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

Menée in vitro et sur un modèle murin de carcinome du côlon, cette étude évalue l'effet de la molécule AB928, un antagoniste des récepteurs de l'adénosine A2A et A2B, sur l'activité des lymphocytes CAR-T

Résumé en anglais

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.