Abstract LB-221: Diversity of tumor infiltrating lymphocyte recognition of diverse mutated antigens in cutaneous melanoma

Abstract

Abstract The adoptive transfer of autologous tumor infiltrating lymphocytes (TIL) can mediate long term tumor regression in some patients with metastatic melanoma. Recent observations suggest that autologous melanoma TIL administered to patients in adoptive T cell therapy (ACT) protocols may frequently recognize multiple tumor-specific somatic mutations, findings that have been facilitated by advances in whole exome sequencing and RNAseq methods. In an attempt to evaluate the antigenic diversity of TIL and gain some insights into the potential association between the recognition of mutated antigens and clinical responses to TIL therapy, we analyzed between 7 and 30 individual cultures derived from resected melanoma tumor fragments and pooled populations of administered TIL from each of 5 patients for their ability to recognize mutated antigens expressed by patients’ autologous tumors. Two of the patients who were evaluated exhibited durable complete tumor regressions, 1 exhibited a partial response, and 2 were non-responders to ACT. Screening assays were carried out by evaluating the interferon gamma release stimulated by the co-culture of autologous patient TIL with autologous dendritic cells or EBV transformed B cells transfected with mini-genes encoding mutated antigens identified by exomic sequencing of patient tumors. Using this approach, we identified 10, 3, and 2 mutated antigens targeted by TIL from the 3 patients who responded to ACT. The TIL that were administered to 1 of the non-responders appeared to recognize at least 4 mutated antigens, whereas TIL administered to the second non-responder failed to recognize any of the mutated minigenes that were tested. Immuno-dominant mutated antigens that were recognized by the majority of the evaluated TIL fragment cultures, as well as the bulk population of infusion TIL, could be identified in each of the 4 patients in this study for whom mutated antigen targets could be identified. In addition, 1 or more sub-dominant mutated antigens that were recognized by one or a relatively small percentage of the screened TIL fragment cultures were identified from each of these same 4 patients. Future studies will be directed at developing methods for enriching T cells reactive with mutated epitopes from TIL or peripheral blood in an attempt to enhance the effectiveness of ACT for the treatment of patients with metastatic melanoma and that will hopefully lead to the development of effective therapies for the treatment of patients with other malignancies. Note: This abstract was not presented at the meeting. Citation Format: Jessica S. Crystal, Todd Prickett, Yong-Chen Lu, Jared J. Gartner, Maria Parkhurst, Alena Gros, Yong F. Li, Mona El-Gamil, Steven A. Rosenberg, Paul F. Robbins. Diversity of tumor infiltrating lymphocyte recognition of diverse mutated antigens in cutaneous melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-221. doi:10.1158/1538-7445.AM2015-LB-221