Year: 2024
Type: review
Abstract: In this commentary, we advance the notion that mutant KRAS (mKRAS) is an ideal tumor neoantigen that is amenable for targeting by the adaptive immune system. Recent progress highlights key advances on various fronts that validate mKRAS as a molecular target and support further pursuit as an immunological target. Because mKRAS is an intracellular membrane localized protein and not normally expressed on the cell surface, we surmise that proteasome degradation will generate short peptides that bind to HLA class I (HLA-I) molecules in the endoplasmic reticulum for transport through the Golgi for display on the cell surface. T-cell receptors (TCR)αβ and antibodies have been isolated that specifically recognize mKRAS encoded epitope(s) or haptenated-mKRAS peptides in the context of HLA-I on tumor cells. Case reports using adoptive T-cell therapy provide proof of principle that KRAS G12D can be successfully targeted by the immune system in patients with cancer. Among the challenges facing investigators is the requirement of precision medicine to identify and match patients to available mKRAS peptide/HLA therapeutics and to increase the population coverage by targeting additional mKRAS epitopes. Ultimately, we envision mKRAS-directed immunotherapy as an effective treatment option for selected patients that will complement and perhaps synergize with small-molecule mKRAS inhibitors and targeted mKRAS degraders.
Source: Clinical Cancer Research
Institution: University of Pennsylvania
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: hybrid
Funders: American Association for Cancer Research, Lustgarten Foundation, Parker Institute for Cancer Immunotherapy, National Institutes of Health, Stand Up To Cancer, National Cancer Institute, Congressionally Directed Medical Research Programs, Cancer Moonshot, DOD Peer Reviewed Cancer Research Program
Awards: PD-1 Blockade and Neoantigen-Specific T Cell Immunity, G2265320945, Next generation T cell therapies for mutant KRAS solid tumors, Engineering the Next Generation of T Cells, Extending Chimeric Antigen (CAR) T cell therapy to thoracic cancers, G6746340345, G722595425, Integrated Discovery Pipeline for Tumor Neoantigens
OpenAlex ID: W4391163101