Identification and validation of T-cell receptors targeting RAS hot-spot mutations in human cancers for use in cell-based immunotherapy
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… G13D, G13R, G13V, Q61R, Q61L, Q61K, and Q61H) and the equivalent WT (G12, G13, Q61).
All peptides were ordered from GenScript or JPT and were HPLC purified (>90%). For tandem?…
BamHI. Gene synthesis and cloning was done by GenScript?… |
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background: 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 cancer patients. These mutations play an important role in both tumor establishment and survival and are commonly found in hotspots.
objective: Discovering T cell receptors (TCR) that recognize shared mutated RAS antigens presented on major histocompatibility complex (MHC) class I and class II molecules are thus promising reagents for "off-the-shelf" adoptive cell therapies (ACT) following insertion of the TCR into lymphocytes.
methods: In this ongoing work, we screened for RAS antigen recognition in tum... More
background: 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 cancer patients. These mutations play an important role in both tumor establishment and survival and are commonly found in hotspots.
objective: Discovering T cell receptors (TCR) that recognize shared mutated RAS antigens presented on major histocompatibility complex (MHC) class I and class II molecules are thus promising reagents for "off-the-shelf" adoptive cell therapies (ACT) following insertion of the TCR into lymphocytes.
methods: In this ongoing work, we screened for RAS antigen recognition in tumor-infiltrating lymphocytes (TIL) or by in-vitro stimulation (IVS) of peripheral blood lymphocytes (PBLs). TCRs recognized 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 TCRs sequences that recognize non-synonymous 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" adoptive cell therapies (ACT).
