PSMA-Directed CAR T Cells Combined with Low-Dose Docetaxel Treatment Induce Tumor Regression in a Prostate Cancer Xenograft Model.

While chimeric antigen receptor (CAR) T cell immunotherapy targeting CD19 has shown remarkable success in patients with lymphoid malignancies, the potency of CAR T cells in solid tumors is low so far. To improve the efficacy of CAR T cells targeting prostate carcinoma, we designed a novel CAR that recognizes a new epitope in the prostate-specific membrane antigen (PSMA) and established novel paradigms to apply CAR T cells in a preclinical prostate cancer model. In vitro characterization of the D7 single-chain antibody fragment-derived anti-PSMA CAR confirmed that the choice of the co-stimulatory domain is a major determinant of CAR T cell activation, differentiation, and exhaustion. In vivo, focal injections of the PSMA CAR T cells eradicated established human prostate cancer xenografts in a preclinical mouse model. Moreover, systemic intravenous CAR T cell application significantly inhibited tumor growth in combination with non-ablative low-dose docetaxel chemotherapy, while docetaxel or CAR T cell application alone was not effective. In conclusion, the focal application of D7-derived CAR T cells and their combination with chemotherapy represent promising immunotherapeutic avenues to treat local and advanced prostate cancer in the clinic.

Molecular therapy oncolytics. 2020 Jun 24*** epublish ***

Jamal Alzubi, Viviane Dettmer-Monaco, Johannes Kuehle, Niko Thorausch, Maximilian Seidl, Sanaz Taromi, Wolfgang Schamel, Robert Zeiser, Hinrich Abken, Toni Cathomen, Philipp Wolf

Institute for Transfusion Medicine and Gene Therapy, Medical Center-University of Freiburg, Freiburg, Germany., Center for Molecular Medicine, University of Cologne, Cologne, Germany., BIOSS Centre for Biological Signaling, University of Freiburg, Freiburg, Germany., Institute of Clinical Pathology, Medical Center-University of Freiburg, Freiburg, Germany., Department of Hematology, Oncology and Stem Cell Transplantation, Medical Center-University of Freiburg, Freiburg, Germany., Department for Genetic Immunotherapy, Regensburg Center for Interventional Immunology, University of Regensburg, Regensburg, Germany., Faculty of Medicine, University of Freiburg, Freiburg, Germany.