Project 1: Clinical and immune impact of radiation and dual checkpoint blockade in patients

项目 1：辐射和双重检查点封锁对患者的临床和免疫影响

基本信息

批准号：
10005190
负责人：
ROBERT H VONDERHEIDE
金额：
$ 64.61万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10005190
关键词：
Address Advanced Development Advanced Malignant Neoplasm Aftercare Antigen-Presenting Cells Antigens Biological Markers Biological Response Modifiers Blocking Antibodies CTLA4 blockade CTLA4 gene Case Study Cessation of life Clinical Clinical Data Clinical Trials Collaborations Data Evaluation Exposure to FDA approved Histology Immune Immune system Immunity Immunologics Immunomodulators Immunosuppression Immunotherapy In complete remission Lesion Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of pancreas Melanoma Cell Metabolic Metastatic Melanoma Modality Modeling Monoclonal Antibodies Mus Nature Nivolumab Non-Small-Cell Lung Carcinoma PD-1/PD-L1 PD-L1 blockade Pathway interactions Patients Pharmacodynamics Phase Program Research Project Grants Publishing Radiation Radiation Interaction Radiation therapy Randomized Relapse Renal Cell Carcinoma Resistance Saints Sampling Schedule T-Cell Activation T-Cell Receptor T-Lymphocyte Toxic effect Treatment Efficacy Tumor Antigens Tumor-Derived arm base checkpoint receptors checkpoint therapy exhaust experimental study immune activation immune checkpoint immune checkpoint blockade immune resistance improved indexing interest ipilimumab irradiation malignant breast neoplasm melanoma objective response rate optimal treatments partial response phase I trial pre-clinical programmed cell death ligand 1 programmed cell death protein 1 randomized trial receptor response safety and feasibility targeted agent treatment arm tumor

项目摘要

Project Summary Immunotherapy has revolutionized the treatment of a variety of advanced cancers, especially immune checkpoint blockade (ICB). Although newly FDA approved antibodies that block CTLA-4 or PD-1 offer hope for some patients, not all patients respond, and others relapse after initial response. Consequently, there is a great importance in evaluating immune checkpoint blockade with other therapies that trigger immune activation. Based on extensive preclinical and clinical results from our group, we are focused on the combination of immune checkpoint blockade with hypofractionated radiotherapy (HFRT). The rationale for this approach is emerging evidence from our group and others that irradiation of tumors can stimulate the immune system, perhaps by releasing tumor-associated antigens which may allow for better response to the immunomodulatory agents. In a previous phase I trial of ipilimumab with HFRT in patients with advanced melanoma, we observed some cases of deep objective responses, reminiscent of prior case reports, but only in 18% of patients. In extensive preclinical experiments in which we modeled the interactions of radiation and ICB, we found across multiple histologies (breast and pancreatic cancer, melanoma) that blockade of CTLA-4 and PDL-1/PD- 1 in combination with HFRT achieved major tumor regressions and complete responses in mice without major toxicity (Tyman-Saint Victor, Nature, 2015). Both CTLA-4 and PD-L1 blockade are required for optimal therapy as each modality non-redundantly improves response and immunity. PD-L1 blockade is especially important to overcome immune resistance, as our data show that efficacy of HFRT plus CTLA-4 blockade alone is limited by PD-L1 expression in the tumor, a finding validated in samples from our initial trial. Based on these pre-clinical data, we propose two immediate clinical trials in collaboration with Core C combining agents that block CTLA-4 (ipilimumab or tremelimumab) or PD- 1/PD-L1 (nivolumab or durvalumab) with HFRT: (Aim 1) a phase 2 randomized trial of ipilimumab and nivolumab with or without HFRT in patients with metastatic melanoma, and (Aim 2) a phase 1 trial of tremelimumab and durvalumab in patients with metastatic pancreatic, lung, and breast cancer. In Aim 3, we will apply a comprehensive plan for immune assessment with collaborations across all Projects and Cores in this P01 to determine the immunological mechanisms of our approach. The expected clinical and immunological findings will significantly advance the development radiation and immune checkpoint therapy for patients. 1

项目概要免疫疗法彻底改变了多种晚期癌症的治疗，特别是免疫疗法检查站封锁（ICB）。尽管 FDA 新批准了阻断 CTLA-4 或 PD-1 的抗体希望对一些患者来说，并非所有患者都有反应，还有一些患者在初次反应后会复发。因此，与其他药物一起评估免疫检查点阻断非常重要。触发免疫激活的疗法。基于我们的广泛临床前和临床结果小组中，我们专注于免疫检查点阻断与大分割的结合放射治疗（HFRT）。这种方法的基本原理是来自我们小组和其他人的新证据肿瘤的辐射可以刺激免疫系统，也许是通过释放肿瘤相关的可以允许对免疫调节剂有更好反应的抗原。在之前的第一阶段在晚期黑色素瘤患者中进行 ipilimumab 联合 HFRT 试验，我们观察到一些深部黑色素瘤病例客观反应，让人想起之前的病例报告，但仅发生在 18% 的患者中。在广泛的在我们模拟辐射和 ICB 相互作用的临床前实验中，我们发现阻断 CTLA-4 和 PDL-1/PD- 的多种组织学（乳腺癌和胰腺癌、黑色素瘤） 1 与 HFRT 组合在小鼠中实现了主要肿瘤消退和完全缓解主要毒性（Tyman-Saint Victor，《自然》，2015）。 CTLA-4 和 PD-L1 阻断都是必需的最佳治疗，因为每种方式都非冗余地改善反应和免疫力。 PD-L1 阻断是对于克服免疫抵抗尤为重要，因为我们的数据表明 HFRT 加的功效单独使用 CTLA-4 阻断剂会受到肿瘤中 PD-L1 表达的限制，这一发现在以下样本中得到验证：我们的初步审判。根据这些临床前数据，我们建议立即进行两项临床试验与 Core C 联合阻断 CTLA-4（ipilimumab 或 tremelimumab）或 PD-的药物合作 1/PD-L1（nivolumab 或 durvalumab）联合 HFRT：（目标 1）ipilimumab 和的 2 期随机试验纳武单抗联合或不联合 HFRT 治疗转移性黑色素瘤患者，以及（目标 2）一项 1 期试验 tremelimumab 和 durvalumab 用于治疗转移性胰腺癌、肺癌和乳腺癌患者。瞄准 3、我们将通过所有项目的合作，应用全面的免疫评估计划和 P01 中的核心以确定我们方法的免疫机制。预期的临床和免疫学发现将显着促进放射和免疫的发展患者的检查点治疗。 1