Combination of agonist anti-OX40 therapy with CTLA-4 blockade augments anti-tumor effector CD4 and CD8 T cells (P4318)

Abstract

Abstract Ligation of the TNF receptor family co-stimulatory molecule OX40 (CD134) with an agonist anti-OX40 mAb enhances anti-tumor immunity by augmenting CD4 and CD8 T cell clonal expansion, effector differentiation, as well as turning off the suppressive activity of FoxP3+CD4+ regulatory T cells (Treg). Moreover, the targeted blockade of the checkpoint inhibitor CTLA-4 on CD4 effector and Treg cells enhances anti-tumor immunity by boosting effector T cell responses and alleviating the suppressive capacity of Treg. However, monotherapy with anti-OX40 or anti-CTLA-4 mAb can have limited efficacy, particularly against poorly immunogenic tumors. Therefore, we investigated whether combination immunotherapy could overcome this defect to generate optimal therapeutic responses. We demonstrate that combined anti-OX40/anti-CTLA-4 therapy significantly enhanced tumor regression and survival of TRAMP-C1 prostate or MCA-205 sarcoma tumor-bearing hosts. Mechanistic studies revealed that combined anti-OX40/anti-CTLA-4 therapy elicited CD8 T cell proliferation and differentiation as well as the expansion of effector CD4 T cells producing Th1 and Th2 cytokines, but did not inhibit the expansion or suppressive function of Treg cells. Together, these data demonstrate that combined anti-OX40/anti-CTLA-4 immunotherapy elicits potent anti-tumor immunity and indicate that clinical evaluation of this combination regimen to boost tumor immunotherapy is warranted.