Prostate cancer that has progressed to metastatic disease remains largely untreatable. One of the most promising modalities for treatment of advanced cancer is immunotherapy based on adoptive transfer of T lymphocytes. It was demonstrated that T lymphocytes expressing tumor-specific chimeric artificial receptor (CAR) exert potent anti-tumor activity upon adoptive transfer into tumor-bearing host. Recent studies identified Prostate-specific membrane antigen (PSMA) and ligands for NK cell –activating receptors (e.g. NKG2D ligands) as the targets primarily expressed on tumor cells but absent on most normal tissues. We generated two sets of chimeric DNA constructs: CAR-PSMA and CAR-NKG2D, that can be used for transduction of human T cells. Both of them consist of an antigen-recognizing domain bound to the transmembrane and intracellular domains of various signal-transducing and/or cell-activating molecules and a signaling molecule. Extracellular antigen-recognizing domain of CAR-PSMA consists of single chain anti-PSMA antibody (scFv) while in another construct set it is human NKG2D receptor. Intracellular CD3 ξ-chain functions as a signaling molecule triggering T-cell activation. Co-stimulatory proteins CD28, CD40L or OX40L which can compensate for the lack of co-stimulation from the target tumor cell are either fused to CD3 ξ-chain as intracellular domains or are expressed on cell surface from bi-cistronic constructs.
Upon transduction of human T cells with these constructs, transduced cells presented surface expression of the chimeric scFv anti-PSMA or NKG2D, respectively. In vitro experiments demonstrated specific binding activity and cytotoxicity of human T lymphocytes expressing anti-PSMA or NKG2D CARs against prostate cancer cells which creates the basis for a viable prostate cancer immunotherapy development.
*VP and SK contributed equally to the project.
Citation Format: Victor Prima, Sergei Kusmartsev, Johannes Vieweg. Prostate cancer immunotherapy development using tumor-specific CAR design. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B13.