Impact of the selective A2 A R and A2 B R dual antagonist AB928/etrumadenant on CAR T cell function.

Autor: Seifert M; Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany., Benmebarek MR; Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.; National Cancer Institute (NCI), Bethesda, MD, USA., Briukhovetska D; Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany., Märkl F; Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany., Dörr J; Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany., Cadilha BL; Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany., Jobst J; Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany., Stock S; Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.; Department of Medicine III, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.; German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany., Andreu-Sanz D; Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany., Lorenzini T; Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany., Grünmeier R; Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany., Oner A; Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany., Obeck H; Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany., Majed L; Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany., Dhoqina D; Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany., Feinendegen M; Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany., Gottschlich A; Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany., Zhang J; Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany., Schindler U; Independent Consultant, Freiburg, Germany., Endres S; Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany., Kobold S; Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany. Sebastian.kobold@med.uni-muenchen.de.; German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany. Sebastian.kobold@med.uni-muenchen.de.; Einheit für Klinische Pharmakologie (EKLiP), Helmholtz Zentrum München, Research Center for Environmental Health (HMGU), Neuherberg, Germany. Sebastian.kobold@med.uni-muenchen.de.
Jazyk: angličtina
Zdroj: British journal of cancer [Br J Cancer] 2022 Dec; Vol. 127 (12), pp. 2175-2185. Date of Electronic Publication: 2022 Oct 20.
DOI: 10.1038/s41416-022-02013-z
Abstrakt: Background: Chimeric antigen receptor (CAR) T cell therapy has been successfully translated to clinical practice for the treatment of B cell malignancies. The suppressive microenvironment of many malignancies is a bottleneck preventing treatment success of CAR T cells in a broader range of tumours. Among others, the immunosuppressive metabolite adenosine is present in high concentrations within many tumours and dampens anti-tumour function of immune cells and consequently therapeutic response.
Methods: Here, we present the impact of the selective adenosine A2 A and A2 B receptor antagonist AB928/etrumadenant on CAR T cell cytokine secretion, proliferation, and cytotoxicity. Using phosphorylation-specific flow cytometry, we evaluated the capability of AB928 to shield CAR T cells from adenosine-mediated signalling. The effect of orally administered AB928 on CAR T cells was assessed in a syngeneic mouse model of colon carcinoma.
Results: We found that immunosuppressive signalling in CAR T cells in response to adenosine was fully blocked by the small molecule inhibitor. AB928 treatment enhanced CAR T cell cytokine secretion and proliferation, granted efficient cytolysis of tumour cells in vitro and augmented CAR T cell activation in vivo.
Conclusions: Together our results suggest that combination therapy with AB928 represents a promising approach to improve adoptive cell therapy.
(© 2022. The Author(s).)
Databáze: MEDLINE
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