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

Seifert, Matthias; Benmebarek, Mohamed-Reda; Briukhovetska, Daria; Märkl, Florian; Dörr, Janina; Cadilha, Bruno L.; Jobst, Jakob; Stock, Sophia ; Andreu-Sanz, David; Lorenzini, Theo; Grünmeier, Ruth ; Oner, Arman; Obeck, Hannah; Majed, Lina; Dhoqina, Dario; Feinendegen, Manouk; Gottschlich, Adrian ; Zhang, Jin; Schindler, Ulrike; Endres, Stefan und Kobold, Sebastian (2022): Impact of the selective A2(A)R and A2(B)R dual antagonist AB928/etrumadenant on CAR T cell function. In: British Journal of Cancer, Bd. 127, Nr. 12: S. 2175-2185

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 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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0007-0920
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 491502892