权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Project 1: Targeting the PD-1 pathway in HCC

项目 1：针对 HCC 中的 PD-1 通路

基本信息

批准号：
10024077
负责人：
Ahmed Kaseb
金额：
$ 38.78万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-25 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10024077
关键词：
Adjuvant Adverse event Affect Attenuated BAY 54-9085 Binding CD3 Antigens CD8-Positive T-Lymphocytes CD80 gene CD86 gene CD8B1 gene CTLA4 gene Cancer Etiology Cells Clinical Clinical Trials Collaborations Combined Modality Therapy Development Event Excision Fibrosis Goals Immune Immune Targeting Immune response Immunity Immunotherapy Infiltration Lead Ligands Malignant Epithelial Cell Molecular Mus Neoadjuvant Therapy Nivolumab Operative Surgical Procedures Outcome Pathologic Pathway interactions Patients Perioperative Pharmaceutical Preparations Primary carcinoma of the liver cells Protein Tyrosine Kinase Randomized Recurrence Regimen Regulatory T-Lymphocyte Reporting Resectable Resected Sampling Signal Transduction T-Lymphocyte TNF gene Testing Therapeutic Treatment Efficacy Tumor-infiltrating immune cells University of Texas M D Anderson Cancer Center Unresectable anti-PD-1 anti-PD1 therapy anti-tumor immune response arm base cancer cell cell killing checkpoint receptors checkpoint therapy curative treatments effector T cell immune checkpoint improved improved outcome inhibitor/antagonist innovation liver transplantation macrophage mortality mouse model novel novel drug combination overexpression partial response programmed cell death ligand 1 programmed cell death protein 1 randomized trial response response biomarker targeted treatment three-arm clinical trial treatment response tumor

项目摘要

Project 1 – SUMMARY/ABSTRACT The multi-kinase inhibitors, sorafenib (first-line use) and regorafenib (second-line use), have been approved for the treatment of advanced HCC; however, the overall survival improves by less than 3 months and the overall response rates are low (<10%). Resection and liver transplantation are curative treatments for HCC; however, less than 20% of HCC patients are eligible for resection and early recurrence is frequent (50% in 2 years). Because the predominant molecular alterations in HCC are not druggable, targeting immune checkpoints such as programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) may be a promising alternative strategy. The anti-PD1 drug, nivolumab, was recently approved for HCC therapy. With a 20% response rate, anti-PD1 therapy is encouraging, opening opportunities for more effective therapeutic approaches. In resected HCC samples, we found tumor-infiltrating T cells expressing PD-1 and CTLA-4, surrounded by a dense macrophage infiltrate rich in the checkpoint ligands PD-L1 and PD-L2. While increased immune response by targeting PD-1 and CTLA-4 pathways has been reported in unresectable HCC, immunotherapy strategies have not yet been evaluated in neoadjuvant (pre-surgery) and adjuvant (post-surgery) settings. In a pilot randomized perioperative trial with nivolumab ± ipilimumab (anti-CTLA-4) for resectable HCC, we observed complete pathologic responses in 2 cases that correlated with an increase in CD8+ T cell infiltration and CD8/Treg ratio. Based on the 6 patients accrued to date, none had drug related events that led to delaying or canceling surgery and we didn’t encounter grade 3 or 4 adverse events. The tyrosine kinase c-MET is overexpressed in HCC, and multiple c-MET inhibitors have been developed and evaluated in clinical trials in HCC. However, the reported outcomes were disappointing. We showed that c-MET inhibitors upregulate PD-L1 expression in HCC cells, which may allow HCC cells to escape from T cell killing. We further showed that the combination of c-MET inhibitors and anti-PD-1 synergistically suppresses HCC development in mice. Our long- term translational goal is to modulate immune cells in HCC microenvironment to improve outcome in patients with advanced HCC or resectable HCC. We hypothesize that neoadjuvant immune checkpoint therapy in HCC can trigger an immune response which may lead to delay in recurrence or increased resectability, and that immune infiltration or fibrosis stage can affect treatment response. We also hypothesize that the efficacy of HCC immunotherapy can be improved by simultaneously targeting immune checkpoint signaling and checkpoint molecule expression. In Aim 1, we propose a neoadjuvant/adjuvant clinical trial targeting PD-1 ± CTLA4 in surgical HCC patients to delay recurrence and in locally advanced unresectable HCC patients to increase resectability. In Aim 2, we will evaluate novel combination therapies including anti-PD-1 and agents upregulating PD-L1 expression, such as c-MET inhibitors, in HCC. The impact of this project would be increased access to surgery for a larger number of HCC patients and improve overall survival in patients with advanced HCC.

项目1 -摘要/摘要