391. Mutated Tumor Neoantigens Are Recognized by Tumor Infiltrating Lymphocytes from Metastatic Ovarian Cancer

Abstract

Somatic mutations expressed by the tumor can serve as neoantigens for autologous T cells. Tumor infiltrating lymphocytes (TIL) with varying degrees of neoantigen-reactivity infused for the treatment of melanoma resulted in 50% overall objective response and 20% complete response rates. A largely oligoclonal population of ERBB2IPE805G mutated neoantigen-specific T cells resulted in a long-term, ongoing partial regression of metastatic cholangiocarcinoma suggesting that infusion of selected mutation-reactive TIL could be efficacious in the treatment of common epithelial cancers. We now studied whether TIL obtained from metastatic ovarian cancer recognized tumor mutations. Exome and transcriptome sequencing was performed from resected metastatic ovarian cancer deposits in parallel with growth of TIL fragment cultures in interleukin-2. Long peptides and tandem minigenes encompassing all mutations were synthesized, introduced into autologous antigen presenting cells, co-cultured with individual TIL fragments and T-cell reactivity was determined by interferon-y ELISPOT and surface expression of 41BB. In the 8 ovarian tumors evaluated, there was a median of 227 mutations (range: 63-332) and an average of 94% of 24 fragments initiated (range: 58% - 100%) available for testing. Six of eight (75%) patients had T cell responses to mutated neoantigens at >5% of the fragment culture. Antigens identified to date were unique to each patient, i.e. no overlapping mutations between patients, and both CD4 and CD8 responses have been detected. One patient had a CD4 T cell response to p53G245S hotspot mutation, which opens opportunities for treatment of other cancer patients with TCR-transduced T cells because this mutation is present in 2.8% of all cancers. The average time from resection to identification of mutation-reactive T cell fragment culture was 8 weeks indicating that this strategy could be used for prospective therapy. In summary, mutation-specific T-cell responses were found in 6 of 8 patients with metastatic ovarian cancer, which opens the opportunity to use these cells for adoptive T cell treatment of advanced ovarian cancer.