Impact of the selective A2AR and A2BR dual antagonist AB928/etrumadenant on CAR T cell function
Matthias Seifert, Mohamed-Reda Benmebarek, Daria Briukhovetska, Florian Märkl, Janina Dörr, Bruno L. Cadilha, Jakob Jobst, Sophia Stock, David Andreu-Sanz, Theo Lorenzini, Ruth Grünmeier, Arman Öner, Hannah Obeck, Lina Majed, Dario Dhoqina, Manouk Feinendegen, Adrian Gottschlich, Jin Zhang, Ulrike Schindler, Stefan Endres, Sebastian Kobold
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: 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.