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Cited by 72Immunotherapy and Immune ResponsesCancer Immunotherapy and Biomarkersvaccines and immunoinformatics approaches

Creating MHC-Restricted Neoantigens with Covalent Inhibitors That Can Be Targeted by Immune Therapy

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Hattori, Takamitsu, Maso, Lorenzo, Araki, Kiyomi Y., Koide, Akiko, Hayman, James, Akkapeddi, Padma, Bang, Injin, Neel, Benjamin G. +1 more·2023·Cancer Discovery
DOI 10.1158/2159-8290.cd-22-1074PMC PMC9827112

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Abstract

Intracellular oncoproteins can be inhibited with targeted therapy, but responses are not durable. Immune therapies can be curative, but most oncogene-driven tumors are unresponsive to these agents. Fragments of intracellular oncoproteins can act as neoantigens presented by the major histocompatibility complex (MHC), but recognizing minimal differences between oncoproteins and their normal counterparts is challenging. We have established a platform technology that exploits hapten–peptide conjugates generated by covalent inhibitors to create distinct neoantigens that selectively mark cancer cells. Using the FDA-approved covalent inhibitors sotorasib and osimertinib, we developed “HapImmune” antibodies that bind to drug–peptide conjugate/MHC complexes but not to the free drugs. A HapImmune-based bispecific T-cell engager selectively and potently kills sotorasib-resistant lung cancer cells upon sotorasib treatment. Notably, it is effective against KRASG12C-mutant cells with different HLA supertypes, HLA-A*02 and A*03/11, suggesting loosening of MHC restriction. Our strategy creates targetable neoantigens by design, unifying targeted and immune therapies. Significance: Targeted therapies against oncoproteins often have dramatic initial efficacy but lack durability. Immunotherapies can be curative, yet most tumors fail to respond. We developed a generalizable technology platform that exploits hapten–peptides generated by covalent inhibitors as neoantigens presented on MHC to enable engineered antibodies to selectively kill drug-resistant cancer cells. See related commentary by Cox et al., p. 19. This article is highlighted in the In This Issue feature, p. 1

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  • A HapImmune-derived BiTE targeting sotorasib-conjugated peptides effectively targeted and eliminated lung cancer cells resistant to sotorasib when exposed to the drug.

    “Remarkably, the HapImmune-derived BiTE demonstrated the ability to effectively target and eliminate lung cancer cells that were resistant to sotorasib when exposed to the drug.”

    From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [87]

  • Covalent KRAS G12C inhibitors could lead to the presentation of drug-modified neoantigens via MHC class I.

    “It has also been reported that covalent KRAS G12C inhibitors could lead to the presentation of drug-modified neoantigens via major histocompatibility complex class I. 45,46”

    From Anti-tumor efficacy of HRS-4642 and its potential combination with proteasome inhibition in KRAS G12D-mutant cancer (2024) · cites this paper as [46]

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Cited by

Sorted by citations

Authors
Hattori, T., Maso, L., Araki, K. Y., Koide, A., Hayman, J., Akkapeddi, P., Bang, I., Neel, B. G., & Koide, S.
Affiliations
NYU Langone Health (US)
Corresponding author
  • Neel, Benjamin G.
  • Koide, Shohei
ORCID
Venue
Cancer Discovery
Publisher
American Association for Cancer Research (AACR)
Published
2022-10-17
Volume
13
Issue
1
Pages
132-145
ISSN
  • 2159-8274 (ISSN-L)
  • 2159-8290
DOI
10.1158/2159-8290.cd-22-1074
PMC
PMC9827112
OpenAlex
W4306410199
Cited by
72
References
13
Citations by year
2026: 8 · 2025: 16 · 2024: 31 · 2023: 16 · 2022: 1
FWCI
6.11
Type
journal article
Language
en
Update notices
correction (2023-04-03)
Open access
Licence
Locations
  • Cancer Discovery (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Padua Research Archive (University of Padova) (submittedVersion, cc-by-nc-nd)
Funders
National Cancer Institute (R21CA246457, R21CA267362, R01CA248896, P30CA016087)
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
covalent inhibitors, sotorasib, osimertinib, bispecific T-cell engagers, KRAS G12C, lung cancer, drug resistance, HLA supertypes, cancer immunotherapy, targeted therapy
MeSH terms
Antigens, Neoplasm, Haptens, Histocompatibility Antigens, Humans, Lung Neoplasms, Major Histocompatibility Complex, Peptides, Histocompatibility Antigens Class I

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