Virtual clinical trials of anti-PD-1 and anti-CTLA-4 immunotherapy in advanced hepatocellular carcinoma using a quantitative systems pharmacology model

• DOI: 10.1136/jitc-2022-005414
• Publication Date: 2022-11-02T15:07:44Z
• Authors: Richard J Sové; Babita K Verma; Hanwen Wang; Won Jin Ho; Mark Yarchoan; Aleksander S Popel
• Keywords: CTLA-4; Immune checkpoint; Cancer Immunotherapy

Background Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer and third-leading cause cancer-related death worldwide. Most patients with HCC are diagnosed at an advanced stage, median survival for treated modern systemic therapy less than 2 years. This leaves stage limited treatment options. Immune checkpoint inhibitors (ICIs) targeting programmed cell protein 1 (PD-1) or its ligand, widely used in associated durable responses a subset patients. ICIs cytotoxic T-lymphocyte-associated 4 (CTLA-4) also have clinical activity HCC. Combination nivolumab (anti-PD-1) ipilimumab (anti-CTLA-4) first option to be approved by Food Drug Administration that targets more one immune checkpoints. Methods In this study, we framework quantitative systems pharmacology (QSP) perform virtual trial Our model incorporates detailed biological mechanisms interactions cells leading antitumor response. To conduct trial, generate patient from cohort 5,000 proposed extending recent algorithms literature. The was calibrated using data CheckMate 040 (ClinicalTrials.gov number, NCT01658878 ). Results Retrospective analyses were performed different therapies as 040. Using machine learning approach, predict importance potential biomarkers blockade therapies. Conclusions QSP predictions consistent clinically observed outcomes. study demonstrates mechanistic understanding underlying pathophysiology, models can facilitate selection design trials improved success.