UBC Theses and Dissertations
Identifying and targeting immunogenic mutations in ovarian cancer Martin, Spencer David
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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