Identification and Validation of T-cell Receptors Targeting RAS Hotspot Mutations in Human Cancers for Use in
Noam Levin1, Biman C Paria1, Nolan R Vale1
1Surgery Branch, National Cancer Institute, Bethesda, Maryland.
Purpose:
Immunotherapies mediate the regression of human tumors through recognition of tumor antigens by immune cells that trigger an immune response. Mutations in the RAS oncogenes occur in about 30% of all patients with cancer. These mutations play an important role in both tumor establishment and survival and are commonly found in hotspots. Discovering T-cell receptors (TCR) that recognize shared mutated RAS antigens presented on MHC class I and class II molecules are thus promising reagents for "off-the-shelf" adoptive cell therapies (ACT) following insertion of the TCRs into lymphocytes.
Experimental Design:
In this ongoing work, we screened for RAS antigen recognition in tumor-infiltrating lymphocytes (TIL) or by in vitro stimulation of peripheral blood lymphocytes (PBL). TCRs recognizing mutated RAS were identified from the reactive T cells. The TCRs were then reconstructed and virally transduced into PBLs and tested.
Results:
Here, we detect and report multiple novel TCR sequences that recognize nonsynonymous mutant RAS hotspot mutations with high avidity and specificity and identify the specific class-I and -II MHC restriction elements involved in the recognition of mutant RAS.
Conclusions:
The TCR library directed against RAS hotspot mutations described here recognize RAS mutations found in about 45% of the Caucasian population and about 60% of the Asian population and represent promising reagents for "off-the-shelf" ACTs.
Insights
Scientists identified novel T-cell receptors (TCRs) that recognize mutated RAS oncogenes, a common cancer driver. These TCRs are promising for developing "off-the-shelf" adoptive cell therapies (ACTs) to treat various cancers.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Mutations in RAS oncogenes are prevalent in approximately 30% of human cancers, driving tumor growth and survival.
- Immunotherapies leverage immune cells to recognize tumor antigens, leading to tumor regression.
- Targeting RAS mutations is a key strategy for developing novel cancer treatments.
Purpose of the Study:
- To discover and characterize T-cell receptors (TCRs) that recognize mutated RAS hotspot mutations.
- To evaluate the potential of these TCRs for developing "off-the-shelf" adoptive cell therapies (ACTs).
Main Methods:
- Screening of tumor-infiltrating lymphocytes (TILs) and peripheral blood lymphocytes (PBLs) for RAS antigen recognition.
- Identification, reconstruction, and viral transduction of TCRs recognizing mutated RAS.
- Testing of engineered lymphocytes for avidity and specificity against RAS mutations.
Main Results:
- Multiple novel TCR sequences recognizing nonsynonymous mutant RAS hotspot mutations were identified.
- High avidity and specificity of the identified TCRs against target mutations were confirmed.
- Specific MHC class I and II restriction elements involved in mutant RAS recognition were identified.
Conclusions:
- The identified TCRs recognize RAS mutations prevalent in significant portions of Caucasian (45%) and Asian (60%) populations.
- These TCRs represent promising reagents for developing broadly applicable "off-the-shelf" ACTs.
- This work advances the development of targeted immunotherapies for RAS-mutated cancers.
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