ArticleProceedings of the National Academy of Sciences of the United States of America2020
High-affinity oligoclonal TCRs define effective adoptive T cell therapy targeting mutant KRAS-G12D.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 90 papers.
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Who cites it
90 citing papers in PubMed, 118 citations in OpenAlex.
- Discovery of TCR-like antibodies to the KRAS G12D neoantigen via in silico-in vitro workflow.Molecular therapy : the journal of the American Society of Gene Therapy · 2026Article
- Structural basis for T-cell receptor recognition of p53Acta crystallographica. Section D, Structural biology · 2026Article
- Hallmarks and correlates of effective adoptive cell immunotherapy for cancer.Nature reviews. Immunology · 2026Review
- A generalizable system for antigenic peptide targeting across HLA-I allotypes.bioRxiv : the preprint server for biology · 2026Article
- Engineering high-fidelity tapasin variants to enhance MHC-I antigen presentation.The Journal of biological chemistry · 2026Article
- Molecular origin, discovery, validation and application of neoantigens.Asian journal of pharmaceutical sciences · 2026Review
- Computational Design of a TCR-Based Bispecific Engager Targeting Cancerous KRAS G12V Mutations.ACS omega · 2026Article
- Targeting metabolic reprogramming to enhance adoptive immunotherapy: emerging mechanisms and translational perspectives.Journal of translational medicine · 2026Review
- Bispecific antibodies and CAR T cells targeting a TP53 mutation-associated neoantigen show discordant affinity requirements.The Journal of clinical investigation · 2026Article
- Research on the Mechanism of "Cold Tumor" Formation and Immunotherapy for Its Transformation into "Hot Tumor".Oncology research · 2026Review
- Avidity-optimized TCR-T cells target KRAS neoantigens for potent cancer clearance and tumor microenvironment remodeling.Frontiers in immunology · 2026Article
- Article
- Structure guided analysis of KRAS G12 mutants in HLA-A*11:01 reveals a length encoded immunogenic advantage in G12D.Communications biology · 2025Article
- IFN-γ-driven UBE2D3 upregulation impairs antigen presentation pathways and anti-tumor immunity in pancreatic cancer.Nature communications · 2025Article
- Targeting KRAS mutations: orchestrating cancer evolution and therapeutic challenges.Signal transduction and targeted therapy · 2025Review
- Molecular basis for selection and inhibition of HIV-1 escape virus by T cells and KIR2DL2Nature communications · 2025Article
- Lymph node-targeted, mKRAS-specific amphiphile vaccine in pancreatic and colorectal cancer: phase 1 AMPLIFY-201 trial final results.Nature medicine · 2025Article
- Pulmonary Delivery of TCR Bispecific Proteins via Mesenchymal Stem Cells Facilitates Efficient Clearance of Lung Cancers.Cancer science · 2025Article
- Cascade-Targeted Nanoparticles for Enhanced Gemcitabine Delivery and Adenosine Metabolism Modulation to Overcome Treatment Resistance in Pancreatic Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Novel paradigms in KRAS targeting: Unveiling strategies to combat drug resistance.Chinese medical journal · 2025Review
30 more citing papers are in PubMed but not listed here.
Corrections and comments
- Erratum issued
Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
Complete cancer regression occurs in a subset of patients following adoptive T cell therapy (ACT) of ex vivo expanded tumor-infiltrating lymphocytes (TILs). However, the low success rate presents a great challenge to broader clinical application. To provide insight into TIL-based immunotherapy, we studied a successful case of ACT where regression was observed against tumors carrying the hotspot mutation G12D in the KRAS oncogene. Four T cell receptors (TCRs) made up the TIL infusion and recognized two KRAS-G12D neoantigens, a nonamer and a decamer, all restricted by human leukocyte antigen (HLA) C*08:02. Three of them (TCR9a, 9b, and 9c) were nonamer-specific, while one was decamer-specific (TCR10). We show that only mutant G12D but not the wild-type peptides stabilized HLA-C*08:02 due to the formation of a critical anchor salt bridge to HLA-C. Therapeutic TCRs exhibited high affinities, ranging from nanomolar to low micromolar. Intriguingly, TCR binding affinities to HLA-C inversely correlated with their persistence in vivo, suggesting the importance of antigenic affinity in the function of therapeutic T cells. Crystal structures of TCR-HLA-C complexes revealed that TCR9a to 9c recognized G12D nonamer with multiple conserved contacts through shared CDR2β and CDR3α. This allowed CDR3β variation to confer different affinities via a variable HLA-C contact, generating an oligoclonal response. TCR10 recognized an induced and distinct G12D decamer conformation. Thus, this successful case of ACT included oligoclonal TCRs of high affinity recognizing distinct conformations of neoantigens. Our study revealed the potential of a structural approach to inform clinical efforts in targeting KRAS-G12D tumors by immunotherapy and has general implications for T cell-based immunotherapies.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.