Matthias Seifert1, Mohamed-Reda Benmebarek1,2, Daria Briukhovetska1, Florian Märkl1, Janina Dörr1, Bruno L Cadilha1, Jakob Jobst1, Sophia Stock1,3,4, David Andreu-Sanz1, Theo Lorenzini1, Ruth Grünmeier1, Arman Oner1, Hannah Obeck1, Lina Majed1, Dario Dhoqina1, Manouk Feinendegen1, Adrian Gottschlich1, Jin Zhang1, Ulrike Schindler5, Stefan Endres1, Sebastian Kobold6,7,8. 1. 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. 2. National Cancer Institute (NCI), Bethesda, MD, USA. 3. Department of Medicine III, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany. 4. German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany. 5. Independent Consultant, Freiburg, Germany. 6. 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. 7. German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany. Sebastian.kobold@med.uni-muenchen.de. 8. Einheit für Klinische Pharmakologie (EKLiP), Helmholtz Zentrum München, Research Center for Environmental Health (HMGU), Neuherberg, Germany. Sebastian.kobold@med.uni-muenchen.de.
Abstract
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 A2A and A2B 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.
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 A2A and A2B 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.
Authors: Kristin Synnestvedt; Glenn T Furuta; Katrina M Comerford; Nancy Louis; Jorn Karhausen; Holger K Eltzschig; Karl R Hansen; Linda F Thompson; Sean P Colgan Journal: J Clin Invest Date: 2002-10 Impact factor: 14.808
Authors: Francesco Di Virgilio; Alba Clara Sarti; Simonetta Falzoni; Elena De Marchi; Elena Adinolfi Journal: Nat Rev Cancer Date: 2018-10 Impact factor: 60.716