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

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

doi:10.1016/j.omto.2020.06.014

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

Mol Ther Oncolytics. 2020 Jun 24:18:226-235. doi: 10.1016/j.omto.2020.06.014. eCollection 2020 Sep 25.

Authors

Jamal Alzubi^{1

2}, Viviane Dettmer-Monaco^{1

2}, Johannes Kuehle³, Niko Thorausch⁴, Maximilian Seidl⁵, Sanaz Taromi^{6

7}, Wolfgang Schamel⁴, Robert Zeiser^{6

8}, Hinrich Abken⁹, Toni Cathomen^{1

2

8}, Philipp Wolf^{8

10}

Affiliations

¹ Institute for Transfusion Medicine and Gene Therapy, Medical Center-University of Freiburg, Freiburg, Germany.
² Center for Chronic Immunodeficiency, Medical Center-University of Freiburg, Freiburg, Germany.
³ Center for Molecular Medicine, University of Cologne, Cologne, Germany.
⁴ BIOSS Centre for Biological Signaling, University of Freiburg, Freiburg, Germany.
⁵ Institute of Clinical Pathology, Medical Center-University of Freiburg, Freiburg, Germany.
⁶ Department of Hematology, Oncology and Stem Cell Transplantation, Medical Center-University of Freiburg, Freiburg, Germany.
⁷ Faculty of Medical and Life Sciences, University Furtwangen, Campus Schwenningen, Villingen-Schwenningen, Germany.
⁸ Faculty of Medicine, University of Freiburg, Freiburg, Germany.
⁹ Department for Genetic Immunotherapy, Regensburg Center for Interventional Immunology, University of Regensburg, Regensburg, Germany.
¹⁰ Department of Urology, Medical Center-University of Freiburg, Freiburg, Germany.

Abstract

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.

Keywords: CAR T cells; chemotherapy; combination therapy; docetaxel; focal therapy; prostate cancer; prostate specific membrane antigen.