autologous anti-PSMA CAR/CD2/dnTGF-BRII/PD-1:CD28 switch receptor-expressing T cells TmPSMA-02

A preparation of autologous T lymphocytes that have been genetically modified and transduced with a lentiviral vector to express a chimeric antigen receptor (CAR) consisting of an anti-prostate specific membrane antigen (PSMA) single chain variable fragment (scFv) and the co-stimulatory domain CD2, a dominant negative (dn) form of transforming growth factor-beta (TGF-beta; TGFb) receptor (dnTGF-BRII), and a PD-1:CD28 switch receptor composed of the extracellular ligand binding domain of the human inhibitory receptor programmed cell death protein 1 (PD-1; PDCD1) fused to the transmembrane and cytoplasmic co-stimulatory signaling domains of CD28, with potential immunomodulating and antineoplastic activities. Upon reintroduction into the patient, autologous anti-PSMA CAR/CD2/dnTGF-BRII/PD-1:CD28 switch receptor-expressing T cells TmPSMA-02 are directed to and induce selective toxicity in PSMA-expressing tumor cells. PSMA, a tumor-associated antigen (TAA) and type II transmembrane protein, is expressed on the membrane of prostatic epithelial cells and overexpressed on prostate tumor cells as well as a variety of other solid tumors. The inclusion of dnTGF-BRII blocks the signaling of the immunosuppressive cytokine TGFb in the tumor microenvironment (TME) and makes the TmPSMA-02 T cells resistant to TGFb. TGFb negatively regulates T-cell proliferation and activation and plays a key role in tumor immune suppression. The PD-1:CD28 switch receptor expressed by the TmPSMA-02 T cells targets and binds to the PD-1 ligands, programmed cell death ligand 1 (PD-L1) and 2 (PD-L2), expressed on tumor cells. The nature of the PD-1/CD28 switch receptor fusion protein prevents the normal PD1/PD-L1-mediated T-cell suppression and, instead, promotes signaling through the CD28 domain, which results in the stimulation of T lymphocytes. This induces enhanced toxicity against tumor cells.