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A preparation of autologous T lymphocytes that have been activated and genetically modified to express immune checkpoint antibodies against the negative immunoregulatory receptors human cell surface receptor programmed cell death protein 1 (PD-1; PDCD1; CD279) and human T-cell receptor cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4; CTLA4), and are transduced with a gene encoding a chimeric antigen receptor (CAR) specific for the human tumor-associated antigen (TAA) mesothelin, with potential immunomodulating and antineoplastic activities. After isolation, activation, transduction, expansion in culture, and reintroduction into the patient, the T cells in the autologous mesothelin-specific CAR-T cells expressing anti-PD-1/CTLA4 antibodies specifically target and kill mesothelin-expressing tumor cells. The anti-PD-1 antibody secreted from the CAR-T cells binds to PD-1 expressed on T cells and prevents the interaction of PD-1 with its ligand programmed cell death 1 ligand 1 (PD-L1, PD-1L1; CD274) expressed on cancer cells, which prevents PD-1-mediated signaling and T-cell exhaustion. The anti-CTLA-4 expressed by the CAR-T cells targets and binds to CTLA4 expressed on T cells, and inhibits the CTLA4-mediated downregulation of T-cell activation. Both antibodies enhance T-cell activation, improve immunosuppression in the tumor microenvironment (TME) and enhance the T-cell mediated immune response against and toxicity in mesothelin-expressing tumor cells. Both PD-1 and CTLA-4 negatively regulate T-cell activation and proliferation, and play a key role in immunosuppression within the TME. Mesothelin, a cell surface glycoprotein involved in cell adhesion, is overexpressed in a variety of cancer cell types. Check for \'https://www.cancer.gov/about-cancer/treatment/clinical-trials/intervention/C150682\' active clinical trials using this agent. (\'http://ncit.nci.nih.gov/ncitbrowser/ConceptReport.jsp?dictionary=NCI%20Thesaurus&code=C150682\' NCI Thesaurus)
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