Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.
National Cancer Institute (NCI), Bethesda, MD, USA.
Br J Cancer. 2022 Dec;127(12):2175-2185. doi: 10.1038/s41416-022-02013-z. Epub 2022 Oct 20.
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.
Here, we present the impact of the selective adenosine A2 and A2 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.
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.
Together our results suggest that combination therapy with AB928 represents a promising approach to improve adoptive cell therapy.
嵌合抗原受体（CAR）T 细胞疗法已成功转化为治疗 B 细胞恶性肿瘤的临床实践。许多恶性肿瘤的抑制性微环境是阻止 CAR T 细胞在更广泛的肿瘤范围内取得治疗成功的瓶颈。其中，免疫抑制代谢物腺苷在许多肿瘤中高浓度存在，并抑制免疫细胞的抗肿瘤功能，从而影响治疗反应。
在这里，我们介绍了选择性腺苷 A2 和 A2 受体拮抗剂 AB928/etrumadenant 对 CAR T 细胞细胞因子分泌、增殖和细胞毒性的影响。我们使用磷酸化特异性流式细胞术评估了 AB928 保护 CAR T 细胞免受腺苷介导信号的能力。我们在结肠癌细胞的同种异体小鼠模型中评估了口服给予 AB928 对 CAR T 细胞的影响。
我们发现小分子抑制剂完全阻断了 CAR T 细胞对腺苷的免疫抑制信号。AB928 治疗增强了 CAR T 细胞细胞因子的分泌和增殖，有效地在体外溶解肿瘤细胞，并增强了 CAR T 细胞在体内的激活。
我们的研究结果表明，AB928 的联合治疗代表了改善过继细胞治疗的一种有前途的方法。
