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A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
Published on: December 7, 2014
Systematic discovery and validation of T cell targets directed against oncogenic KRAS mutations
Jaewon Choi1, Scott P Goulding1, Brandon P Conn1
1BioNTech US Inc., 40 Erie Street, Suite 110, Cambridge, MA 02139, USA.
Abstract:
Oncogenic mutations in KRAS can be recognized by T cells on specific class I human leukocyte antigen (HLA-I) molecules, leading to tumor control. To date, the discovery of T cell targets from KRAS mutations has relied on occasional T cell responses in patient samples or the use of transgenic mice. To overcome these limitations, we have developed a systematic target discovery and validation pipeline. We evaluate the presentation of mutant KRAS peptides on individual HLA-I molecules using targeted mass spectrometry and identify 13 unpublished KRASG12C/D/R/V mutation/HLA-I pairs and nine previously described pairs. We assess immunogenicity, generating T cell responses to nearly all targets. Using cytotoxicity assays, we demonstrate that KRAS-specific T cells and T cell receptors specifically recognize endogenous KRAS mutations. The discovery and validation of T cell targets from KRAS mutations demonstrate the potential for this pipeline to aid the development of immunotherapies for important cancer targets.
Insights
Researchers developed a new pipeline to identify KRAS mutation targets for T-cell therapies. This systematic approach validates novel targets, advancing cancer immunotherapy development for KRAS-mutant tumors.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Oncogenic KRAS mutations are key drivers in many cancers.
- T-cell recognition of KRAS mutations via HLA-I molecules can control tumors.
- Current methods for identifying T-cell targets are limited.
Purpose of the Study:
- To develop and validate a systematic pipeline for discovering T-cell targets from KRAS mutations.
- To identify novel KRAS mutation/HLA-I pairs for cancer immunotherapy.
Main Methods:
- Utilized targeted mass spectrometry to evaluate mutant KRAS peptide presentation on HLA-I molecules.
- Assessed immunogenicity of identified targets.
- Employed cytotoxicity assays to validate T-cell recognition of endogenous KRAS mutations.
Main Results:
- Identified 13 novel and nine previously described KRAS mutation/HLA-I pairs.
- Demonstrated T-cell responses to nearly all validated targets.
- Confirmed specific recognition of endogenous KRAS mutations by KRAS-specific T-cells and T-cell receptors.
Conclusions:
- The developed pipeline offers a systematic approach for discovering and validating T-cell targets in KRAS-mutant cancers.
- This strategy holds significant potential for advancing the development of novel immunotherapies against KRAS-driven tumors.
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