Project Summary/Abstract: HCC is the third most common cause of cancer-related death worldwide. Recurrence rates after curative resection remain high, especially in high-risk HCC which includes large tumors (>5 cm), multifocal disease and tumors with vascular invasion. Further complicating clinical management of HCC is the fact that currently no neoadjuvant or adjuvant therapies are available. We now also appreciate that recurrence is mediated via immune mechanisms. In support of this are observations that increased tumor infiltrating CD8+ T cells are associated with better outcomes and less recurrence in resected HCC. Conversely, high proportions of immune inhibitory cells including tumor associated fibroblast (TAMs), myeloid derived suppressor cells (MDSCs), T regulatory cells (Tregs) contribute to resistance to immune checkpoint blockade and poor prognosis in HCC. Other soluble mediators such as vascular endothelial growth factor (VEGF), colony stimulating factor 1 (CSF-1), and platelet- derived growth factor (PDGF), are also secreted by tumor cells to promote an immunosuppressive environment. This proposal will determine how the multikinase activity of regorafenib complements antitumor activity of anti- PD-L1 antibody therapy, by targeting key pathways of relevance to Tregs, MDSCs, and TAMs, all of which contribute to resistance to immunotherapy. Thus, by targeting multiple kinases that foster maintenance of these cells, we postulate regorafenib will limit their persistence in the microenvironment and improve the efficacy of PD-L1 blockade in the neoadjuvant setting of HCC. The central hypothesis of this proposal is that multikinase inhibition with regorafenib will limit suppressive features in the HCC tumor microenvironment and permit more robust effector CD8+ T cell expansion and infiltration upon immune checkpoint blockade. This hypothesis will be tested via two aims: 1: To determine the effects of regorafenib and durvalumab on suppressive immune features in HCC. 2: To define the impact of neoadjuvant regorafenib and durvalumab on chemokine signatures and infiltrating T cell phenotypes in HCC tumors. In the current proposal, we will advance the field by applying this novel combination in high-risk HCC in the preoperative setting. Using innovative translational approaches and patient specimens from early to intermediate stage HCC, we will address relationships between inhibitory immune cells and CD8+ T cell subsets. This approach also provides a unique opportunity to explore mechanistic effects of the regorafenib and durvalumab combination in the TME by utilizing paired tissue samples. It will further our knowledge of changes in the TME induced by the immunotherapy/targeted therapy combination, help understand mechanisms of resistance and define the next steps in improving the current regimen. Developing a new and effective preoperative systemic therapy at this critical point in disease progression may provide the best chance for improved long-term survival and therefore have a significant impact on the outcome of HCC.

Project Narrative Hepatocellular carcinoma is third most common cause of cancer-related death worldwide. Recurrence after curative surgery is influenced by interactions with white blood cells in the immune system. The proposed research will explore the impact of a novel immune-based systemic therapy given before surgery. We will obtain patient tissue and blood to define the mechanism of this novel treatment combination, and identify factors associated with response or resistance that can be used in future studies.