To determine the predictive biomarkers and mechanisms of response or resistance to anti-PD-L1 and anti-VEGF combination therapy, Zhu et al. performed an integrated molecular analysis of 358 baseline tumors of HCC. High expression of CD274 (PD-L1), a Teff signature, and intratumoral CD8+ T cell density were associated with better prognosis with the combination, but high TMB or neoantigen load were not. A high Treg/Teff ratio and high GPC3 and AFP expression were associated with reduced clinical benefit. Anti-VEGF therapy inhibited VEGF-mediated angiogenesis, myeloid cell presence, and Treg proliferation to enhance anti-PD-L1 in vivo.
Contributed by Shishir Pant
ABSTRACT: Atezolizumab (anti-programmed death-ligand 1 (PD-L1)) and bevacizumab (anti-vascular endothelial growth factor (VEGF)) combination therapy has become the new standard of care in patients with unresectable hepatocellular carcinoma. However, potential predictive biomarkers and mechanisms of response and resistance remain less well understood. We report integrated molecular analyses of tumor samples from 358_patients with hepatocellular carcinoma (HCC) enrolled in the GO30140 phase_1b or IMbrave150 phase_3 trial and treated with atezolizumab combined with bevacizumab, atezolizumab alone or sorafenib (multikinase inhibitor). Pre-existing immunity (high expression of CD274, T-effector signature and intratumoral CD8(+)_T_cell density) was associated with better clinical outcomes with the combination. Reduced clinical benefit was associated with high regulatory T_cell (Treg) to effector T_cell (Teff) ratio and expression of oncofetal genes (GPC3, AFP). Improved outcomes from the combination versus atezolizumab alone were associated with high expression of VEGF Receptor 2 (KDR), Tregs and myeloid inflammation signatures. These findings were further validated by analyses of paired pre- and post-treatment biopsies, in situ analyses and in vivo mouse models. Our study identified key molecular correlates of the combination therapy and highlighted that anti-VEGF might synergize with anti-PD-L1 by targeting angiogenesis, Treg proliferation and myeloid cell inflammation.
Author Info: (1) Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA. Jiahui International Cancer Center, Jiahui Health, Shanghai, China. (2) Department of Onc
Author Info: (1) Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA. Jiahui International Cancer Center, Jiahui Health, Shanghai, China. (2) Department of Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA, USA. (3) Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (4) Department of Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA, USA. (5) Department of Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA, USA. (6) Department of Research Pathology, Genentech, Inc., South San Francisco, CA, USA. (7) Roche Tissue Diagnostics, Tucson, AZ, USA. (8) Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan. (9) Division of Hematology and Oncology, Georgetown University Medical Center, Washington, DC, USA. (10) Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. (11) Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China. (12) Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (13) Division of Hematology-Oncology, UC San Diego Moores Cancer Center, La Jolla, CA, USA. (14) Department of Medicine, Division of Hematology-Oncology, UC Irvine Health, Orange, CA, USA. (15) Product Development, Genentech, Inc., South San Francisco, CA, USA. (16) Product Development, Genentech, Inc., South San Francisco, CA, USA. (17) The Jonsson Comprehensive Cancer Center, Geffen School of Medicine at UCLA, Los Angeles, CA, USA. (18) Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore. (19) Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Graduate School of Biomedical Sciences at Icahn School of Medicine at Mount Sinai, New York, NY, USA. (20) Department of Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA, USA. wang.yulei@gene.com.
