The small molecule TGFβ signaling inhibitor SM16

Authors: Kendra Garrison Tobias Hahn WenCherng Lee Leona E Ling Andrew D Weinberg Emmanuel T Akporiaye

Publish Date: 2011/10/05

Volume: 61, Issue: 4, Pages: 511-521

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Abstract

Effective tumor immunotherapy may require not only activation of antitumor effector cells but also abrogation of tumormediated immunosuppression The cytokine TGFβ is frequently elevated in the tumor microenvironment and is a potent immunosuppressive agent and promoter of tumor metastasis OX40 CD134 is a member of the TNFα receptor superfamily and ligation by agonistic antibody antiOX40 enhances effector function expansion and survival of activated T cells In this study we examined the therapeutic efficacy and antitumor immune response induced by the combination of a small molecule TGFβ signaling inhibitor SM16 plus antiOX40 in the poorly immunogenic highly metastatic TGFβsecreting 4T1 mammary tumor model Our data show that SM16 and antiOX40 mutually enhanced each other to elicit a potent antitumor effect against established primary tumors with a 79 reduction in tumor size a 95 reduction in the number of metastatic lung nodules and a cure rate of 38 This positive treatment outcome was associated with a 32fold increase of tumorinfiltrating activated CD8+ T cells an overall accumulation of CD4+ and CD8+ T cells and an increased tumorspecific effector T cell response Complete abrogation of the therapeutic effect in vivo following depletion of CD4+ and CD8+ T cells suggests that the antitumor efficacy of SM16+ antiOX40 therapy is T cell dependent Mice that were cured of their tumors were able to reject tumor rechallenge and manifested a significant tumorspecific peripheral memory IFNγ response Taken together these data suggest that combining a TGFβ signaling inhibitor with antiOX40 is a viable approach for treating metastatic breast cancer

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