Abstract IA15: T-Cells targeting mutated RAS—clinical trials

Abstract

Abstract Durable complete regressions of metastatic cancers can be achieved by the transfer of in vitro expanded tumor-reactive T-cells. In patients with melanoma, this can be done by giving tumor-infiltrating lymphocytes (TIL) reactive with tumor-specific mutated antigens (“neoantigens”). Unfortunately, the vast majority of immunogenic neoantigens have been shown to be totally patient specific. One exception is that T cells recognizing mutated KRAS have been found in the TIL of multiple patients. In one patient with G12D-mutated colon cancer, these cells were grown and administered to that patient (after a course of preparative immunosuppression) and mediated regression of multiple pulmonary metastases. A single lesion that had lost its presenting MHC Class I allele grew and was resected, and the patient remains disease free over 2 years later. Other patients have demonstrated additional Class I and Class II presented epitopes from mutated RAS, although they have not yet been administered clinically. In an effort to develop standardized reagents to target common RAS mutations, HLA-A11 transgenic mice were immunized with peptides containing G12D and G12V RAS mutations and HLA-A11 restricted T cells isolated. Murine T-cell receptors specific for these mutated epitopes were cloned and when retrovirally introduced into human PBL, they conferred recognition of mutated RAS but not wild-type RAS. Such cells could cause regression of established palpable pancreatic cancer xenografts in NSG mice. Two clinical trials targeting the G12D and G12V RAS variants with T-cell receptor-engineered autologous PBL in any patient who is HLA-A11 are now open to enrollment. Future efforts are under way to expand the library of receptors to encompass additional RAS mutations, other HLA alleles, and other shared mutations in common driver oncogenes. Citation Format: James Yang, Kenichi Hanada, Steven Rosenberg. T-Cells targeting mutated RAS—clinical trials [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr IA15.