Abstract 4704: Neo-antigen enriched TIL therapy mediates superior tumor eradication in a patient-derived xenograft model of human melanoma

Abstract

Abstract The mutational load in melanoma is high relative to that in most other human malignancies, resulting in the possible expression of large numbers of patient-specific mutated antigens. This may, in part, explain the immunogenicity of this disease and the high rate of responsiveness to immunotherapeutic strategies such as tumor-infiltrating lymphocyte (TIL) therapy. Indeed, recent data have shown that cytotoxic T-cell reactivity targeting neo antigens may be common in human melanoma TILs. Importantly though, the clinical relevance of neo-antigen specific T cell populations remains uncertain. To directly address the tumoricidal potential of defined neo-antigen specific T cell populations, we first identified two neo-antigen specific T-cell populations within a bulk melanoma TIL culture by the combination of exome sequencing and MHC multimer-based T cell screens. Subsequently, we generated TIL products that are highly enriched for these neo-antigen reactivities and we compared the anti-tumor activity of these neo-antigen enriched TIL with that of ‘standard’ bulk TIL in NSG mice bearing the autologous tumor. We observed outgrowth of the tumors in mice treated with standard TIL. In contrast, tumors in mice treated with enriched TILs were controlled long-term. Additional experiments showed that this superior activity of neo-antigen enriched TIL was caused by the increased numbers of T cells with a high anti-tumor activity, rather than the depletion of cell populations with inhibitory activity. Furthermore, once tumors eventually recurred these were still recognized in vitro by cells from the initially infused TIL culture. Together, these preclinical data demonstrate that neo-antigen reactive T cells within bulk TIL cultures form a critical component of anti-tumor reactivity and provide a further basis to target mutated antigens with cancer immunotherapy. Citation Format: Sander Kelderman, Laura Bies, Marit M. Van Buuren, Nienke Van Rooij, John Haanen, Pia Kvistborg, Ton Schumacher. Neo-antigen enriched TIL therapy mediates superior tumor eradication in a patient-derived xenograft model of human 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 4704. doi:10.1158/1538-7445.AM2015-4704