Mutant Kirsten rat sarcoma virus oncogene homolog-derived neoantigen peptides presented by specific Human Leukocyte Antigen class I alleles (Mutant KRAS-HLA class I complex)

Mutant KRAS-derived neoantigen peptides presented by specific HLA class I alleles are highly specific targets for cancer immunotherapy, arising from somatic mutations in the KRAS gene that are prevalent in pancreatic, colorectal, and lung cancers (Simanshu et al., 2017, Cell). These mutations, such as G12D or G12V, create novel peptide sequences that are processed and displayed on the tumor cell surface by specific Human Leukocyte Antigen (HLA) molecules, forming a peptide-MHC complex (Leidner et al., 2022, NEJM). Because these complexes are unique to malignant cells and absent in healthy tissues, they allow the immune system to distinguish between tumor and normal cells, making them ideal for targeted therapies like TCR-engineered T cells and neoantigen vaccines (Pant et al., 2024, Nature Medicine). Drugs targeting these complexes, such as the ELI-002 amphiphile vaccine or experimental TCR-T therapies, work by inducing or providing T cells with receptors that specifically recognize the mutant KRAS-HLA combination. However, the therapeutic application is limited by the requirement for patients to possess both the specific KRAS mutation and the corresponding HLA allele, such as HLA-A*11:01 or HLA-C*08:02 (Wang et al., 2020, Science Immunology). Furthermore, tumors may develop resistance through the loss of HLA expression, a process known as HLA loss of heterozygosity, which prevents the presentation of the neoantigen to the immune system.

Other names

KRAS neoepitopesKRAS mutant peptide-MHC complexesKRAS neoantigensmKRAS-HLA complexMutant KRAS-derived neoantigens

Therapeutic agents target this complex by providing or eliciting T-cell receptors (TCRs) that specifically recognize the mutant KRAS peptide sequence in the context of a specific HLA molecule, leading to the selective activation of cytotoxic T lymphocytes and subsequent lysis of tumor cells (Leidner et al., 2022, NEJM).