5.1A2aR mAb combined with PD-1/PD-L1 mAb
Since the expression of A2a is increased on antigen-activated T cells and PD-1 is involved in inhibiting T cells function, the combination of targeted blocking of these two molecules is considered as a new direction for tumor therapy. Recent clinical researches show in RCC (renal cell cancer) patients, the A2AR and PD-L1 expression in the primary tumors may foresee the consequences of therapy with anti-VEGF agents and ICIs[47], the A2AR antagonist Ciforadenant, showed monotherapy activity in patients who are resistant to or intractable to previous anti-PD-L1 therapy. Though this trial did not compare the effects of monotherapy with combination therapy deliberately, treatment with A2AR antagonist plus anti-PD-L1 appeared to improve efficacy[46]. Studies have shown that blocking A2aR with CPI-444 reduces the expression of checkpoints of various pathways on T-effs and Tregs, including PD-1 and LAG-3. By reducing the expression of immune checkpoints on these T cells, the threshold of anti-PD-1 treatment is lowered. That is, the synergistic reaction of CPI-444 combined with PD-1 mAb therapy[9, 44]. Moreover, A2aR blocker significantly reduced the expression of PD-1 and LAG-3 in draining lymph nodes of mice which were tumor-bearing [49]. Another group successfully combined A2aR blockers with anti-PD-1 inhibitors in an anti-tumor regimen in a mouse model[31]. Mittal et al.[45] also reported that uniting SCH58261, the A2aR inhibitor, with antiĀ­-PD-1 therapy significantly reduced the burden of metastasis compared with either monotherapy alone. Uniting therapy with PD-1 mAbs and CPI-444 showed significant improvement in tumor regression and survival in tumor models of CT26 and MC38(more significant in CT26 tumor models)[44].In NSCLC mouse models, A2a receptor inhibition overcomes resistance of tumor cell to PD-1/PD-L1 blocking treatment. Meanwhile, A2AR and CD73 were up-regulated in mice treated with PD-1 mAbs or PD-L1 mAbs[48, 49].In mouse models of breast, colon, and hepatocellular carcinoma, drug resistance of tumor cells to PD-1/PD-L1 can be prevented by dual blocking of PD-1 and A2aR. Blocking A2aR after virus attack also reduced the expression of PD-1, LAG-3, and TIM-3 on the cover of CD8+T cells and Tregs. These abundant in vivo and in vitro experiments suggest that the combination of A2aR blocker and PD-1/PD-L1 antibody is of great significance in the treatment of tumors in the clinical[30, 67].