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

• 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
• 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

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 手术切除可治愈肝细胞癌（HCC）。不幸的是，手术病例常常遭受痛苦 早期复发（两年内高达 50%），这会导致令人沮丧的结果。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，HCC 中宿主免疫的抑制是癌症形成和进展的标志。 程序性细胞死亡蛋白 1 (PD-1) 是 T 细胞上的一种免疫检查点受体，可结合 肿瘤基质和癌细胞上的特异性配体（PD-L1、PD-L2）。在初步研究中，我们有 分析了早期 HCC 术前免疫治疗后切除的 HCC 组织。我们发现了特定的集群 与有希望的反应相关，包括在治疗时频繁的病理完全反应 手术（癌症免疫研究 2019）。此外，我们证明PD-​​1阻断可以稳定肿瘤 血管系统，从而在与 VEGF 通路阻断相结合时增强抗肿瘤免疫 HCC 的临床前模型（Hepatology 2020）。我们的目标是证明免疫重编程 肝癌的微环境将为免疫治疗带来更大的益处。我们假设：1） 新辅助抗 PD-L1/VEGF 治疗是可行的、有效的，并且会在可切除的患者中诱导病理完全缓解 HCC，以及 2) 对新辅助抗 PD-L1/VEGF 治疗有反应的 HCC 瘤内 CD8+ 会增加 T 细胞：Treg 比率、循环细胞因子水平以及成像上有利的代谢变化。我们将测试这些 2 个具体目标的假设： 目标 1：评估抗 PD-L1/VEGF 联合治疗的安全性和有效性 在可切除的 HCC 患者的新辅助治疗中。这项随机、多中心 II 期临床研究将 根据 2:1 随机化招募 90 名患者（新辅助 atezo/bev = 60，对比前期手术 = 30） 有 2 个子目标：目标 1a 将评估安全性和病理反应率作为主要终点 atezo/bev 臂；目标 1b 将评估 3 年无复发生存率和 OS 作为次要终点 atezo/bev 组与对照组的比较。目标 2：确定抗肿瘤免疫的激活是否与 可切除的 HCC 患者在新辅助治疗中接受双重抗 PD-L1/VEGF 治疗后产生持久反应， 通过研究组织、外周血和成像参数来实现 3 个子目标。目标 2a 是分析免疫 T- 治疗前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 探索可以预测反应的生物标志物特征。目标 2c 是评估之间的相关性 使用 PET MRI 扫描治疗前后的反应和肿瘤代谢活动的变化。影响 该项目的主要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愈治疗。