Thursday, May 2, 2024
5/2/2024
SUMMARY Surgical resection is curative in hepatocellular carcinoma (HCC). Unfortunately, surgical cases often suffer from early recurrence (up to 50% in two years), which leads to dismal outcomes. Currently, there are no approved neoadjuvant therapy options to induce pathologic response and reduce the rate of recurrence. Notably, suppression of host immunity in HCC is a hallmark of cancer establishment and progression. Programmed cell death protein 1 (PD-1) is an immune checkpoint receptor present on T-cells that binds to specific ligands (PD-L1, PD-L2) on both tumor stroma and cancer cells. In preliminary studies, we have analyzed resected HCC tissues after preoperative immunotherapy in early HCC. We found specific clusters correlating with promising responses, including frequent pathologic complete responses at the time of surgery (Cancer Immunol Res 2019). In addition, we demonstrated that PD-1 blockade can stabilize tumor vasculature, thus enhancing anti-tumor immunity when combined with VEGF pathway blockade in preclinical models of HCC (Hepatology 2020). Our goal is to show that reprogramming of immune microenvironment in HCC will result in greater benefit for immunotherapy. We hypothesize that: 1) Neoadjuvant anti-PD-L1/VEGF therapy is feasible, active and will induce pathologic complete response in resectable HCCs, and 2) HCCs responding to neoadjuvant anti-PD-L1/VEGF therapy will have increased intratumoral CD8+ T-cell : Treg ratio, circulating cytokine levels, and favorable metabolic changes on imaging. We will test these hypotheses in 2 specific aims: Aim 1: To evaluate the safety and efficacy of anti-PD-L1/VEGF combination therapy in neoadjuvant setting in resectable HCC patients. This randomized, multi-site phase II clinical study will accrue 90 patients based on 2:1 randomization (neoadjuvant atezo/bev = 60, versus upfront surgery = 30) and has 2 sub-aims: Aim 1a will evaluate safety and pathologic response rate as the primary endpoints in the atezo/bev arm; Aim 1b will evaluate 3-year recurrence-free survival rate and OS as secondary endpoints in the atezo/bev arm versus control. Aim 2: To determine if activation of anti-tumor immunity correlates with durable responses after dual anti-PD-L1/VEGF therapy in neoadjuvant setting in resectable HCC patients, which has 3 sub-aims through studying tissue, peripheral blood, and imaging parameters. Aim 2a is to analyze immune T- cell clusters in pretreatment biopsies and posttreatment surgical resection specimens to evaluate CD8+ T- cell : Treg ratio using multiplexed immunofluorescence and single cell RNA sequencing. Aim 2b is to study changes in tissue immune cells, regulatory proteins, and plasma cytokines (multiplexed protein array) to explore a biomarker signature that may predict response. Aim 2c is to evaluate correlation between response and changes in tumor metabolic activity using PET MRI scan pre- and posttreatment. The impact of this project is that it may transform the role of immunotherapy in HCC from palliative to curative.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
