Abstract 7608: Exploring the efficacy of atezolizumab plus bevacizumab for advanced hepatocellular carcinoma in relation to tumor-infiltrating lymphocytes
Authors: Kanzaki Hiroaki , Ishino Takamasa , Ogasawara Sadahisa , Yumita Sae , Nakagawa Miyuki , Kojima Ryuta , Koroki Keisuke , Inoue Masanori , Kobayashi Kazufumi , Kanogawa Naoya , Kiyono Soichiro , Nakamura Masato , Kondo Takayuki , Nakamoto Shingo , Takayashiki Tsukasa , Lin Jason , Kawazu Masahito , Komuta Mina , Ikeda Jun-ichiro , Ohtsuka Masayuki , Togashi Yosuke , Kato Naoya 
Published: March 2024

Abstract
Background and Aims: Bevacizumab, an anti-angiogenic agent, is reported to enhance antitumor immunity through various mechanisms, including the suppression of regulatory T (Treg) cells. Additionally, a combination therapy involving the anti-PD-L1 monoclonal antibody, atezolizumab, plus bevacizumab (AtezoBev) has emerged as a standard treatment for advanced hepatocellular carcinoma (aHCC). Given that more than half of treated patients do not respond effectively, identifying biomarkers predictive of clinical efficacy has become an urgent matter. However, the investigation into the tumor microenvironment (TME) has been lagging in aHCC compared to other malignancies due to the difficulty in obtaining tumor samples just before the commencement of systemic therapy.
Methods: We have established a scheme to analyze the TME by obtaining tumor samples immediately before AtezoBev administration, and explored the relevance to its efficacy, focusing on the tumor-infiltrating lymphocytes (TILs) within those samples. Tumor samples from 94 aHCC patients were collected before AtezoBev administration. TME was assessed in 54 patients via flow cytometry and in 72 patients through RNA sequencing, with certain samples undergoing both analyses.
Results: Predominant etiologies in 94 patients were HCV (n=22, 23%), followed by HBV (n=17, 18%), and alcohol abuse (n=16, 17%). The objective response (OR) and disease control rates were 17% and 81%, respectively, with a median progression-free survival (PFS) of 7.6 months. Groups exhibiting high PD-1 positivity of CD8+ T cells (median values as cutoffs) demonstrated superior AtezoBev treatment effects (PFS: 13.1 vs. 4.4 months, p=0.001). In contrast, PD-1 positivity of effector Treg (eTreg) cells in TILs, which reportedly can be one of resistant mechanisms to PD-1 blockade therapy (Togashi Y, et al. Nat Immunol 2020), was not correlated with efficacy. Gene set enrichment analysis highlighted the importance of antigen presentation for OR in groups exhibiting high PD-1 positivity of CD8+ T cells. Additionally, HLA class I expression was elevated in patients achieving an OR. Although previous studies suggest that immunotherapy efficacy could be reduced in non-alcoholic steatohepatitis-related HCC compared with viral-related HCC, no clear association was found between PD-1 positivity of CD8+ T cells or eTreg cells in TILs and etiology. Among the 94 patients, samples from 11 were analyzable at the point of AtezoBev refractoriness, revealing a trend toward reduction in PD-1 positivity of eTreg cells in TILs.
Conclusions: Our findings suggest a correlation between the efficacy of AtezoBev for aHCC and the presence of PD-1+CD8+ T cells within the tumor. In contrast, PD-1+ eTreg cells did not induce resistance along with a trend toward reduction after the treatment possibly due to combination with bevacizumab.
Citation Format: Hiroaki Kanzaki, Takamasa Ishino, Sadahisa Ogasawara, Sae Yumita, Miyuki Nakagawa, Ryuta Kojima, Keisuke Koroki, Masanori Inoue, Kazufumi Kobayashi, Naoya Kanogawa, Soichiro Kiyono, Masato Nakamura, Takayuki Kondo, Shingo Nakamoto, Tsukasa Takayashiki, Jason Lin, Masahito Kawazu, Mina Komuta, Jun-ichiro Ikeda, Masayuki Ohtsuka, Yosuke Togashi, Naoya Kato. Exploring the efficacy of atezolizumab plus bevacizumab for advanced hepatocellular carcinoma in relation to tumor-infiltrating lymphocytes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7608.