Creating a Timeline of Immune Response to DEB-TACE to Optimize Combined Therapy with Immune Checkpoint Blockade in an Animal Model of HCC

Trans-arterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) has demonstrated improved time to progression, survival, and quality of life. However, therapeutic efficacy in intermediate-stage disease is limited, with median survival between 3 to 45 months depending on liver function. There is a critical need for optimizing this treatment to prevent recurrence, prolong survival, and potentially provide curative intent. Immunotherapy, another novel treatment option for cancer, may serve to meet this need. More specifically, immune checkpoint inhibitors targeting programmed cell death 1 (PD-1) have demonstrated efficacy in HCC. Nivolumab (anti-PD-1 antibody) was recently approved for use in HCC, with a response rate of 20% in advanced disease. However, its optimization requires further study. The immunomodulatory effects of chemotherapy have demonstrated the potential to be combined synergistically with immune-targeting agents such as an anti-PD-1 antibody. The objective of this proposal is to characterize the immune response to chemoembolization in order to determine the optimal time period in which to initiate immunotherapy. Characterization of this response will determine the most advantageous timing of chemoembolization-immunotherapy administration to maximize their combined efficacy. We propose studying these effects in a rat model of HCC. HCC will be induced in rats by administration of diethylnitrosamine (DEN) and treated with radiopaque beads pre-loaded with doxorubicin (cytotoxic inhibitor of DNA replication). Unloaded beads will be used as a control group. The baseline and DEB-TACE-induced immune profile will be characterized by comparison of both immune cell presence (CD4/CD8) and PD-1/PD-L1 expression at multiple time points within treatment groups (24 hours, 48 hours, 1 week, 2 weeks, 4 weeks) using flow cytometry and histopathology. This will allow identification of potential immune changes following DEB-TACE that could synergize with immun