This was a study prospectively evaluating intratumoral T-cell responses to autologous somatic mutated neoepitopes expressed by human metastatic ovarian cancers. Tumor-infiltrating lymphocytes (TIL) 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 and then cocultured with TIL fragment cultures. Secretion of IFNγ or upregulation of 41BB indicated a T-cell response. Seven women with metastatic ovarian cancer were evaluated， and 5 patients had clear， dominant T-cell responses to ... More
This was a study prospectively evaluating intratumoral T-cell responses to autologous somatic mutated neoepitopes expressed by human metastatic ovarian cancers. Tumor-infiltrating lymphocytes (TIL) 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 and then cocultured with TIL fragment cultures. Secretion of IFNγ or upregulation of 41BB indicated a T-cell response. 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 with 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 "hotspot" mutations (c.659A>G; p.Y220C and c.733G>A; p.G245S) expressed by two different patients' tumors were both immunogenic in the context of HLA-DRB3*02:02. Mutation-reactive T cells infiltrated ovarian cancer metastases at sufficient frequencies to warrant their investigation as adoptive cell therapy. In addition， transfer of "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.
