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

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.

The Gut Microbiome Controls Liver Tumors via the Vagus Nerve

“…To assess direct ACh-CD8+ T cell interaction, we measured intracellular cytokine production following acute (4 h) ACh exposure as described ( 27 , 36 ). Splenic lymphocytes were expanded with IL2 or CD3/CD28 as reported ( 43 ). ACh exposure reduced CD8+ T cell production of TNFα, but not IL10, in a dose-dependent manner (Fig.…”

Subtle Structural Changes across the Boundary between A2AR/A2BR Dual Antagonism and A2BR Antagonism: A Novel Class of 2-Aminopyrimidine-Based Derivatives

“…25 Cotargeting A 2A R/A 2B R promotes activation and effector function of T cells in adoptive cell therapy. 26 This evidence strongly demonstrates that dual blockade of immunosuppressive A 2A R and A 2B R signaling is a promising strategy to overcome adenosine-mediated immunosuppression in cancer. Several small-molecule A 2A R/A 2B R dual antagonists have been reported (Figure 1), and the efficacy of these antagonists in alleviating immunosuppression in preclinical models or clinical trials in cancer has been described.…”

“…It is reported that antitumor CD8 + T cells express the cAMP-boosting functional A 2A R and A 2B R, promoting T cell dysfunction . Co-targeting A 2A R/A 2B R promotes activation and effector function of T cells in adoptive cell therapy . This evidence strongly demonstrates that dual blockade of immunosuppressive A 2A R and A 2B R signaling is a promising strategy to overcome adenosine-mediated immunosuppression in cancer.…”

The Role of NAD+ and NAD+-Boosting Therapies in Inflammatory Response by IL-13

“…CD73 creates adenosine from several precursors, including NAD-derived cADPR, after NAD + has been processed by CD38 to carry out signaling activities [ 55 ]. Adenosine produced by CD73 has potent anti-inflammatory effects, including suppressing T cell function [ 56 , 57 ]. This is evidenced by reports of silencing CD73 in cultured lymphocytes resulting in a pro-inflammatory phenotype [ 58 ].…”