Abstract 1909: Pan-TGF-β inhibition with PD-1 blockade as a combination treatment strategy to augment anti-tumor immune response in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide, accounting for more than 700,000 deaths per year. Although transforming growth factor beta (TGF-β) can function as a tumor-suppressor in premalignant cells, patient data suggest that it plays a role in the progression of HCC. Recently, immunotherapy targeting PD-1 has been approved for HCC, however, success is limited to only ~17% objective response rate in the treated HCC patients. Analysis of genomic data from two HCC patient cohorts revealed that TGF-β pathway is highly activated in patients with advanced HCC. Collectively, these findings indicate that targeting TGF-β in combination with PD-1 blockade may be a compelling therapeutic strategy. Therefore, using two syngeneic mouse models of HCC (Hepa1-6 and H22), we examined the effect of a pan-TGF-β neutralizing antibody (1D11) in combination with PD-1 blockade. Results from our study show that co-inhibiting TGF-β with PD-1 resulted in significant tumor growth inhibition in both HCC models. Flow cytometry analysis of the tumor revealed the combination treatment group exhibited a reduction in potentially suppressive tumor-associated-macrophages relative to either single agent groups. In addition, we show that combination therapy was associated with increase in the intra-tumoral levels of proinflammatory cytokines - IFNγ, IL-1β, TNF-α as well as enhanced expression of anti-tumor immune related genes. Based on these data, clinical testing of SAR439459 (TGF-β antibody) and Cemiplimab (anti-PD1) combination has recently been initiated in HCC patients (NCT03192345). Citation Format: Natalia Malkova, Joachim Theilhaber, Mikhail Levit, Tatiana Tolstykh, Andrew Hebert, Kevin Atchison, Adalis Maisonet, Sara Sara Sinicropi-Yao, Alexei Protopopov, Jack Pollard, Sukhvinder Sidhu, Tun Tun Lin, Lily Pao, Dmitri Wiederschain, Sharad K. Sharma. Pan-TGF-β inhibition with PD-1 blockade as a combination treatment strategy to augment anti-tumor immune response in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1909.