A Phase II and Biomarker Study of Dual VEGF/PD-L1 Blockade in Neoadjuvant Setting in Resectable HCC Patients

可切除 HCC 患者新辅助治疗中双重 VEGF/PD-L1 阻断的 II 期和生物标志物研究

基本信息

批准号：
10614487
负责人：
HESHAM M AMIN
金额：
$ 60.87万
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：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10614487
关键词：
Adjuvant Therapy Adverse event Aftercare Area BAY 54-9085 Binding Biological Markers Biopsy Blood Vessels CD8-Positive T-Lymphocytes Catchment Area Cells Clinical Clinical Research Combined Modality Therapy Data Early Intervention Excision General Hospitals Geography Goals Hepatology Image Immune Immune response Immunity Immunofluorescence Immunologic Immunotherapy In complete remission Incidence Industry Institution Intervention Invaded Letters Ligands MRI Scans Malignant Neoplasms Massachusetts Metabolic Methodist Church Necrosis Neoadjuvant Study Neoadjuvant Therapy Nivolumab Operative Surgical Procedures Outcome PD-L1 blockade Pathologic Pathway interactions Patients Pharmaceutical Preparations Phase Pilot Projects Plasma Positron-Emission Tomography Pre-Clinical Model Primary carcinoma of the liver cells Prospective cohort Protein Array Randomized Recurrence Regimen Regulatory T-Lymphocyte Resectable Resected Role Safety Site Specimen Survival Rate T cell infiltration T-Lymphocyte Testing Time Tissues Toxic effect Tumor Immunity Tumor Tissue Unresectable Vascular Endothelial Growth Factors alpha-Fetoproteins anti-PD-L1 anti-cancer arm bevacizumab biobank biomarker signature cancer cell checkpoint receptors clinical biomarkers cost cytokine design effector T cell genetic regulatory protein imaging biomarker immune checkpoint improved innovation ipilimumab liver cancer model mortality novel objective response rate palliative peripheral blood phase 2 study phase 3 study phase III trial preclinical study predicting response primary endpoint programmed cell death ligand 1 programmed cell death protein 1 randomized, clinical trials response routine practice secondary endpoint single-cell RNA sequencing standard of care synergism targeted treatment treatment arm trial design tumor tumor-immune system interactions

项目摘要

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.

概括手术切除术在肝细胞癌（HCC）中是治愈性的。不幸的是，手术病例经常受苦从早期复发（两年内最高50％），这会导致惨淡的结果。目前，没有批准的新辅助治疗方案可诱导病理反应并降低复发率。值得注意的是，在HCC中抑制宿主免疫是癌症建立和进展的标志。程序性细胞死亡蛋白1（PD-1）是T细胞上存在的免疫检查点受体，该受体结合到肿瘤基质和癌细胞上的特定配体（PD-L1，PD-L2）。在初步研究中，我们有在早期HCC中，分析了术前免疫疗法后切除的HCC组织。我们找到了特定的群集与有希望的反应相关，包括在手术（癌症Immunol Res 2019）。此外，我们证明了PD-1封锁可以稳定肿瘤脉管系统，从 HCC的临床前模型（肝病学2020）。我们的目标是证明免疫的重新编程 HCC中的微环境将为免疫疗法带来更大的好处。我们假设：1）新辅助抗PD-L1/VEGF疗法是可行的，有效的，并且会诱导可切除的病理完全反应 HCC和2）响应新辅助抗PD-L1/VEGF治疗的HCC将增加肿瘤内CD8+ T细胞：Treg比率，循环细胞因子水平以及成像的有利代谢变化。我们将测试这些两个特定目标中的假设：目标1：评估抗PD-L1/VEGF组合疗法的安全性和功效在可切除的HCC患者中的新辅助设置中。这项随机的多站点II期临床研究将基于2：1随机分组的90例患者（Neoadjuvant atezo/bev = 60，与前期手术相比= 30）并有2个子aims：AIM 1A将评估安全性和病理反应率作为主要终点 atezo/bev臂； AIM 1B将评估3年无复发的生存率和OS作为次要终点在Atezo/BEV组与对照中。目标2：确定抗肿瘤免疫的激活是否与在可切除的HCC患者的新辅助设置中，双重抗PD-L1/VEGF治疗后的耐用反应通过研究组织，外周血和成像参数的3个亚ims。目标2a是分析免疫T- 预处理活检和治疗后手术切除标本中的细胞簇，以评估CD8+ T- 细胞：使用多重免疫荧光和单细胞RNA测序的Treg比率。目标2B是学习组织免疫细胞，调节蛋白和血浆细胞因子（多重蛋白阵列）的变化探索一个可以预测反应的生物标志物签名。 AIM 2C是评估相关性使用PET MRI扫描前后治疗的反应和肿瘤代谢活性的变化。影响这个项目的是，它可能会将免疫疗法在HCC中的作用从姑息治疗转变为治疗。