Identification of T-cell Receptors Targeting KRAS-Mutated Human Tumors
Qiong J Wang1, Zhiya Yu2, Kayla Griffith2
1Surgery Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland. qiongwang@mail.nih.gov James_Yang@nih.gov.
Abstract:
KRAS is one of the most frequently mutated proto-oncogenes in human cancers. The dominant oncogenic mutations of KRAS are single amino acid substitutions at codon 12, in particular G12D and G12V present in 60% to 70% of pancreatic cancers and 20% to 30% of colorectal cancers. The consistency, frequency, and tumor specificity of these "neoantigens" make them attractive therapeutic targets. Recent data associate T cells that target mutated antigens with clinical immunotherapy responses in patients with metastatic melanoma, lung cancer, or cholangiocarcinoma. Using HLA-peptide prediction algorithms, we noted that HLA-A*11:01 could potentially present mutated KRAS variants. By immunizing HLA-A*11:01 transgenic mice, we generated murine T cells and subsequently isolated T-cell receptors (TCR) highly reactive to the mutated KRAS variants G12V and G12D. Peripheral blood lymphocytes (PBL) transduced with these TCRs could recognize multiple HLA-A*11:01(+) tumor lines bearing the appropriate KRAS mutations. In a xenograft model of large established tumor, adoptive transfer of these transduced PBLs reactive with an HLA-A*11:01, G12D-mutated pancreatic cell line could significantly reduce its growth in NSG mice (P = 0.002). The success of adoptive transfer of TCR-engineered T cells against melanoma and other cancers supports clinical trials with these T cells that recognize mutated KRAS in patients with a variety of common cancer types.
Insights
Researchers developed T-cell receptors targeting KRAS mutations G12V and G12D. These engineered T cells showed promise in reducing tumor growth in preclinical models, supporting potential cancer immunotherapy trials.
Area of Science:
- Oncology
- Immunology
- Cancer Genetics
Background:
- KRAS proto-oncogene mutations, particularly at codon 12 (G12D, G12V), are prevalent in pancreatic and colorectal cancers.
- These specific KRAS mutations function as tumor-specific neoantigens, making them promising targets for cancer immunotherapy.
- Previous studies show T-cell targeting of mutated antigens correlates with positive immunotherapy outcomes in various cancers.
Purpose of the Study:
- To investigate the potential of HLA-A*11:01 to present mutated KRAS variants.
- To generate and isolate T-cell receptors (TCRs) reactive to KRAS G12V and G12D mutations.
- To evaluate the efficacy of TCR-engineered T cells in targeting and reducing tumor growth in preclinical models.
Main Methods:
- Utilized HLA-peptide prediction algorithms to identify potential KRAS variant presentation by HLA-A*11:01.
- Generated murine T cells and isolated specific TCRs by immunizing HLA-A*11:01 transgenic mice.
- Transduced peripheral blood lymphocytes (PBLs) with isolated TCRs and tested their recognition of KRAS-mutated tumor lines.
- Assessed the anti-tumor effect of adoptive transfer of engineered PBLs in a xenograft model.
Main Results:
- HLA-A*11:01 was identified as a potential presenter of mutated KRAS variants.
- Isolated TCRs demonstrated high reactivity to KRAS G12V and G12D mutations.
- TCR-transduced PBLs effectively recognized and targeted multiple HLA-A*11:01-positive tumor lines with relevant KRAS mutations.
- Adoptive transfer of engineered PBLs significantly reduced tumor growth in a pancreatic cancer xenograft model (P = 0.002).
Conclusions:
- TCR-engineered T cells targeting KRAS G12V and G12D mutations are feasible and effective in preclinical settings.
- These findings support the clinical investigation of TCR-based immunotherapies for KRAS-mutated cancers.
- The approach holds potential for treating various common cancer types harboring specific KRAS mutations.
