):
Afsahi, Arya. “Development of novel chimeric receptors for delivery of costimulation to tumor-reactive engineered T cells.” 2015. Masters Thesis, McMaster University. Accessed September 19, 2019.
http://hdl.handle.net/11375/18413.
MLA Handbook (7th Edition):
Afsahi, Arya. “Development of novel chimeric receptors for delivery of costimulation to tumor-reactive engineered T cells.” 2015. Web. 19 Sep 2019.
Vancouver:
Afsahi A. Development of novel chimeric receptors for delivery of costimulation to tumor-reactive engineered T cells. [Internet] [Masters thesis]. McMaster University; 2015. [cited 2019 Sep 19].
Available from: http://hdl.handle.net/11375/18413.
Council of Science Editors:
Afsahi A. Development of novel chimeric receptors for delivery of costimulation to tumor-reactive engineered T cells. [Masters Thesis]. McMaster University; 2015. Available from: http://hdl.handle.net/11375/18413
University of Illinois – Urbana-Champaign
21.
Harris, Daniel Thomas.
Engineering and characterizing human T cell receptors for cancer immunotherapies.
Degree: PhD, Biochemistry, 2016, University of Illinois – Urbana-Champaign
URL: http://hdl.handle.net/2142/95531
► The T cell receptor (TCR) is an heterodimer that binds to a short peptide bound to a product of the major histocompatibility complex (MHC). The…
(more)
▼ The T cell receptor (TCR) is an heterodimer that binds to a short peptide bound to a product of the major histocompatibility complex (MHC). The chains each contain variable (V) and constant (C) region domains, followed by a transmembrane region. Each V domain contains three loops, called complementarity-determining regions (CDR1, CDR2, and CDR3), which interact with the peptide (pep)MHC antigen. The conserved docking angle of the six CDRs over the pepMHC antigens is thought to confer maximal signaling capabilities and it places the two most hypervariable loops (CDR3s) over the most diverse portion of the antigen (the peptide). Recent adoptive T cell trials have shown promising results using TCRs directed towards pepMHC complexes expressed in various types of malignancies. The process of immunological tolerance leads to the deletion of T cells with TCRs against possible cancer peptide self- antigens. Those TCRs that remain typically do not have the required affinity to mediate a sufficient T cell response. To overcome this, TCRs can be engineered for higher- affinity ex vivo and reintroduced into patient’s peripheral T cells.
In chapter two, a TCR with a switch in peptide specificity was characterized. In previous studies, a TCR called RD1-MART1HIGH was engineered to bind to the cancer peptide MART1/HLA-A2, using libraries of mutants form the parental TCR, which is specific for a viral peptide, Tax/HLA-A2. The switch in peptide specificity was achieved by a limited number of CDR substitutions. To understand which residues contributed to the new peptide specificity and TCR binding, single codon libraries were created at every CDR residue. Libraries were pooled and sorted for binding to MART1/HLA-A2 to produce a sequence fitness landscape, which measured the effect that each individual substitution had on pepMHC binding. The sequence fitness landscape of RD1- MART1HIGH was compared to a sequence fitness landscape of its parent TCR A6 to identify the key residues involved with peptide specificity. Our collaborators (Professor Brian Baker at Notre Dame) solved the structure of the RD1-MART1HIGH TCR/MART1/HLA-A2 complex and this structure showed that the switch in specificity was accomplished by the reorientation of the TCR over the pep/HLA-A2 and the distributed action of many CDR residues. Despite the reorientation of the TCR, RD1- MART1HIGH TCR was able to mediate MART1/HLA-A2-specific activity when introduced into T cells.
In chapter three, I analyzed the enriched mutants from the sequence fitness landscape. Mutants were characterized as individual mutants and combined as double and triple mutants. When combined, the enriched mutations from the sequence fitness landscape were able to increase the affinity of RD1-MART1HIGH by nearly 100-fold. Additionally, the surface expression level on yeast was substantially increased. The enriched mutants were compared to a high-affinity clone of RD1-MART1HIGH isolated from a directed evolution approach.
Chapter four is an analysis of the activity and specificity of two…
Advisors/Committee Members: Kranz, David M (advisor), Kranz, David M (Committee Chair), Roy, Edward J (committee member), Zhang, Kai (committee member), Kalsotra, Auinash (committee member).
Subjects/Keywords: Immunotherapy; T Cell Receptor
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APA (6th Edition):
Harris, D. T. (2016). Engineering and characterizing human T cell receptors for cancer immunotherapies. (Doctoral Dissertation). University of Illinois – Urbana-Champaign. Retrieved from http://hdl.handle.net/2142/95531
Chicago Manual of Style (16th Edition):
Harris, Daniel Thomas. “Engineering and characterizing human T cell receptors for cancer immunotherapies.” 2016. Doctoral Dissertation, University of Illinois – Urbana-Champaign. Accessed September 19, 2019.
http://hdl.handle.net/2142/95531.
MLA Handbook (7th Edition):
Harris, Daniel Thomas. “Engineering and characterizing human T cell receptors for cancer immunotherapies.” 2016. Web. 19 Sep 2019.
Vancouver:
Harris DT. Engineering and characterizing human T cell receptors for cancer immunotherapies. [Internet] [Doctoral dissertation]. University of Illinois – Urbana-Champaign; 2016. [cited 2019 Sep 19].
Available from: http://hdl.handle.net/2142/95531.
Council of Science Editors:
Harris DT. Engineering and characterizing human T cell receptors for cancer immunotherapies. [Doctoral Dissertation]. University of Illinois – Urbana-Champaign; 2016. Available from: http://hdl.handle.net/2142/95531
Boston University
22.
Kim, Susie.
Recent advancements in cancer immunotherapeutics.
Degree: MS, Medical Sciences, 2015, Boston University
URL: http://hdl.handle.net/2144/16217
► Cancer affects a wide range of organs and tissues within the body and epidemiologically is forecasted to affect almost half of the world's population. As…
(more)
▼ Cancer affects a wide range of organs and tissues within the body and epidemiologically is forecasted to affect almost half of the world's population. As an industry, cancer therapeutics represent a booming field. Standard treatment options, however, still heavily rely upon chemotherapeutics developed over fifty years ago. The past decade has seen a huge proliferation of different types of cancer drugs. Recently, an entirely new class of drugs has been unveiled and holds promising results of preventing further relapse incidents. Immunotherapeutics come in many varieties and currently several strategies are under intense investigation. Because these drugs harness the body's own immune system to specifically attack tumor cells, these drugs hold an advantage to current therapeutic options in that they induce notably less severe side effects, facilitating patients' abilities to maintain quality of life. In addition, these drugs potentially hold the promise to cure certain types of cancer, as the body's memory T cells will prevent relapse of the same tumor type. This review will focus on dendritic cell-based therapies, which attempt to program these antigen-presenting cell types to prime T cell responses, checkpoint blockade drugs that inhibit immunosuppression, and neoadjuvants that aim to render the surrounding tumor microenvironment more susceptible for immune attack. In addition, some documented and projected downsides to immunotherapeutics will be discussed, as well as the need to combine multiple modalities in order to create an effective and personalized treatment regimen for cancer patients.
Subjects/Keywords: Medicine; Cancer; Immunotherapy; Review
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APA (6th Edition):
Kim, S. (2015). Recent advancements in cancer immunotherapeutics. (Masters Thesis). Boston University. Retrieved from http://hdl.handle.net/2144/16217
Chicago Manual of Style (16th Edition):
Kim, Susie. “Recent advancements in cancer immunotherapeutics.” 2015. Masters Thesis, Boston University. Accessed September 19, 2019.
http://hdl.handle.net/2144/16217.
MLA Handbook (7th Edition):
Kim, Susie. “Recent advancements in cancer immunotherapeutics.” 2015. Web. 19 Sep 2019.
Vancouver:
Kim S. Recent advancements in cancer immunotherapeutics. [Internet] [Masters thesis]. Boston University; 2015. [cited 2019 Sep 19].
Available from: http://hdl.handle.net/2144/16217.
Council of Science Editors:
Kim S. Recent advancements in cancer immunotherapeutics. [Masters Thesis]. Boston University; 2015. Available from: http://hdl.handle.net/2144/16217
Drexel University
23.
Arhontoulis, Dimitrios C.
Tumor Microenvironment-Responsive Nanogel for Therapeutic Delivery of Interleukin-12.
Degree: 2016, Drexel University
URL: http://hdl.handle.net/1860/idea:6834
► Various forms of immunotherapy have arisen and shown promise in treating cancer. The administration of cytokines such as Interleukin-12 (IL-12) was thought to robustly stimulate…
(more)
▼ Various forms of immunotherapy have arisen and shown promise in treating cancer. The administration of cytokines such as Interleukin-12 (IL-12) was thought to robustly stimulate innate immunity, and increase the number of endogenous tumor specific cytotoxic T-cells. However, patients enrolled in clinical trials involving the administration of IL-12 were reported to have IFNγ toxicity, and suffered from multiple organ system complications and in some instances, death. To address this issue, a tumor microenvironment-responsive nanogel composed of modified hyaluronic acid has been developed. This hypoxia sensitive methacrylated hyaluronic acid (HS- MAHA) aims to actively release IL-12 in the presence of the hypoxic tumor microenvironment, and eliminate the systemic toxicity exhibited in the intravenous administration of recombinant human IL-12. The nanogel has also shown increased degradation in the presence of hyaluronidase, indicating an additional component of tumor microenvironmentsensitivity. The nanogel is able to differentiate CD4+ T-cells into the Th1 Phenotype in vitro, and recruit an increased number of tumor specific cytotoxic T-cells in vivo. The particles have shown sufficient accumulation in the tumor, while avoiding accumulation in the brain, heart, and lungs. Furthermore, the administration of antiPD1 antibody in combination with the nanogel containing IL-12 has shown delayed tumor growth in an aggressive B16-F10 melanoma model.
M.S., Biomedical Engineering – Drexel University, 2016
Advisors/Committee Members: Cheng, Hao.
Subjects/Keywords: Biomedical engineering; Cancer – Immunotherapy; Interleukins
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APA (6th Edition):
Arhontoulis, D. C. (2016). Tumor Microenvironment-Responsive Nanogel for Therapeutic Delivery of Interleukin-12. (Thesis). Drexel University. Retrieved from http://hdl.handle.net/1860/idea:6834
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):
Arhontoulis, Dimitrios C. “Tumor Microenvironment-Responsive Nanogel for Therapeutic Delivery of Interleukin-12.” 2016. Thesis, Drexel University. Accessed September 19, 2019.
http://hdl.handle.net/1860/idea:6834.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Arhontoulis, Dimitrios C. “Tumor Microenvironment-Responsive Nanogel for Therapeutic Delivery of Interleukin-12.” 2016. Web. 19 Sep 2019.
Vancouver:
Arhontoulis DC. Tumor Microenvironment-Responsive Nanogel for Therapeutic Delivery of Interleukin-12. [Internet] [Thesis]. Drexel University; 2016. [cited 2019 Sep 19].
Available from: http://hdl.handle.net/1860/idea:6834.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Arhontoulis DC. Tumor Microenvironment-Responsive Nanogel for Therapeutic Delivery of Interleukin-12. [Thesis]. Drexel University; 2016. Available from: http://hdl.handle.net/1860/idea:6834
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Oxford
24.
Calderon, Hugo.
Investigating the oncolytic properties of a group B adenovirus on cancer cells and its effects on the local immune response.
Degree: PhD, 2017, University of Oxford
URL: http://ora.ox.ac.uk/objects/uuid:da89b317-5f76-4447-bbb1-26740db3b3ef
;
https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.748889
► Oncolytic viruses are characterised by their ability to selectively infect and kill tumour cells. Recently it has emerged that they can exert an additional anticancer…
(more)
▼ Oncolytic viruses are characterised by their ability to selectively infect and kill tumour cells. Recently it has emerged that they can exert an additional anticancer mechanism stimulating adaptive immune-mediated cancer cell killing. Enadenotucirev (EnAd, formerly known as ColoAd1), is a chimeric Ad11p/Ad3 virus group B oncolytic adenovirus that binds CD46 and is under development for the systemic treatment of metastatic carcinomas. The central aim of this thesis was to to assess whether EnAd provides an adjuvant effect on tumour-associated antigen presenting cells (APCs) that could drive TH1 polarisation for an effective anti-tumour immune response. This thesis describes the potent oncolytic properties, fast replication and high numbers of virus progeny production by EnAd in cancer cells. Recombinant EnAd variants were engineered to investigate the roles of the mutant regions in the genome of EnAd, and how these influence the modified phenotype. A chemical drug panel was used to identify pathways and cellular factors involved in cellular production of EnAd, finding that several mTOR inhibitors and microtubule inhibitors could improve virus replication. An in vitro system using partially matured human monocyte-derived dendritic cells (DCs), which displayed a similar phenotype to tumour-infiltrating DCs, was used to explore the effect of EnAd on APC responses. EnAd induced a strong adjuvant effect on these cells by up-regulating surface markers and secretion of pro-inflammatory factors. Further mechanistic experiments, alongside a CAR-binding group C adenovirus 5, indicated these adjuvant effects were virus particle-mediated and dependent on CD46 binding. To understand the functional implications downstream of these interactions, T cell activation and phenotype was assessed using a mixed lymphocyte reaction approach. The data indicated EnAd was a good candidate compared to other adenoviruses, that may steer the response of activated T-cells towards a TH1 phenotype, for an effective immune response. In conclusion, the potent oncolytic properties of EnAd virus may provide an adjuvant effect on tumour-associated APCs, helping to harness an adaptive immune response.
Subjects/Keywords: Oncology; Cancer; Immunotherapy; Oncolytic virus
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APA (6th Edition):
Calderon, H. (2017). Investigating the oncolytic properties of a group B adenovirus on cancer cells and its effects on the local immune response. (Doctoral Dissertation). University of Oxford. Retrieved from http://ora.ox.ac.uk/objects/uuid:da89b317-5f76-4447-bbb1-26740db3b3ef ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.748889
Chicago Manual of Style (16th Edition):
Calderon, Hugo. “Investigating the oncolytic properties of a group B adenovirus on cancer cells and its effects on the local immune response.” 2017. Doctoral Dissertation, University of Oxford. Accessed September 19, 2019.
http://ora.ox.ac.uk/objects/uuid:da89b317-5f76-4447-bbb1-26740db3b3ef ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.748889.
MLA Handbook (7th Edition):
Calderon, Hugo. “Investigating the oncolytic properties of a group B adenovirus on cancer cells and its effects on the local immune response.” 2017. Web. 19 Sep 2019.
Vancouver:
Calderon H. Investigating the oncolytic properties of a group B adenovirus on cancer cells and its effects on the local immune response. [Internet] [Doctoral dissertation]. University of Oxford; 2017. [cited 2019 Sep 19].
Available from: http://ora.ox.ac.uk/objects/uuid:da89b317-5f76-4447-bbb1-26740db3b3ef ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.748889.
Council of Science Editors:
Calderon H. Investigating the oncolytic properties of a group B adenovirus on cancer cells and its effects on the local immune response. [Doctoral Dissertation]. University of Oxford; 2017. Available from: http://ora.ox.ac.uk/objects/uuid:da89b317-5f76-4447-bbb1-26740db3b3ef ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.748889
Cornell University
25.
Chandrasekaran, Siddarth.
Engineering Approaches To Analyze And Target Cancer Invasion And Metastasis
.
Degree: 2015, Cornell University
URL: http://hdl.handle.net/1813/41158
► Metastasis of primary tumor accounts for 90% of all deaths in cancer patients. Interaction between cells in the primary tumor is known to play an…
(more)
▼ Metastasis of primary tumor accounts for 90% of all deaths in cancer patients. Interaction between cells in the primary tumor is known to play an important role in determining the metastatic potential of cancer cells that leave the primary site. Cancer cells that metastasize through the bloodstream invade through the basement membrane surrounding the primary tumor to enter the adjacent blood capillaries. Then, they can evade the host immune response in the circulation and interact with E-selectin on endothelial cells lining the blood vessel wall to exit the circulation and establish at a secondary site. The first focus of my project was to study the effect of homotypic and heterotypic cell-cell interactions on the metastatic potential of cancer cells using a 3D tumor spheroid model. 3D spheroids generated by culturing breast cancer cell lines on polydimethylsiloxane had stronger interaction with E-selectin, increased invasiveness and resistance to apoptosis inducing signals in the circulation when compared to their respective 2D monolayer grown counterparts on tissue culture plate. Cancer cells entering the lymphatic system get lodged within the tumor draining lymph nodes (TDLN), thus contributing to the lymphatic spread of cancer. Natural killer (NK) cells in the TDLN elicit an anti-tumor response by expressing Tumor necrosis factor-[alpha] Related Apoptosis Inducing Ligand (TRAIL) on their surface. TRAIL can bind to death receptors on cancer cells and induce apoptosis. Despite the presence of immunoregulatory NK cells, lymph node metastases are prevalent in several types of cancers. This is because of the abnormalities of NK cells in the TDLN, including reduced count and decreased cytotoxicity. Given the coexistence of cancer cells and NK cells within the TDLN, the second part of this dissertation was focused on demonstrating a nanomedicine-based approach to enhance the therapeutic efficacy of endogenous NK cells by coating them with liposomes functionalized with TRAIL. Human NK cells coated with TRAIL liposomes were able to induce apoptosis in cancer cells cultured in engineered lymph node microenvironments. Liposomes functionalized with TRAIL and an antibody against mouse NK cells were carried to the TDLN and prevented the lymphatic spread of a subcutaneous tumor in mice.
Advisors/Committee Members: Shen,Xiling (committeeMember), Putnam,David A. (committeeMember).
Subjects/Keywords: Cancer Metastasis;
Drug Delivery;
Immunotherapy
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APA (6th Edition):
Chandrasekaran, S. (2015). Engineering Approaches To Analyze And Target Cancer Invasion And Metastasis
. (Thesis). Cornell University. Retrieved from http://hdl.handle.net/1813/41158
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):
Chandrasekaran, Siddarth. “Engineering Approaches To Analyze And Target Cancer Invasion And Metastasis
.” 2015. Thesis, Cornell University. Accessed September 19, 2019.
http://hdl.handle.net/1813/41158.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Chandrasekaran, Siddarth. “Engineering Approaches To Analyze And Target Cancer Invasion And Metastasis
.” 2015. Web. 19 Sep 2019.
Vancouver:
Chandrasekaran S. Engineering Approaches To Analyze And Target Cancer Invasion And Metastasis
. [Internet] [Thesis]. Cornell University; 2015. [cited 2019 Sep 19].
Available from: http://hdl.handle.net/1813/41158.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Chandrasekaran S. Engineering Approaches To Analyze And Target Cancer Invasion And Metastasis
. [Thesis]. Cornell University; 2015. Available from: http://hdl.handle.net/1813/41158
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Vanderbilt University
26.
Dockery, Mary Diana.
Focused Ultrasound for the Generation of Cancer Immunotherapy.
Degree: MS, Biomedical Engineering, 2016, Vanderbilt University
URL: http://etd.library.vanderbilt.edu/available/etd-11212016-145818/
;
► Cancer immunotherapies, which seek to arm the patient’s own immune system for personalized therapy, are a promising option for effective elimination of tumors. Focused ultrasound…
(more)
▼ Cancer immunotherapies, which seek to arm the patient’s own immune system for personalized therapy, are a promising option for effective elimination of tumors. Focused ultrasound (FUS) is one propitious method for generating anti-tumor
immunotherapy, advantageous in its capacity to deliver non-ionizing, non-invasive, tumor-localized treatment; this involves the transdermal deposition of sonic energy at a focal point in the tumor, which induces acute inflammation capable of activating an anti-tumor immune response. Here, we characterize,
in vivo, the early (48 hours) adaptive anti-tumor immune responses induced by FUS treatment of tumors. Compared to untreated tumors, tumors treated with mechanical FUS (mFUS) demonstrated increased NF-κB activation in local and distant tumors. Additionally, a “responder” subset of mFUS-treated mice was identified and mFUS-treated tumors exhibited an increased percent of CD4+ T cells and an increased CD4+/CD8+ T cell ratio, as compared to untreated tumors. Immunohistochemical analysis of CD4+ T cells revealed a higher presence of immunostimulatory phenotypes in mFUS-treated tumors compared to untreated tumors. Taken together, these results suggested a FUS-induced shift towards anti-tumor immune activity.
Advisors/Committee Members: Todd D Giorgio (chair), Charles F Caskey (committee member).
Subjects/Keywords: immunotherapy; focused ultrasound; breast cancer
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APA (6th Edition):
Dockery, M. D. (2016). Focused Ultrasound for the Generation of Cancer Immunotherapy. (Masters Thesis). Vanderbilt University. Retrieved from http://etd.library.vanderbilt.edu/available/etd-11212016-145818/ ;
Chicago Manual of Style (16th Edition):
Dockery, Mary Diana. “Focused Ultrasound for the Generation of Cancer Immunotherapy.” 2016. Masters Thesis, Vanderbilt University. Accessed September 19, 2019.
http://etd.library.vanderbilt.edu/available/etd-11212016-145818/ ;.
MLA Handbook (7th Edition):
Dockery, Mary Diana. “Focused Ultrasound for the Generation of Cancer Immunotherapy.” 2016. Web. 19 Sep 2019.
Vancouver:
Dockery MD. Focused Ultrasound for the Generation of Cancer Immunotherapy. [Internet] [Masters thesis]. Vanderbilt University; 2016. [cited 2019 Sep 19].
Available from: http://etd.library.vanderbilt.edu/available/etd-11212016-145818/ ;.
Council of Science Editors:
Dockery MD. Focused Ultrasound for the Generation of Cancer Immunotherapy. [Masters Thesis]. Vanderbilt University; 2016. Available from: http://etd.library.vanderbilt.edu/available/etd-11212016-145818/ ;
University of California – San Francisco
27.
Williams, Jasper Zee.
Engineering T cells with diverse mechanisms for improved tumor recognition precision.
Degree: Pharmaceutical Sciences and Pharmacogenomics, 2019, University of California – San Francisco
URL: http://www.escholarship.org/uc/item/0zn3g33t
► Engineered T cells are proven cancer therapeutics capable of executing potent antigen-dependent cell killing, and have gained FDA-approval after unprecedented results against certain blood cancers.…
(more)
▼ Engineered T cells are proven cancer therapeutics capable of executing potent antigen-dependent cell killing, and have gained FDA-approval after unprecedented results against certain blood cancers. However, successful treatment of solid tumors has been limited in large part by the lack of targetable antigens that are not also expressed in healthy tissues, as exhibited by ON-target OFF-tumor cross-reactive fatal toxicities seen in various human trials. An advantage of cell-based therapies is that cells can “compute” and execute more sophisticated programs than traditional drugs. Combinatorial antigen recognition has recently been introduced to overcome ON-target OFF-tumor toxicity limitations associated with traditional single antigen-targeted T cell therapies. This dissertation focuses on developing T cell engineering and biomaterials toolkits to expand the capabilities of combinatorial antigen-sensing T cell therapies. First presented is a set of approaches that use synNotch receptors and other synthetic receptors to program T cells with a diverse array of novel combinatorial antigen sensing circuits. It is shown that these Boolean logic-gated synNotch T cells can be engineered to sense both extracellular and intracellular antigens, target up to 3 antigens, integrate positive and negative regulation, and incorporate bispecific receptors. These abilities could enable engineering therapeutic T cells with the ability to target truly tumor-specific antigen combination signatures identified via bioinformatic analysis of antigen expression in cancer versus healthy cells. Also presented is a system to engineer T cells to recognize an orthogonal cue on biocompatible particles and incorporate this detection into combinatorial antigen-sensing circuits to specifically kill antigen positive tumor cells only in the presence of the particles. Using particles to control therapeutic cell activity in the body has the potential to enhance safety by enabling dynamic, local user-control of engineered cells during treatment. Together, the technologies presented here facilitate the development of engineered T cells to safely target a broader range of cancers. The toolkits developed here can be used to engineer T cell therapies to target cancer cells with significantly improved precision by taking advantage of our modern capabilities in cancer informatics, cell engineering, and biomaterials.
Subjects/Keywords: Pharmaceutical sciences; Antigens; Cancer; Immunotherapy
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APA ·
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to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Williams, J. Z. (2019). Engineering T cells with diverse mechanisms for improved tumor recognition precision. (Thesis). University of California – San Francisco. Retrieved from http://www.escholarship.org/uc/item/0zn3g33t
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):
Williams, Jasper Zee. “Engineering T cells with diverse mechanisms for improved tumor recognition precision.” 2019. Thesis, University of California – San Francisco. Accessed September 19, 2019.
http://www.escholarship.org/uc/item/0zn3g33t.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Williams, Jasper Zee. “Engineering T cells with diverse mechanisms for improved tumor recognition precision.” 2019. Web. 19 Sep 2019.
Vancouver:
Williams JZ. Engineering T cells with diverse mechanisms for improved tumor recognition precision. [Internet] [Thesis]. University of California – San Francisco; 2019. [cited 2019 Sep 19].
Available from: http://www.escholarship.org/uc/item/0zn3g33t.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Williams JZ. Engineering T cells with diverse mechanisms for improved tumor recognition precision. [Thesis]. University of California – San Francisco; 2019. Available from: http://www.escholarship.org/uc/item/0zn3g33t
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Toronto
28.
Berinstein, Elliot.
The Development Of A Novel Chimeric Antigen Receptor Specific For Syndecan-1.
Degree: 2016, University of Toronto
URL: http://hdl.handle.net/1807/90143
► The adoptive transfer of T lymphocytes expressing chimeric antigen receptors (CARs) has become a promising treatment for various cancers. CARs have been shown to redirect…
(more)
▼ The adoptive transfer of T lymphocytes expressing chimeric antigen receptors (CARs) has become a promising treatment for various cancers. CARs have been shown to redirect the cytotoxicity of T lymphocytes towards cancerous cells independent of the interactions between T cell receptors and major histocompatibility complexes. Given that CARs tie together an extracellular recognition domain with intracellular signaling domains of immune cells, there exists flexibility in designing CARs specific for different antigens in order to target different malignancies.
Here, we established murine antibodies specific for CD138 with the goal of designing a novel CAR. We designed a 2nd generation CAR using a single chain variable fragment derived from the 3E9B6 monoclonal antibody as the extracellular recognition domain. The expression of the 3E9B6 HL CAR specifically enhanced the cytotoxicity of the NK-92 cell line against CD138+ cells. Downstream activation of ZAP70 in NK-92 3E9B6 HL CAR cells was also dependent on the presence of CD138+ target cells. This work shows that the 3E9B6 HL CAR is functionally able to recognize CD138 and to initiate the CD3Îś activation pathway.
M.Sc.
2018-08-09 00:00:00
Advisors/Committee Members: Medin, Jeffrey A, Medical Biophysics.
Subjects/Keywords: Cancer; Gene Therapy; Immunotherapy; 0992
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APA (6th Edition):
Berinstein, E. (2016). The Development Of A Novel Chimeric Antigen Receptor Specific For Syndecan-1. (Masters Thesis). University of Toronto. Retrieved from http://hdl.handle.net/1807/90143
Chicago Manual of Style (16th Edition):
Berinstein, Elliot. “The Development Of A Novel Chimeric Antigen Receptor Specific For Syndecan-1.” 2016. Masters Thesis, University of Toronto. Accessed September 19, 2019.
http://hdl.handle.net/1807/90143.
MLA Handbook (7th Edition):
Berinstein, Elliot. “The Development Of A Novel Chimeric Antigen Receptor Specific For Syndecan-1.” 2016. Web. 19 Sep 2019.
Vancouver:
Berinstein E. The Development Of A Novel Chimeric Antigen Receptor Specific For Syndecan-1. [Internet] [Masters thesis]. University of Toronto; 2016. [cited 2019 Sep 19].
Available from: http://hdl.handle.net/1807/90143.
Council of Science Editors:
Berinstein E. The Development Of A Novel Chimeric Antigen Receptor Specific For Syndecan-1. [Masters Thesis]. University of Toronto; 2016. Available from: http://hdl.handle.net/1807/90143
29.
O'donnell, Kyle.
Avian IgY As An Immunotherapy For Flaviviral Infections.
Degree: PhD, Biomedical Sciences, 2019, University of North Dakota
URL: https://commons.und.edu/theses/2478
► Flaviviruses compose a group of positive single strand RNA viruses. This group possess 70 individual viruses that cause disease in humans and animals. This…
(more)
▼ Flaviviruses compose a group of positive single strand RNA viruses. This group possess 70 individual viruses that cause disease in humans and animals. This group contains the most prevalent arbovirus dengue virus (DENV) and a recently emerging arbovirus zika virus (ZIKV). Both DENV and ZIKV represent significant world health threats and both viruses, at the moment, are contained to tropical and sub tropical regions due to vector habitat restrictions. DENV can cause severe hemorrhagic fever termed dengue hemorrhagic fever and dengue shock syndrome depending on the extent of vascular permeability. The disease burden attributed to dengue infection is approximately 390 million infections per year. Of these infections, 96 million will result in clinical disease and 500,000 patients require hospitalization resulting in 25,000 deaths a year. ZIKV presents a less severe disease pathology, with a majority of infections in healthy adults being asymptomatic. The more severe infections in adults result in an autoimmune disease called Guillain-Barre syndrome. What caused the world health organization to declare ZIKV a world health emergency in 2016 is the viruses’ ability to transverse the placenta barrier and infect a developing fetus. The most severe symptom associated with in utero infection is the development of microcephaly, which leads to severe cognitive impairment. As case studies expand and the disease pathology of ZIKV is more fully understood a class of symptoms termed congenital zika syndrome fully classifies the extent of cognitive abnormalities induced by this virus. A commonality of these two viruses is that there are no approved treatments for either of these viral infections. A vaccine for DENV was recently introduced, but due to immunological complications it was withdrawn from distribution. A significant issue to combat with the development of therapies for dengue and zika viral infection is the induction of antibody dependent enhancement (ADE). ADE is mediated when cross-reactive low affinity antibodies bind to the virus and are internalized via the FcR on myeloid cells, but do not neutralize the virus resulting in an induction of pro-inflammatory cytokines and increased viral titer. In the studies presented here we hypothesized that the utilization of avian IgY, which does not interact with mammalian Fc receptors, would provide a viable therapy for ZIKV and DENV viral infection. Polyvalent anti-ZIKV IgY was purified from eggs of ZIKV immunized geese. The purified anti-ZIKV IgY preparation was assessed for it’s ability to neutralize ZIKV infection in vitro and in vivo. We also assessed for the ability of polyvalent anti-ZIKV IgY to enhance viral infection in vitro. Our data suggests that anti-ZIKV IgY is able to neutralize ZIKV infection in vitro and in vivo without inducing ADE. Our data also demonstrates novel viral epitopes recognized in our polyvalent anti-ZIKV IgY preparation. Previously our lab had established that polyvalent anti-DENV IgY was able to neutralize ZIKV infection in vitro and in vivo…
Advisors/Committee Members: David S. Bradley.
Subjects/Keywords: Dengue; Flavivirus; IgY; Immunotherapy; Zika
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APA ·
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Export
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APA (6th Edition):
O'donnell, K. (2019). Avian IgY As An Immunotherapy For Flaviviral Infections. (Doctoral Dissertation). University of North Dakota. Retrieved from https://commons.und.edu/theses/2478
Chicago Manual of Style (16th Edition):
O'donnell, Kyle. “Avian IgY As An Immunotherapy For Flaviviral Infections.” 2019. Doctoral Dissertation, University of North Dakota. Accessed September 19, 2019.
https://commons.und.edu/theses/2478.
MLA Handbook (7th Edition):
O'donnell, Kyle. “Avian IgY As An Immunotherapy For Flaviviral Infections.” 2019. Web. 19 Sep 2019.
Vancouver:
O'donnell K. Avian IgY As An Immunotherapy For Flaviviral Infections. [Internet] [Doctoral dissertation]. University of North Dakota; 2019. [cited 2019 Sep 19].
Available from: https://commons.und.edu/theses/2478.
Council of Science Editors:
O'donnell K. Avian IgY As An Immunotherapy For Flaviviral Infections. [Doctoral Dissertation]. University of North Dakota; 2019. Available from: https://commons.und.edu/theses/2478
Victoria University of Wellington
30.
Cameron, Alanna.
Targeted BRAF inhibitors: Immunological effects and combination with immunotherapy.
Degree: 2015, Victoria University of Wellington
URL: http://hdl.handle.net/10063/4937
► Metastatic melanoma is the most aggressive form of skin cancer, associated with a poor prognosis, and the incidence worldwide is increasing. Recently, selective mutant BRAF…
(more)
▼ Metastatic melanoma is the most aggressive form of skin cancer, associated with a poor prognosis, and the incidence worldwide is increasing. Recently, selective mutant BRAF inhibitors and checkpoint blockade
immunotherapy have advanced clinical treatment of metastatic melanoma. However, efficacy of these therapies individually is limited. Combining treatments may allow BRAF inhibition to augment
immunotherapy by increasing tumour antigen availability and improving immune system targeting of tumours. The success of this approach depends upon fully elucidating immunological interactions of BRAF inhibitors, and optimizing combination strategies.
To study the immunological effects of BRAF inhibitors and their combination with
immunotherapy, novel murine BrafV600E Pten-/- Cdkn2a cell lines were characterized. These were found to be moderately sensitive to BRAF inhibition compared with the widely used human BRAFV600E cell lines A375 and SK-mel-5. In vitro targeted BRAF inhibition was shown to induce cell death through apoptosis, and partially reverse melanoma-mediated immunosuppression by human melanoma cell lines.
Utilising subcutaneously injected syngeneic, murine BRAFV600E cell lines, the BRAF inhibitor PLX4720 was shown to decrease tumour growth in vivo. Host immune involvement in BRAF inhibitor efficacy was determined by comparing PLX4720 treatment in NOD/Scid and C57BL/6 mice. PLX4720 control of tumour growth was significantly less effective in immunocompromised mice, resulting in reduced survival advantage. These findings demonstrate that the anti-tumour effects of mutant BRAF inhibitors are partially immune dependent, although the nature of this immune involvement remains to be defined. It was further shown that BRAFV600E inhibition directly affected immune responses. In vitro, both human and murine T cell activation were boosted by low concentrations of mutant BRAF inhibitors. This was confirmed in vivo, with antigen-specific T cell proliferation significantly increased by PLX4720 treatment.
The final chapters of this thesis explored the combination of active
immunotherapy with targeted BRAF inhibition. A vaccine was devised that consisted of irradiated, autologous tumour cells loaded with the adjuvant α-galactosylceramide. This vaccine was shown to be effective in both prophylactic and therapeutic settings in a BRAFV600E melanoma model. Mechanistically, vaccine increased effector T cell responses and decreased frequencies of Tregs. Vaccine efficacy was CD4⁺ T cell-dependent, and did not require CD8⁺ T cells. Combination of vaccine with targeted BRAF inhibition was investigated in different settings. A combination therapy strategy was developed that achieved additive, but not synergistic benefit. Additionally, targeting specific aspects of the tumour microenvironment that may confer tumour resistance to BRAF inhibitor-mediated cell death was investigated. Both depletion of Tregs and inhibition of TNFα were explored, but did not result in a significant improvement in therapy.
In summary, the studies…
Advisors/Committee Members: Berridge, Michael, Herst, Patries.
Subjects/Keywords: Melanoma; Immunotherapy; BRAF inhibitors
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Manager
APA (6th Edition):
Cameron, A. (2015). Targeted BRAF inhibitors: Immunological effects and combination with immunotherapy. (Doctoral Dissertation). Victoria University of Wellington. Retrieved from http://hdl.handle.net/10063/4937
Chicago Manual of Style (16th Edition):
Cameron, Alanna. “Targeted BRAF inhibitors: Immunological effects and combination with immunotherapy.” 2015. Doctoral Dissertation, Victoria University of Wellington. Accessed September 19, 2019.
http://hdl.handle.net/10063/4937.
MLA Handbook (7th Edition):
Cameron, Alanna. “Targeted BRAF inhibitors: Immunological effects and combination with immunotherapy.” 2015. Web. 19 Sep 2019.
Vancouver:
Cameron A. Targeted BRAF inhibitors: Immunological effects and combination with immunotherapy. [Internet] [Doctoral dissertation]. Victoria University of Wellington; 2015. [cited 2019 Sep 19].
Available from: http://hdl.handle.net/10063/4937.
Council of Science Editors:
Cameron A. Targeted BRAF inhibitors: Immunological effects and combination with immunotherapy. [Doctoral Dissertation]. Victoria University of Wellington; 2015. Available from: http://hdl.handle.net/10063/4937
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. 
Open Access Theses and Dissertations
