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

Article Details

Citation
Copy to clipboard

Greco R, Qu H, Qu H, Theilhaber J, Shapiro G, Gregory R, Winter C, Malkova N, Sun F, Jaworski J, Best A, Pao L, Hebert A, Levit M, Protopopov A, Pollard J, Bahjat K, Wiederschain D, Sharma S

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

Oncoimmunology. 2020 Sep 13;9(1):1811605. doi: 10.1080/2162402X.2020.1811605.

PubMed ID
33224628 [ View in PubMed
]
Abstract

TGFbeta 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 TGFbeta in suppression of antitumor immunity. Here we show that SAR439459, a pan-TGFbeta neutralizing antibody, inhibits all active isoforms of human and murine TGFbeta, blocks TGFbeta-mediated pSMAD signaling, and TGFbeta-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 TGFbeta 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 TGFbeta 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).

DrugBank Data that Cites this Article

Drugs