Patient-specific tumor neoantigen-major histocompatibility complex (Neoantigen-MHC)

Patient-specific tumor neoantigens presented on Major Histocompatibility Complex (MHC) molecules represent a class of highly specific cancer targets derived from non-synonymous somatic mutations unique to an individual's tumor (Schumacher & Schreiber, Science, 2015). These mutations result in novel peptide sequences, or neoepitopes, that are processed and displayed on the cell surface by MHC Class I or II molecules (Blass & Ott, Nature Reviews Clinical Oncology, 2021). Because these neoantigens are absent from the normal human genome, they bypass central thymic tolerance, allowing for the generation of high-affinity T-cell responses with minimal risk of autoimmunity (Ott et al., Nature, 2017). Recognition of the neoantigen-MHC complex by T-cell receptors (TCRs) is a critical step in the adaptive immune response against cancer. Therapeutic approaches include personalized vaccines (mRNA, DNA, or peptide-based) designed to stimulate the patient's own immune system and adoptive cell therapies using TCR-engineered T cells (Sahin et al., Nature, 2017). The clinical utility of these targets depends on advanced genomic sequencing and computational algorithms to predict which mutations will produce immunogenic peptides capable of stable MHC binding.

Other names

Tumor-specific antigen (TSA)NeoepitopePersonalized tumor antigenSomatic mutation-derived antigenPeptide-MHC (pMHC) complex

Therapeutic agents targeting these complexes work by either actively immunizing the patient (vaccines) to expand endogenous neoantigen-specific T cells or by providing exogenous T cells (TCR-T) or molecules (bispecifics) that bind the peptide-MHC complex to induce tumor cell lysis (Blass & Ott, Nat Rev Clin Oncol, 2021).