Pan-TGFβ inhibition by SAR439459 relieves immunosuppression and improves antitumor efficacy of PD-1 blockade

TGF beta is a pleiotropic cytokine that may have both tumor inhibiting and tumor promoting properties, depending on tissue and cellular context. Emerging data support a role for TGF beta in suppression of antitumor immunity. Here we show that SAR439459, a pan-TGF beta neutralizing antibody, inhibits all active isoforms of human and murine TGF beta, blocks TGF beta-mediated pSMAD signaling, and TGF beta-mediated suppression of T cells and NK cells. In vitro, SAR439459 synergized with anti-PD1 to enhance T cell responsiveness. In syngeneic tumor models, SAR439459 treatment impaired tumor growth, while the combination of SAR439459 with anti-PD-1 resulted in complete tumor regression and a prolonged antitumor immunity. Mechanistically, we found that TGF beta inhibition with PD-1 blockade augmented intratumoral CD8(+) T cell proliferation, reduced exhaustion, evoked proinflammatory cytokines, and promoted tumor-specific CD8(+) T cell responses. Together, these data support the hypothesis that TGF beta neutralization using SAR439459 synergizes with PD-1 blockade to promote antitumor immunity and formed the basis for the ongoing clinical investigation of SAR439459 in patients with cancer (NCT03192345).