Targeting KRASG12V mutations with HLA class II-restricted TCR for the immunotherapy in solid tumors

Abstract

KRAS mutation is a significant driving factor of tumor, and KRAS^G12V mutation has the highest incidence in solid tumors such as pancreatic cancer and colorectal cancer. Thus, KRAS^G12V neoantigen-specific TCR-engineered T cells could be a promising cancer treatment approach for pancreatic cancer. Previous studies had reported that KRAS^G12V-reactive TCRs originated from patients' TILs could recognized KRAS^G12V neoantigen presented by specific HLA subtypes and remove tumor persistently <i>in vitro</i> and <i>in vivo</i>. However, TCR drugs are different from antibody drugs in that they are HLA-restricted. The different ethnic distribution of HLA greatly limits the applicability of TCR drugs in Chinese population. In this study, we have identified a KRAS^G12V-specific TCR which recognized classII MHC from a colorectal cancer patient. Interestingly, we observed that KRAS^G12V-specific TCR-engineered CD4⁺ T cells, not CD8⁺ T cells, demonstrated significant efficacy <i>in vitro</i> and in xenograft mouse model, exhibiting stable expression and targeting specificity of TCR when co-cultured with APCs presenting KRAS^G12V peptides. TCR-engineered CD4⁺ T cells were co-cultured with APCs loaded with neoantigen, and then HLA subtypes were identified by the secretion of IFN-γ. Collectively, our data suggest that TCR-engineered CD4⁺ T cells can be used to target KRAS^G12V mutation presented by HLA-DPB1*03:01 and DPB1*14:01, which provide a high population coverage and are more suitable for the clinical transformation for Chinese, and mediate tumor killing effect like CD8⁺ T cells. This TCR hold promise for precision therapy in immunotherapy of solid tumors as an attractive candidate.