Combination of anti-CD73 and agonistic anti-CD137 antibody therapy leads to tumor regression (TUM2P.1030)

Abstract

Abstract Agonist antibodies (Ab) directed against costimulatory molecule CD137 (4-1BB) on the surface of antigen-primed T-lymphocytes are currently in various stages of pre-clinical and clinical development, though therapeutic benefit has been limited as single agents. Here, we examined the inhibitory role of CD73 on the antitumor efficacy of agonistic anti-CD137 Ab therapy. CD73-deificient mice treated with anti-CD137 Ab completely rejected CD73-nonexpressing B16-SIY melanoma growth when compared with wild-type mice, highlighting the importance of an inhibitory role for host-derived CD73. To explore the therapeutic relevance of these observations, we combined anti-CD137 and anti-CD73 Ab to treat mice with established B16-SIY melanoma. This combination therapy induced tumor regression associated with enhanced antitumor CD8+ T cell responses and reduced CD4+Foxp3+ regulatory T cells number and function. In contrast, neither anti-41BB nor anti-CD73 monotherapy is effective to control the growth of established melanoma. Our study demonstrates that CD73 blockade has critical implications for effective clinical targeting of CD137 and possibly other costimulatory molecules.