Targeting KRAS(G12V) mutations with HLA class II-restricted TCR for the immunotherapy in solid tumors

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 in vitro and in vivo. 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 in vitro 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.