Accumulating correlative evidence suggests that the clinical responses observed in some patients with cancer after treatment with checkpoint inhibitors or adoptive T-cell therapy are mediated by T cells that target cancer mutations. More direct evidence that mutation-reactive T cells can mediate antitumor activity in humans was recently demonstrated in a patient with metastatic cholangiocarcinoma who experienced tumor regression after receiving a highly enriched population CD4+ T cells targeting a mutation in the ERBB2IP protein uniquely expressed by her cancer. Thus, strategies to identify and harness the mutation-reactive T-cell response may provide clinical benefit to some patients with cancer. To this end, we used a next-generation sequencing approach combined with high-throughput immunologic screening and found that tumor-infiltrating lymphocytes (TIL) from 29/32 patients with metastatic gastrointestinal (GI) cancers contained CD4+ and/or CD8+ T cells that recognized at least one neoepitope derived from somatic mutations expressed by the patient's own tumor. Most of the immunogenic mutations were unique and patient specific, however we also identified HLA-C*08:02-restricted CD8+ T cells from two patients with colorectal cancer that targeted the KRASG12D hotspot driver mutation found in many human cancers. Treatment of one of these patients with ~1.1 x 1011 KRASG12D-reactive T cells led to the regression of all metastatic lesions, but one lesion progressed 9 months after therapy. This lesion was resected and found to have loss of the chromosome 6 haplotype that encoded the HLA-C*08:02 allele thereby providing the tumor with a direct mechanism of immune escape from the transferred HLA-C*08:02-restricted KRASG12D-reactive T cells. The treatment of ten additional patients with variable frequencies of TIL targeting predominantly one patient-specific mutation has been largely ineffective. Thus, TIL therapy targeting somatic mutations can mediate tumor regression in some patients with metastatic GI cancers but most patients have not responded. We are currently investigating strategies to enhance the efficacy of T-cell transfer therapy against cancer mutations.
Citation Format: Eric Tran. T-cell transfer therapy targeting somatic mutations in human gastrointestinal cancers. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr IA27.