autologous KRAS G12D mutant-specific HLA-C*08:02-/KRAS G12D mutant-specific HLA-A*11:01-/KRAS G12V mutant-specific HLA-C*01:02-/TP53 R175H mutant-specific HLA-A*02:01-restricted TCR genes engineered T lymphocytes

A preparation of autologous T lymphocytes that have been genetically modified to express a T-cell receptor (TCR) specific for the human leukocyte antigen (HLA)-C*08:02-restricted oncogenic K-RAS (KRAS) substitution mutation G12D, a TCR specific for the HLA-A*11:01-restricted KRAS G12D, a TCR specific for the HLA-C*01:02-restricted KRAS G12V, and a TCR specific for the HLA-A*02:01-restricted oncogenic TP53 (p53) substitution mutation R175H, with potential antineoplastic activity. Upon isolation of peripheral blood lymphocytes (PBLs), transduction, expansion ex vivo and re-introduction into the patient, the autologous KRAS G12D mutant-specific HLA-C*08:02-/KRAS G12D mutant-specific HLA-A*11:01-/KRAS G12V mutant-specific HLA-C*01:02-/TP53 R175H mutant-specific HLA-A*02:01-restricted TCR genes engineered T-lymphocytes target and bind to tumor cells expressing the mutants KRAS G12D, KRAS G12V and/or TP53 R175H, resulting in cytotoxic T-lymphocyte (CTL)-mediated killing of KRAS G12D, KRAS G12V and/or TP53 R175H-expressing tumor cells. KRAS, a member of the RAS family of oncogenes, serves an important role in cell signaling, division and differentiation. Mutations of KRAS may induce constitutive signal transduction leading to tumor cell proliferation, invasion, and metastasis. p53, a tumor suppressor gene, is mutated in many tumor cells, resulting in the loss of apoptosis regulation and abnormal cell proliferation.