Combining anti-OX40 with an inhibitor of TGF-β signaling overcomes the immunosuppressive environment in established tumors (P2026)

OX40 (CD134, TNFRSF4), a member of the tumor necrosis factor receptor (TNFR) superfamily is expressed on activated CD4+ and CD8+ T cells. Engagement of OX40 with cognate ligand or soluble agonist enhances T cell proliferation, survival and cytokine production by memory T cells. Although αOX40 therapy has been effective at controlling incipient tumors in a variety of mouse tumor models, it has been less effective at eradicating large established tumors. Pervasive immunosuppression in the tumor microenvironment has been implicated as a potential mechanism of immune evasion by tumor cells. Here we show that combining agonist antibody (αOX40) with an orally bioavailable small molecule inhibitor of TGF-β signaling, results in complete regression of well-established tumors in ~85% of treated mice. Tumor infiltrating lymphocytes (TIL) from these dual treated mice produce increased levels of Granzyme-B and IFNγ and higher levels of the proliferation marker Ki67. Differences seen in STAT3 expression by the TIL led us to investigate the role of STAT3 in this anti-tumor effect. Using an OX40 promoter-driven CRE model to knock out the STAT3 gene in activated T-lymphocytes, we demonstrated that STAT3 is essential for the therapeutic efficacy of the combination treatment as a 50% drop in tumor cure rate was observed in STAT-3 deficient mice compared to STAT3 sufficient mice. Together these results demonstrate the anti-tumor efficacy of combining OX40 therapy with TGF-β inhibition.