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UBC Theses and Dissertations
Identifying and targeting immunogenic mutations in ovarian cancer Martin, Spencer David
Abstract
A hallmark of cancer is the accumulation of mutations, and a small proportion of these give rise to mutant neoantigens – mutated peptides bound to Major Histocompatibility Complex (MHC) and recognized by T cells. Accumulating evidence suggests that mutant neoantigens (hereafter referred to as “neoantigens”) underlie successful immune therapies in cancers with high mutation loads, such as melanoma. Moreover, neoantigen-specific vaccines have successfully targeted highly mutated murine tumor models. However, less is known about neoantigen-specific T cell responses in cancers with moderate mutation loads, such as ovarian cancer. I hypothesized that (1) modified peptide-based vaccination schedules can lead to enhanced antigen-specific T cell responses; (2) neoantigen-specific vaccines can elicit T cell responses that eradicate murine ovarian tumors; and (3) neoantigen-reactive T cells are detectable in human ovarian tumors and peripheral blood. To activate high frequencies of antigen-specific T cells, I developed a vaccination method involving repeated, daily immunizations with long peptides and adjuvant. This method elicited robust T cell responses that eliminated established murine tumors. I used these enhanced vaccination methods to target tumor-specific mutations identified by exome- and RNA-sequencing of the ovarian tumor model ID8-G7. Prophylactic and therapeutic vaccinations were performed targeting all expressed mutations that had a predicted MHCI binding affinity < 1500 nM (n=17 mutations). Though the vaccines elicited robust T cell responses to most mutations, activated T cells failed to recognize ID8-G7 tumors in vitro and failed to control tumor growth in vivo, indicating that none of the evaluated mutations represented authentic neoantigens. I also investigated the neoantigen-specific T cell repertoire in blood and tumor samples donated by an ovarian cancer patient. A neoantigen-specific T cell response was identified in the first recurrence tumor sample, and a derived T cell clone recognized tumor from each of three time points. Furthermore, peripheral blood samples donated prior disease recurrence harbored T cells recognizing the same mutation. The results presented here show that neoantigen-specific T cells can arise spontaneously in ovarian tumors and are detectable in peripheral blood; however, low mutation burdens in ovarian cancer may limit the utility of neoantigen-targeted vaccines to a minority of patients with this disease.
Item Metadata
Title |
Identifying and targeting immunogenic mutations in ovarian cancer
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Creator | |
Publisher |
University of British Columbia
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Date Issued |
2016
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Description |
A hallmark of cancer is the accumulation of mutations, and a small proportion of these give rise to mutant neoantigens – mutated peptides bound to Major Histocompatibility Complex (MHC) and recognized by T cells. Accumulating evidence suggests that mutant neoantigens (hereafter referred to as “neoantigens”) underlie successful immune therapies in cancers with high mutation loads, such as melanoma. Moreover, neoantigen-specific vaccines have successfully targeted highly mutated murine tumor models. However, less is known about neoantigen-specific T cell responses in cancers with moderate mutation loads, such as ovarian cancer. I hypothesized that (1) modified peptide-based vaccination schedules can lead to enhanced antigen-specific T cell responses; (2) neoantigen-specific vaccines can elicit T cell responses that eradicate murine ovarian tumors; and (3) neoantigen-reactive T cells are detectable in human ovarian tumors and peripheral blood. To activate high frequencies of antigen-specific T cells, I developed a vaccination method involving repeated, daily immunizations with long peptides and adjuvant. This method elicited robust T cell responses that eliminated established murine tumors. I used these enhanced vaccination methods to target tumor-specific mutations identified by exome- and RNA-sequencing of the ovarian tumor model ID8-G7. Prophylactic and therapeutic vaccinations were performed targeting all expressed mutations that had a predicted MHCI binding affinity < 1500 nM (n=17 mutations). Though the vaccines elicited robust T cell responses to most mutations, activated T cells failed to recognize ID8-G7 tumors in vitro and failed to control tumor growth in vivo, indicating that none of the evaluated mutations represented authentic neoantigens. I also investigated the neoantigen-specific T cell repertoire in blood and tumor samples donated by an ovarian cancer patient. A neoantigen-specific T cell response was identified in the first recurrence tumor sample, and a derived T cell clone recognized tumor from each of three time points. Furthermore, peripheral blood samples donated prior disease recurrence harbored T cells recognizing the same mutation. The results presented here show that neoantigen-specific T cells can arise spontaneously in ovarian tumors and are detectable in peripheral blood; however, low mutation burdens in ovarian cancer may limit the utility of neoantigen-targeted vaccines to a minority of patients with this disease.
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Genre | |
Type | |
Language |
eng
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Date Available |
2017-05-31
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Provider |
Vancouver : University of British Columbia Library
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Rights |
Attribution-NonCommercial-NoDerivatives 4.0 International
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DOI |
10.14288/1.0304879
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URI | |
Degree | |
Program | |
Affiliation | |
Degree Grantor |
University of British Columbia
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Graduation Date |
2016-09
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Campus | |
Scholarly Level |
Graduate
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Rights URI | |
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DSpace
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Rights
Attribution-NonCommercial-NoDerivatives 4.0 International