PSMA-Directed CAR T Cells Combined with Low-Dose Docetaxel Treatment Induce Tumor Regression in a Prostate Cancer Xenograft Model
| Autor: | Toni Cathomen, Philipp Wolf, Sanaz Taromi, Wolfgang W. A. Schamel, Maximilian Seidl, Hinrich Abken, Niko Thorausch, Jamal Alzubi, Robert Zeiser, Johannes Kuehle, Viviane Dettmer-Monaco |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Combination therapy medicine.medical_treatment chemotherapy CAR T cells lcsh:RC254-282 Article CD19 combination therapy 03 medical and health sciences Prostate cancer 0302 clinical medicine Glutamate carboxypeptidase II focal therapy Medicine docetaxel Pharmacology (medical) biology business.industry prostate specific membrane antigen Cancer Immunotherapy medicine.disease prostate cancer lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Chimeric antigen receptor 030104 developmental biology Oncology Docetaxel 030220 oncology & carcinogenesis Cancer research biology.protein Molecular Medicine business human activities medicine.drug |
| Zdroj: | Molecular Therapy: Oncolytics, Vol 18, Iss, Pp 226-235 (2020) Molecular Therapy Oncolytics |
| ISSN: | 2372-7705 |
| Popis: | 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. Graphical Abstract Alzubi and colleagues developed novel PSMA-targeting CARs that enabled the eradication of human prostate cancer xenografts in a mouse tumor model upon focal application of the resulting CAR T cells. Moreover, in combination with a non-ablative dose of docetaxel chemotherapy, systemic PSMA-CAR T cell application significantly inhibited tumor growth. |
| Databáze: | OpenAIRE |
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