T-cell Responses to TP53 “Hotspot” Mutations and Unique Neoantigens Expressed by Human Ovarian Cancers

Abstract

COUNTS Statement of Translational RelevanceThis study demonstrated that T cells with specificity to mutated neoantigens were present in tumor infiltrating lymphocytes in patients with metastatic ovarian cancer, sometimes at high frequencies and with multivalent reactivity, suggesting that these T cells could be used for adoptive cell therapy. Furthermore, T cells from two of the patients were specific for TP53 "hotspot" mutations (c.659A>G; p.Y220C and c.733G>A; p.G245S), which are also expressed in a broad range of tumor types in unrelated individuals. Genetic transfer of the TP53 "hotspot" mutation-specific T-cell receptors into autologous lymphocytes could be used to generate cells for use in the adoptive cell transfer immunotherapy of cancer.Research. Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 31, 2018; DOI: 10.1158/1078-0432.CCR-18-0573 3 AbstractPurpose: This was a study prospectively evaluating intratumoral T-cell responses to autologous somatic mutated neoepitopes expressed by human metastatic ovarian cancers.Experimental Design: Tumor infiltrating lymphocytes (TILs) were expanded from resected ovarian cancer metastases, which were analyzed by whole exome and transcriptome sequencing to identify autologous somatic mutations. All mutated neoepitopes, independent of prediction algorithms, were expressed in autologous antigen presenting cells then co-cultured with TIL fragment cultures. Secretion of interferon-gamma or up-regulation of 41BB indicated a T-cell response.Results: Seven women with metastatic ovarian cancer were evaluated and 5 patients had clear, dominant T-cell responses to mutated neoantigens, which were corroborated by comparison to the wild type sequence, identification of the minimal epitope, human leukocyte antigen (HLA) restriction element(s) and neoantigen-specific T-cell receptor(s). Mutated neoantigens were restricted by HLA-B, -C, -DP, -DQ and/or -DR alleles and appeared to principally arise from random, somatic mutations unique to each patient. We established that TP53 "hotspot" mutations (c.659A>G; p.Y220C and c.733G>A; p.G245S) expressed by two different patient's tumors were immunogenic both in the context of HLA-DRB3*02:02.Conclusions: Mutation-reactive T cells infiltrated ovarian cancer metastases at sufficient frequencies to warrant their investigation as adoptive cell therapy. Additionally, transfer of TP53 "hotspot" mutation-reactive T-cell receptors into peripheral blood T cells could be evaluated as a gene therapy for a diverse range of tumor histologies.Research.on April 28,

Comprehensive genomic profiling of high‐grade serous ovarian carcinoma from Chinese patients identifies co‐occurring mutations in the Ras/Raf pathway with TP53

“…Hemotoxylin and eosin staining of HGSOC tumors from these three individuals were attached in . Although no targeted therapies are yet available for these TP53 mutations, in a recent study, tumor infiltrating T‐cell responses to two TP53 hotspot mutations G245S and Y220C were identified in the context of HLA‐DRB3*02:02 in two separate ovarian cancer patients . Among the tumors sequenced in this cohort, five harbored the TP53 Y220C mutation and one had the G245S mutation.…”

“…Although no targeted therapies are yet available for these TP53 mutations, in a recent study, tumor infiltrating T-cell responses to two TP53 hotspot mutations G245S and Y220C were identified in the context of HLA-DRB3*02:02 in two separate ovarian cancer patients. 20 Among the tumors sequenced in this cohort, five harbored the TP53 Y220C mutation and one had the G245S mutation. Although HLA typing was not performed for this cohort, HLA-DRB3*02:02 had over 22% population frequency among the Chinese population in the US.…”

T cell receptor‐based cancer immunotherapy: Emerging efficacy and pathways of resistance

“…Although previously thought to be rare, the number of identified public neoantigens has rapidly increased in recent years. These include public neoantigens associated with common driver oncogenes, such as KRAS, BRAF, beta‐catenin, CDK4, H3.3K27M, and IDH1 as well as tumor suppressor genes, like TP53 . Whether immunogenic epitopes can be discovered for the 119 other known driver oncogenes remains an area of active investigation.…”

“…These include public neoantigens associated with common driver oncogenes, such as KRAS, 11,18,206,207 BRAF, 170 beta-catenin, 198 CDK4, 208,209 H3.3K27M, 210 and IDH1 211 as well as tumor suppressor genes, like TP53. 212,213 Whether immunogenic epitopes can be discovered for the 119 other known driver oncogenes 214 have provided in vivo evidence that infusion of public neoantigenspecific T cells can be associated with durable cancer regression in humans. 11,170 Notwithstanding these exciting findings, it remains the case that most cancer neoantigens are privately held by individual patients.…”

Adoptive Cell Therapy—Harnessing Antigen-Specific T Cells to Target Solid Tumours

“…Neoantigen-specific T cells can be identified in patients not only with melanoma, but also with epithelial cancers, such as lung cancer [119,120], gastrointestinal cancer [121][122][123], ovarian cancer [124][125][126], breast cancer [127] and pancreatic cancer [128]. Case reports have demonstrated that treatment of the gastrointestinal and breast cancer patients with a T cell population highly enriched in neoepitope-specific T cells caused tumour regression [121,123,127].…”