5.2A2aR mAb combined with CTLA-4 mAb
Combining A2aR mAb CPI-444 with anti-CTLA-4 therapy eliminated tumors in
up to 90 percent of treated mice, including restoring an immune response
in a model against an incomplete response to CTLA-4 monotherapy.
Moreover, tumor cells remained suppressed after reinoculated mice with
tumor cells, suggesting that CPI-444 induces systemic antineoplastic
immune memory, and that combination of CPI-444 with CTLA-4 mAb increases
the presence of CD8+T cells and IFNγ and Gzm B levels in
tumors[67].In a melanoma model of mice, inhibiting both CD73 and
A2aR increased CTLA-4 blockade therapeutic effect. Blocking A2aR plays
an important role in regulating function of T cells and significantly
reduces melanoma growth[43].Most importantly, the combination of
A2aR antagonists and anti-CTLA-4 therapy significantly restricted tumor
growth and enhanced anti-tumor immune response[9, 67]. Additionally,
other studies have shown that the concomitant blocking of A2aR and
CTLA-4 in T cells can synergistically enhance the anti-tumor response
through downregulating PKA, SHP2 and PP2Aα signaling pathways, providing
theoretical basis for A2aR mAb combined with CTLA-4 mAb as a new
treatment regimen for tumors[50].