A phase I clinical trial of PSMA-directed/TGFβ-insensitive CAR-T cells in metastatic castration-resistant prostate cancer.
Vivek Narayan, Whitney L. Gladney, Gabriela Plesa, Neha Vapiwala, Erica L. Carpenter, Shannon L. Maude, Priti Lal, Simon F. Lacey, J. Joseph Melenhorst, Joseph A. Fraietta, Ronnie Sebro, Michael D. Farwell, Michael Moniak, Joan Gilmore, Lester Lledo, Karen Dengel, Amy Marshall, Christina Coughlin, Carl H. June, Naomi B. Haas
Abstract
TPS269 Background: Adoptive immunotherapy with Chimeric Antigen Receptor (CAR)-T cells is a novel approach for the treatment of prostate cancer. However, the prostate cancer immunosuppressive microenvironment, including high levels of TGFβ, may limit the therapeutic potential of re-directed T cells upon tumor infiltration. The inhibition of TGFβ signaling via co-expression of a dominant negative TGFβ receptor (TGFβRdn) can enhance antitumor immunity. Co-expression of TGFβRdn on PSMA-redirected CAR-T cells in in vivo disseminated tumor models led to increased T cell proliferation, enhanced cytokine secretion, resistance to exhaustion, long-term persistence, and greater induction of tumor eradication. Methods: We are conducting a first-in-human phase 1 clinical trial evaluating the safety and preliminary efficacy of lentivirally-transduced PSMA-redirected/TGFβ-insensitive CAR-T cells (CART-PSMA-TGFβRdn) in metastatic CRPC (NCT03089203). In a 3+3 dose-escalation design, patients received a single dose of 1-3 x 10 7 /m 2 (Cohort 1) or 1-3 x 10 8 /m 2 (Cohort 2) CART-PSMA-TGFβRdn cells without lymphodepleting chemotherapy. In Cohort 3, 1-3 x 10 8 /m 2 CART-PSMA-TGFβRdn cells are administered following a lymphodepleting chemotherapy regimen of cyclophosphamide and fludarabine (cy/flu). A currently accruing modified protocol seeks to optimize the therapeutic window with CART-PSMA-TGFβRdn (CAR-T dose of 1-3 x 10 7 /m2 following lymphodepleting cy/flu). Eight patients have received a single dose of CART-PSMA-TGFβRdn. CAR-T expansion and persistence in peripheral blood and trafficking to target tissues is evaluated via quantitative PCR of CART-PSMA-TGFβRdn DNA. Bioactivity of CAR-T cells in peripheral blood is evaluated via multiplex immunoassays. Additional correlative analyses will interrogate the therapeutic contribution of TGFβRdn, as well as early markers of response and resistance to CART-PSMA-TGFβRdn therapy. Clinical trial information: NCT03089203.