Abstract 2771: Circulating biomarkers to predict antitumor response to immunotherapy in advanced unresectable hepatoma
Authors: Feun Lynn G. , Li Ying-Ying , Wu Chunjing , Wangpaichitr Medhi , Chicco Alfred , Savaraj Niramol 
Published: June 2022

Abstract
Background: Hepatocellular carcinoma (HCC) remains one of the most common cancers worldwide. Immunotherapy with various check point inhibitors has been shown to have antitumor activity in HCC. The combination of Atezolizumab plus Bevacizumab resulted in better overall survival and progression-free survival outcome than sorafenib and is now approved for first line for the treatment of HCC. Other PD-1 inhibitors, nivolumab and pembrolizumab, have been shown to have antitumor activity with an overall response rate 20-30% as second line agents. The important question is whether one can find biomarkers which could predict response.
Methods: Plasma biomarkers were measured by ELISA before and during treatment with pembrolizumab for advanced unresectable HCC patients. MiR RNA was carried out by Ocean Ridge Biosciences. Circulating MDSC (CD14+ CD33+ HLA-DR (low) Treg CD4+ CD25+NK cells and exhausted CD8 re-invigoration (Ki 67 in PD-1 + CD8+) were analyzed by flow cytometry.
Results: Serum IL-1β, Il-6, IL-12, IL18, IFN-γ, IL-10, CXCL9, CCL4, CCl5, and circulating PD-L1 were not predictive of response. However, baseline serum TGF-β is one of the predictors for lack of response. Using a cutoff point of 200 pg/ml, TGF-β is also a predictor for progression free survival (P=0.008) and overall survival (p=0.005). In addition, several candidate miRNA were detected higher in responders compared to non-responders. Among them, three miRNAs:1) HsamiR-145b-3p which functions to suppress CD4+ T cell differentiation into Th2/Th17, a tumor suppressor targeting oncogene (i.e. DNMT3 b), 2 ) Has-miR93-5p which targets IL-8, VEGF, diminishing CXCL12 and PD-L1 expression and 3) Has-miR-23b-3b which regulates inflammatory factors (including IL-6, TNF alpha VCAM-1) are consistently higher in the responders compared to non-responders. Among immune cells analyzed, only MDSC (CD14+ CD33+ HLA-DR low) was a good predictor for responders. The responders had a lower MDSC (4.2) and non-responders had high (56.2, p=0.047). Using a cutoff point of 25, MDSC was also a predictor for overall survival (p= 0.026). Both circulating Treg and exhausted CD8 re -invigoration exhibited no differences between responders and non-responders. (12.8 vs 6.2 for Treg and 18.7 vs 25.7 for PD1+ CD8+.T cell re-invigoration, respectively).
Conclusion: Serum TGF-β, MDSC, and miR -145b-3p, miR94-5p, miR -23b-3p are possible circulating biomarkers which one can use to design future clinical trials. In addition, combination therapy with TGF-β inhibitor and checkpoint inhibitor is possible to improve response and survival in these HCC patients, and should be evaluated in a prospective clinical trial. Supported in part by a grant from Sylvester Comprehensive Cancer Center.
Citation Format: Lynn G. Feun, Ying-Ying Li, Chunjing Wu, Medhi Wangpaichitr, Alfred Chicco, Niramol Savaraj. Circulating biomarkers to predict antitumor response to immunotherapy in advanced unresectable hepatoma [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 2771.