The small molecule TGF-β signaling inhibitor SM16 synergizes with agonistic OX40 antibody to suppress established mammary tumors and reduce spontaneous metastasis

Abstract

Effective tumor immunotherapy may require not only activation of anti-tumor effector cells, but also abrogation of tumor-mediated immunosuppression. The cytokine, TGF-β, 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 TNF-α receptor superfamily and ligation by agonistic antibody (anti-OX40) enhances effector function, expansion and survival of activated T cells. In this study, we examined the therapeutic efficacy and anti-tumor immune response induced by the combination of a small molecule TGF-β signaling inhibitor, SM16, plus anti-OX40 in the poorly immunogenic, highly metastatic, TGF-β-secreting 4T1 mammary tumor model. Our data show that SM16 synergizes with anti-OX40 to elicit a potent anti-tumor 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 3.2-fold increase of tumor-infiltrating, activated CD8+ T cells, an overall accumulation of CD4+ and CD8+ T cells, and an increased tumor-specific effector T cell response. Complete abrogation of the therapeutic effect in vivo following depletion of CD4+ and CD8+ T cells, suggests that the anti-tumor efficacy of SM16 + anti-OX40 therapy is T cell dependent. Mice that were cured of their tumors were able to reject tumor re-challenge and manifested a significant tumor-specific peripheral memory IFN-γ response. Taken together, these data suggest that combining a TGF-β signaling inhibitor with anti-OX40 is a viable approach for treating metastatic breast cancer.

Targeting TGF-β Signaling for Therapeutic Gain

“…The nonadditive nature of the galunisertib and lomustine responses and the suggestive trend toward reduced efficacy of galunisertib when combined with lomustine, might suggest a predominantly immune-mediated mechanism of action, impaired by the alkylating effects of lomustine on immune cells. Galunisertib may indeed be most effective with agents that stimulate rather than deplete the immune system (Garrison et al 2012;Triplett et al 2015).…”

STAT3 Signaling Is Required for Optimal Regression of Large Established Tumors in Mice Treated with Anti-OX40 and TGFβ Receptor Blockade

“…We also found an increase in the proportion of the Tregs undergoing proliferation in the spleens of SM16/aOX40-treated mice. The expansion of peripheral Tregs in the absence of TGFb signaling has also been observed in other tumor models (18,31), and in our model, the increase in peripheral Tregs may help quell off-target inflammation while the mice are receiving this potent dual therapy.…”

“…We hypothesized that using an agonist (aOX40) to boost effector T-cell function in conjunction with an inhibitor of T-cell suppression (SM16) would endow the immune system with the ability to eradicate large established tumors. Indeed, this combination has recently been shown to be effective in eradicating smaller tumors via an immune-dependent mechanism in the poorly immunogenic 4T1 breast carcinoma model (31). Therefore, we wanted to determine if this combination would be effective in curing mice of large established tumors.…”

The Marine-Derived Oligosaccharide Sulfate MS80, a Novel Transforming Growth Factor β1 Inhibitor, Reverses Epithelial Mesenchymal Transition Induced by Transforming Growth Factor-β1 and Suppresses Tumor Metastasis

“…Therefore, strategies that inhibit TGF-b-induced EMT have the potential to treat cancer metastasis. Indeed, several TGF-b signaling inhibitors, such as SB431542, SD-208 [2-(5-chloro-2-fluorophenyl)-N-pyridin-4-ylpteridin-4-amine], LY2109761 (4-[2-[4-(2-pyridin-2-yl-5, 6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)quinolin-7-yl]oxyethyl] morpholine), LY2157299 (galunisertib), and belagenpumatucel-L, have been reported to have the potent antimetastatic efficacy in vitro and in vivo via blocking TGF-b-induced EMT (Inman et al, 2002;Laping et al, 2002;Uhl et al, 2004;Ge et al, 2006;Melisi et al, 2008;Rausch et al, 2009;Zhang et al, 2011;Garrison et al, 2012). Specially, LY2157299 presents distinct safety and efficacy in phase I/II trials, appearing to block metastasis (Herbertz et al, 2015).…”