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Cited by 14Immunotherapy and Immune ResponsesCancer Immunotherapy and Biomarkersvaccines and immunoinformatics approaches

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Facts and Hopes in Immunotherapy Strategies Targeting Antigens Derived from KRAS Mutations

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Linette, Gerald P., Bear, Adham S., Carreno, Beatriz M.·2024·Clinical Cancer Research
DOI 10.1158/1078-0432.ccr-23-1212PMC PMC11094419
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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.

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  • Additional emerging modalities for KRAS-targeted therapy include RNA-targeted therapeutics, antisense oligonucleotides, siRNA-based suppression, neoantigen vaccines, and adoptive T-cell therapies targeting mutant KRAS-derived epitopes.

    “Additional emerging modalities include RNA-targeted therapeutics, antisense oligonucleotides, siRNA-based suppression [65,66], neoantigen vaccines [67,68], and adoptive T-cell therapies targeting mutant KRAS-derived epitopes [69,70].”

    From Precision Targeting of KRAS-Mutant Cancers: Beyond G12C Toward G12D and Pan-RAS Therapeutic Strategies (2026) · cites this paper as [68]

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Metadata

Authors
Linette, G. P., Bear, A. S., & Carreno, B. M.
Affiliations
University of Pennsylvania (US)
Corresponding author
Carreno, Beatriz M.
ORCID
Venue
Clinical Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2024-01-24
Volume
30
Issue
10
Pages
2017-2024
ISSN
  • 1078-0432 (ISSN-L)
  • 1557-3265
DOI
10.1158/1078-0432.ccr-23-1212
PMC
PMC11094419
OpenAlex
W4391163101
Cited by
14
References
16
Citations by year
2026: 4 · 2025: 8 · 2024: 2
FWCI
0.62
Type
journal article
Language
en
Open access
Licence
Locations
  • Clinical Cancer Research (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • DOD Peer Reviewed Cancer Research Program (LC220079)
  • Stand Up To Cancer (SU2C-AACR-PCC-07-18)
  • Cancer Moonshot (U54 CA244711)
  • National Cancer Institute (R01 CA204261, P01CA217805, R21 CA205794)
  • Lustgarten Foundation
  • Parker Institute for Cancer Immunotherapy
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
Keywords
mutant KRAS, neoantigens, KRAS G12D, cancer immunotherapy, HLA class I, T cell receptor, adoptive T cell therapy, epitope mapping, proteasomal degradation, precision medicine, KRAS inhibitors
MeSH terms
Antigens, Neoplasm, Humans, Immunotherapy, Mutation, Neoplasms, Proto-Oncogene Proteins p21(ras), Molecular Targeted Therapy

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