LAUSR

TGFβ may act as a tumor suppressor early in tumorigenesis; however, TGFβ is also known to support tumor growth via multiple mechanisms, including promotion of epithelial-mesenchymal transition, fibroblast recruitment, ECM deposition, neovascularization, and immunosuppression of both adaptive and innate immune cells. SAR439459 is pan-neutralizing TGFβ antibody that is being developed for the treatment of solid tumors. In this study, we investigated the effect of SAR439459 on the immune system in primary human immune cells in vitro and in murine syngeneic tumor models in vivo. Exogenous TGFβ inhibited proliferation of CD8pos primary human T cells and suppressed the production of inflammatory cytokines such as IFNγ. The addition of SAR439459 blocked these effects. Additionally, TGFβ enhanced the development of inducible Tregs by approximately 4-fold, while the inclusion of SAR439459 abrogated this effect. The effects of exogenous TGFβ and SAR439459 were next examined in the context of T Cell Receptor signaling in a co-culture system of Jurkat cells expressing luciferase reporter under the control of NFAT-responsive promoter and PD-L1pos APCs. The addition of anti-PD1 stimulated TCR signaling in this system, while the addition of TGFβ inhibited anti-PD1-mediated response. SAR439459 restored the ability of anti-PD1 to stimulate the TCR signaling. These data support the notion that TGFβ neutralization could positively impact T effector cells and inhibit Tregs development. Therefore, combining a TGFβ-neutralizing antibody with anti-PD1 could enhance T cell responsiveness. Compared to checkpoint inhibitors, which are suggested to cause the reactivation and de-repression of exhausted T cells, the effects of TGFβ on the immune system are thought to be distinct. To test this, the combination of anti-PD1 and SAR439459 was examined in syngeneic mouse models. Established MC38 tumors were treated with anti-PD1, SAR439459 or the combination of both antibodies. In tumor-bearing mice treated with either anti-PD1 or SAR439459 alone, neither Ab resulted in significant tumor growth inhibition. However, the combination of anti-PD-1 and SAR439459 led to tumor regression in the majority of tumor-bearing mice. These results provide the rationale for combining TGF-β neutralization with checkpoint inhibitors, specifically anti-PD1, for the treatment of human cancers. Citation Format: Richard C. Gregory, Rita Greco, Hongjing Qu, Natalia Malkova, Mikhail Levit, Keli Perron, Waldemar Racki, Fangxian Sun, Gary Shapiro, Christopher Winter, Dmitri Wiederschain, Tun Tun Lin, Jack Pollard. The anti-TGFβ neutralizing antibody, SAR439459, blocks the immunosuppressive effects of TGFβ and inhibits the growth of syngeneic tumors in combination with anti-PD1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2790.