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Seifert, M.* ; Benmebarek, M.R.* ; Briukhovetska, D.* ; Märkl, F.* ; Dörr, J.* ; Cadilha, B.L.* ; Jobst, J.* ; Stock, S.* ; Andreu-Sanz, D.* ; Lorenzini, T.* ; Grünmeier, R.* ; Oner, A.* ; Obeck, H.* ; Majed, L.* ; Dhoqina, D.* ; Feinendegen, M.* ; Gottschlich, A.* ; Zhang, J.* ; Schindler, U.* ; Endres, S.* ; Kobold, S.

Impact of the selective A2AR and A2BR dual antagonist AB928/etrumadenant on CAR T cell function.

Br. J. Cancer 127, 2175-2185 (2022)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Adenosine Receptors; Antigen; Inhibition; Immunotherapy; Activation; Expression; Suppression; Remissions; Metabolism; Generation
ISSN (print) / ISBN 0007-0920
e-ISSN 1532-1827
Journal British Journal of Cancer BJC
Quellenangaben Volume: 127, Issue: 12, Pages: 2175-2185 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Publishing Place Campus, 4 Crinan St, London, N1 9xw, England
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Unit for Clinical Pharmacology (KKG-EKLiP)
Grants Deutsche Forschungsgemeinschaft (German Research Foundation)