Greco and Qu et al. investigated SAR439459, a second-generation pan-TGFβ-neutralizing antibody, in preclinical studies to elucidate its role in antitumor immunity. Comparably active in vitro to fresolimumab, SAR439459 impaired tumor growth in syngeneic tumor models. In combination with anti-PD-1, SAR439459 increased i.t. cytokines (IFNγ, TNFα, and IL-6) by inhibiting tumor TGFβ levels, and resulted in complete tumor regression and long-term immunity. ScRNA sequencing indicated the combination boosted proliferation and decreased exhaustion of CD8+ T cells in the tumor and draining LNs. Human MLR assays demonstrated comparable effects.
Contributed by Katherine Turner
ABSTRACT: TGFβ 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 TGFβ in suppression of antitumor immunity. Here we show that SAR439459, a pan-TGFβ neutralizing antibody, inhibits all active isoforms of human and murine TGFβ, blocks TGFβ-mediated pSMAD signaling, and TGFβ-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 TGFβ 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 TGFβ 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).