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].