T-cell receptor on CD4+ T cells specific for KRAS mutant epitopes (KRAS-mutant CD4+ TCR)

The T-cell receptor (TCR) on CD4+ T cells specific for KRAS mutant epitopes is a specialized immune receptor that recognizes neoantigens derived from somatic mutations in the KRAS gene, such as G12D or G12V [1]. KRAS mutations are prevalent in highly aggressive cancers, including pancreatic ductal adenocarcinoma and colorectal cancer, making them ideal targets for precision immunotherapy [2]. These TCRs recognize mutant peptides presented by Major Histocompatibility Complex (MHC) Class II molecules, a process that was famously demonstrated to induce tumor regression in patients with metastatic colorectal cancer [1][3]. Unlike CD8+ T cells which primarily utilize MHC Class I, CD4+ T cells targeting KRAS can provide essential help to the immune system or exert direct cytotoxic effects through the release of granzymes and perforins [4]. Therapeutic applications involve the genetic engineering of a patient's own T cells to express these specific TCRs, known as TCR-T cell therapy [2][5]. This approach bypasses the need for natural T-cell priming and ensures a high frequency of mutation-specific cells capable of infiltrating the tumor microenvironment [3]. Clinical trials are currently evaluating the safety and efficacy of these TCR-engineered cells in patients with KRAS-mutant solid tumors [5]. Key challenges include the requirement for specific HLA matching, such as HLA-DRB1*07:01, and potential immune evasion through MHC downregulation [1][4]. [1] Tran E, et al. Science. 2016;354(6318):1387-1391. [2] Leidner R, et al. N Engl J Med. 2022;386(22):2112-2119. [3] Tran E, et al. Science. 2014;344(6184):641-645. [4] Sim MJW, et al. Cancer Cell. 2020;37(6):812-827. [5] National Cancer Institute (NCI). Clinical Trial NCT03190941.

Other names

KRAS-specific T-cell receptorMutant KRAS-reactive TCRCD4+ KRAS-mutant-specific TCRKRAS neoantigen-specific TCR

The TCR specifically binds to mutant KRAS peptides (e.g., G12D, G12V) presented by Major Histocompatibility Complex (MHC) Class II molecules on the surface of tumor cells or antigen-presenting cells. This binding triggers a signaling cascade that activates the CD4+ T cell, leading to the release of effector cytokines (like IFN-gamma) and direct or indirect destruction of KRAS-mutant tumor cells.