Abstract 3146: T cell therapy targeting a neoantigen reducesin vivotumour growth

T-cell receptor (TCR) transfer is an attractive strategy to increase the number of cancer-specific T cells in adoptive cell therapy. However, recent clinical and pre-clinical findings indicate that careful consideration of the target antigen is required to avoid on-target, off-site toxicity. A safer alternative to targeting tumour-associated self-antigens may be to direct engineered T cells against mutated proteins such as frequently occurring frameshift mutations. Furthermore, such frameshift mutations result in novel polypeptides allowing selection of TCRs from the non-tolerant T-cell repertoire circumventing the problem of low affinity TCRs due to central tolerance. The transforming growth factor β Receptor II frameshift mutation (TGFβRIImut) is found in Lynch syndrome cancer patients and in around 15% of sporadic colorectal and gastric cancers displaying microsatellite instability. The -1A mutation within a stretch of 10 adenine bases (nucleotides 709-718) of the TGFβRII gene gives rise to immunogenic peptides previously used for vaccination of MSI+ colorectal cancer patients in a Phase I clinical trial. From a clinically responding patient we isolated a CD8neg/CD4neg CTL clone from which we cloned an HLA-A2-restricted TGFβRIImut-specific TCR. We showed that both CD8+ and CD4+ T cells transiently redirected with this TGFβRIImut-TCR recognised colon carcinoma cell lines harbouring the frameshift mutation, indicating CD8+ co-receptor independency. Cysteine modification of the TCR enhanced its expression and function and we have demonstrated that these TCR-redirected T cells significantly enhanced survival and reduced tumour growth in a NOD/SCID xenograft mouse model of colorectal cancer. Citation Format: Else M. Inderberg-Suso, Sebastien Walchli, Marit R. Myhre, Mengyu Wang, Hilde Almasbak, Gunnar Kvalheim, Gustav Gaudernack. T cell therapy targeting a neoantigen reduces in vivo tumour growth. [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 3146. doi:10.1158/1538-7445.AM2015-3146