Abstract 4213: Targeting the cMet inhibitors combined with anti-PD-1 therapy: Preclinical approach to turn the resistance into opportunities for overcoming tumor evasion
Authors: de Azevedo Ricardo Alexandre , Cheng-En Hsieh , Jayaprakash Priyamvada , Bhanu Krithikaa Rajkumar , Srinivasamani Anupallavi , Morrow Brittany , Winkler Michelle , Hedge Shweta Mahendra , Liu Arthur , Curran Michael A. 
Published: June 2022

Abstract
Liver cancer is the fourth most common cause of cancer-related mortality world-wide, and Hepatocellular carcinoma (HCC) is the most common form of liver cancer accounting for 90% of cases. Therapeutic strategies include surgical resection, radiotherapy, liver transplantation and pharmacological treatment with small-molecules multikinase inhibitors and/or immune-checkpoint blockade (ICB); however, outcomes remain poor and improvements to systemic therapy are desperately needed. Recently, Cabozantinib a kinase inhibitor with activity against VEGFR2, AXL and cMET, has been approved for second line use in advanced HCC; however, monotherapy achieves less than a 4-month extension of overall survival. Previously, our collaborators demonstrated that the efficacy of cMet inhibition is self-limited by induction of high PD-L1 expression. Given this data, the goal of our study was to investigate the efficacy of combining cMet inhibition with either capmatinib or cabozantinib with antibody blockade of the PD-1 immune checkpoint receptor for therapy of HCC. Using multiple syngeneic, immunocompetent models of HCC (Hepa1-6, HCA) in two different strains of mice (C57BL6, C3H), we investigated the combination potential of each of these cMet inhibitors with anti-PD-1 antibodies. Further, we profiled the changes to the tumor infiltrating myeloid and T cell repertoires which correlated to mono- as well as combination therapy responses in these animals using high content flow cytometry on a BD X-30. We found Hepa1-6 to be exquisitely anti-PD-1 sensitive with 100% of animals being cured by the combination. In the less immunotherapy-sensitive HCA-1 model, we also found that the cMet inhibitors cooperate with PD-1 blockade to promote rejection of HCA-1 HCC model. Again, we found that combination therapy could cure nearly all animals of pre-implanted HCA-1 tumors. Mechanistically, we found that concomitant cMet inhibition enhances the efficacy of PD-1 therapy increasing the number of tumor-infiltrating CD4 Teff cells while decreasing the CD4 Treg population. We also found that combined therapy improves CD8+ T cell infiltration, memory CD8 T cell fraction and NK cytotoxic potential within the tumor microenvironment. Within the HCA-1 myeloid compartment, we discovered a significant decrease in the tumor-associated neutrophil (N2-TAN) population (PMN-MDSC). Further, we found that combination therapy promotes pro-inflammatory M1 conversion of stromal macrophages. Collectively, these data provide a rationale for combining anti-PD-1 therapy with cMet inhibitors as a potential strategy to overcome resistance to immune checkpoint blockade therapy in HCC.
Citation Format: Ricardo Alexandre de Azevedo, Hsieh Cheng-En, Priyamvada Jayaprakash, Krithikaa Rajkumar Bhanu, Anupallavi Srinivasamani, Brittany Morrow, Michelle Winkler, Shweta Mahendra Hedge, Arthur Liu, Michael A. Curran. Targeting the cMet inhibitors combined with anti-PD-1 therapy: Preclinical approach to turn the resistance into opportunities for overcoming tumor evasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4213.