T-Cell Transfer Therapy Targeting Mutant KRAS in Cancer
Open accessAbstract
HLA-C*08:02-restricted tumor-infiltrating lymphocytes that were composed of four different T-cell clonotypes that specifically targeted KRAS G12D. However, one of these lesions had progressed on evaluation 9 months after therapy. The lesion was resected and found to have lost the chromosome 6 haplotype encoding the HLA-C*08:02 class I major histocompatibility complex (MHC) molecule. The loss of expression of this molecule provided a direct mechanism of tumor immune evasion. Thus, the infusion of CD8+ cells targeting mutant KRAS mediated effective antitumor immunotherapy against a cancer that expressed mutant KRAS G12D and HLA-C*08:02.
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Adoptive T-cell therapy targeting mutant KRAS fragments has shown efficacy in colon cancer and NSCLC patients with mutant KRAS G12D and HLA-C*08:02 expression.
“This approach has shown efficacy in colon cancer and NSCLC patients with mutant KRAS G12D and HLA-C*08:02 expression [88].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [88]
The Case Report identifies one patient with metastatic colorectal cancer, and the Clinical Evaluation reports regression of her lung metastases after therapy. The paper does not report efficacy in patients with primary NSCLC; lung metastases from colorectal cancer are not NSCLC. Page numbers were not available in our copy. (LLM, conf=0.91)
Experimental — accuracy not yet measuredTumors with mutant KRAS can express neoantigen fragments containing the oncogenic driver mutation on the MHC.
“Tumors with mutant KRAS can express neoantigen fragments containing the oncogenic driver mutation on the major histocompatibility complex [88,89].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [88]
CD8+ tumor-infiltrating lymphocytes and TCRs in CD4+ T cells specifically recognize KRAS-related mutations and can be used to engineer T cells.
“CD8+ TILs and TCRs in CD4+ T cells have been found to specifically recognize KRAS-related mutations, which can be further used to engineer T cells.604,605”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [604]
Peptides derived from KRASG12 variants and from KRASQ61H/L/R are presented on the surface of malignant cells by various MHC I (HLA-A) molecules.
“As noted above, peptides derived from KRASG12 variants193,194, and also from KRASQ61H/L/R (ref.198), have been demonstrated to be presented on the surface of malignant cells by various MHC I (HLA-A) molecules.”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [193]
Adoptive cell therapy with these specific TILs caused regression of all seven pulmonary metastases in a patient with KRASG12D-mutant colorectal cancer.
“ACT with these specific TILs resulted in regression of all seven pulmonary metastases in a patient with KRASG12D-mutant CRC from whom they had been isolated193.”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [193]
Loss of MHC was identified as an immune-evasion mechanism in a tumour that progressed nine months after TIL infusion.
“Notably, loss of MHC was identified as an immune-evasion mechanism in a tumour that progressed 9 months after TIL infusion193.”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [193]
Endogenous immune responses against KRAS-mutant cancer cells were first described in 2016 by Tran et al., who identified CD8+ TILs with TCRs recognizing MHC I HLA-C*08:02-presented KRASG12D neoepitopes.
“Endogenous immune responses against KRAS-mutant cancer cells were first described in 2016 by Tran et al.193, who identified CD8+ TILs with T cell receptors (TCRs) that recognize MHC I (HLA-C*08:02)-presented peptide neoepitopes derived from KRASG12D.”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [193]
Using CD8+ T cells that were reactive to KRASG12D mutant, a patient with CRC experienced prolonged partial response.
“Using CD8+ T cells that were reactive to KRASG12D mutant, a patient with CRC experienced prolonged partial response [64].”
From KRAS, a New Target for Precision Medicine in Colorectal Cancer? (2024) · cites this paper as [64]
CD8+ T cells possessing HLA-C08:02-restricted T-cell receptors specifically recognize mutant KRASG12D.
“It was found that CD8+ T cells, possessing HLA-C08:02-restricted T-cell receptors, specifically recognize the mutant KRASG12D.”
From RAS Mutations in Advanced Colorectal Cancer: Mechanisms, Clinical Implications, and Novel Therapeutic Approaches (2025) · cites this paper as [106]
Following intravenous administration of expanding TCRs in an ex vivo environment, a complete response was observed in lung lesions, resulting in prolonged PFS.
“Following the intravenous administration of expanding TCRs in an ex vivo environment, a complete response was observed in lung lesions, resulting in prolonged PFS.”
From RAS Mutations in Advanced Colorectal Cancer: Mechanisms, Clinical Implications, and Novel Therapeutic Approaches (2025) · cites this paper as [106]
A recent publication presented the relationship between the KRASG12D mutation and TCRs in a patient diagnosed with metastatic mCRC with lung metastasis.
“A recent publication presented the relationship between the KRASG12D mutation and TCRs in a patient diagnosed with metastatic mCRC with lung metastasis [106].”
From RAS Mutations in Advanced Colorectal Cancer: Mechanisms, Clinical Implications, and Novel Therapeutic Approaches (2025) · cites this paper as [106]
Despite the rarity of HLA-C*08:02, this study demonstrated the promise of T-cell-based immunotherapy for targeting KRASG12D and HLA-C*08:02.
“Despite the rarity of HLA-C*08:02, this study demonstrated the promise of T-cell–based immunotherapy for targeting KRASG12D and HLA-C*08:02.”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [44]
Tran et al. described a patient with metastatic colorectal cancer treated with autologous T cells specific for mutant KRASG12D, restricted to HLA-C*08:02.
“Tran and colleagues described a case of a patient with metastatic colorectal cancer treated with autologous T cells specific for mutant KRASG12D, which was restricted to the major histocompatibility complex class I allele HLA-C*08:02 (44).”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [44]
The anti-tumor activity of immune checkpoint blockade depends on CD8+ T cell and HLA class I-dependent immune activity.
“The anti-tumor activity of ICB has been shown to depend on CD8+ T cell, HLA class I–dependent immune activity (34–36).”
From Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy (2018) · cites this paper as [36]
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- Authors
- Tran, E., Robbins, P. F., Lu, Y.-C., Prickett, T. D., Gartner, J. J., Jia, L., Pasetto, A., Zheng, Z., Ray, S., Groh, E. M., Kriley, I. R., & Rosenberg, S. A.
- Affiliations
- National Institutes of Health (US)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2016-12-08
- Volume
- 375
- Issue
- 23
- Pages
- 2255-2262
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC5178827
- OpenAlex
- W2559953355
- Cited by
- 1,368
- References
- 27
- Citations by year
- 2026: 96 · 2025: 132 · 2024: 129 · 2023: 162 · 2022: 162 · 2021: 183 · 2020: 149 · 2019: 134 · 2018: 118 · 2017: 98 · 2016: 3 · 2015: 1 · 2014: 1
- FWCI
- 71.21
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (Z01BC010984)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Health Sciences › Medicine › Oncology › CAR-T cell therapy research
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- tumor-infiltrating lymphocytes, mutant KRAS, KRAS G12D, CD8+ T cells, tumor immune evasion, MHC class I loss, cancer immunotherapy
- MeSH terms
- Female, Flow Cytometry, Humans, Lung, Lung Neoplasms, Middle Aged, Colorectal Neoplasms, Proto-Oncogene Proteins p21(ras), CD8-Positive T-Lymphocytes, Lymphocyte Count
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