Abstract 3587: TCR-transduced T cells targeting a truncal mutation caused by a nsSNV destroy large solid tumors despite intratumoral genetic heterogeneity

Most if not all cancers have individually specific, so-called unique antigens that we discovered in 1995 to be caused by somatic tumor-specific, non-synonymous single nucleotide substitutions, now usually referred to as nsSNVs, and we showed already then that adoptive transfer of nsSNV-specific T cells has specific anti-cancer effects (Monach P. et al. Immunity 2:45-59, 1995). With the rapid advances in sequencing technologies, these antigens, now generally also called "mutant neoantigens", have been discovered on all primary cancers examined in the past decade, human or experimental, (unless a cancer was the result of artificial genetic engineering). The number of somatic mutations, mostly nsSNVs, differs widely between cancers and tumor types. Importantly however, even patients bearing cancers with a low mutational burden usually have 12 different HLA alleles to possibly present a given mutant peptide as antigen to T cells. Since most mutations in cancers are individually patient-specific, a truly personalized, i.e., patient-specific therapy is required. Encouragement for investing into developing such an approach comes from our recent studies in which we show that a single type of T cell receptor (TCR) targeting a single cancer-specific point mutation, i.e. nsSNV-encoded mutant peptide, can eradicate large solid tumors when the mutation-specific TCR is transduced into peripheral T cells and adoptively transferred (Leisegang, M. et al. Clin. Cancer Res. 22: 2734-43 2016). Here, we examine the relative influence of mutant antigen expression level, intratumoral heterogeneity as well as competence of the transferred mutation-specific T cells on escape of the cancer from therapy using adoptive transfer of T cells specific for a given mutation. The importance and mechanisms of bystander killing in cancer escape will also be discussed and the importance of cross-presentation of the neoantigen by the tumor stroma will be examined. Together, our current studies are consistent with the notion that adoptive transfer of T cells transduced with TCRs recognizing nsSNV-encoded peptides may provide a novel and potentially extremely powerful completely cancer-specific approach in patients with established solid tumors. In addition, the concept should be applicable to most cancer patients, if efforts are made to truly individualize cancer therapy. This requires focus on identifying the set of patient-specific nsSNV and the set of 12 patient-specific MHCI and MHCII that are available to potentially present the mutant peptides of a given patient9s cancer as targets for tumor destruction. Supported by NIH grants R01-CA22677 and R01-CA37156, the Cancer Research Foundation, a collaborative research grant by the Berlin Institute of Health and the Einstein-Stiftung Berlin. Citation Format: Matthias Leisegang, Karin Schreiber, Steven P. Wolf, Vasiliki Anastosopolou, Kimberley Borutta, PohYin Yew, Kazuma Kiyotani, Yusuke Nakamura, Hans Schreiber. TCR-transduced T cells targeting a truncal mutation caused by a nsSNV destroy large solid tumors despite intratumoral genetic heterogeneity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3587.