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

项目摘要 免疫疗法彻底改变了各种晚期癌症的治疗，特别是免疫治疗。 检查点封锁（ICB）。尽管FDA新批准的阻断CTLA-4或PD-1的抗体提供了 对有些病人希望，但不是所有病人都有反应，还有一些病人在最初反应后复发。 因此，用其他方法评估免疫检查点阻断是非常重要的。 触发免疫激活的疗法基于我们的广泛的临床前和临床结果， 组，我们专注于免疫检查点阻断与低分次 放疗（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更好应答的抗原。在前一阶段， 伊匹单抗与HFRT在晚期黑色素瘤患者中的试验中，我们观察到一些病例的深部 客观反应，让人想起以前的病例报告，但只有18%的患者。在广泛 在临床前实验中，我们模拟了辐射和ICB的相互作用， 阻断CTLA-4和PDL-1/PD-1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的肿瘤消退和完全反应，而没有 主要毒性（Tyman-Saint维克托，Nature，2015）。CTLA-4和PD-L1阻断都是需要的， 最佳治疗，因为每种方式都能非冗余地提高反应和免疫力。PD-L1阻断是 尤其重要的是克服免疫抵抗，因为我们的数据显示，HFRT + 单独的CTLA-4阻断受到肿瘤中PD-L1表达的限制，这一发现在来自 我们的初审基于这些临床前数据，我们提出了两项立即临床试验， 与阻断CTLA-4（伊匹单抗或曲美木单抗）或PD-1的核心C联合药物合作 1/PD-L1（nivolumab或durvalumab）联合HFRT：（目的1）一项伊匹单抗和 nivolumab联合或不联合HFRT治疗转移性黑色素瘤患者，以及（目的2）一项1期试验， 曲美木单抗和杜伐鲁单抗在转移性胰腺癌、肺癌和乳腺癌患者中的应用。在Aim中 3.我们将在所有项目中采用全面的免疫评估计划 和核心，以确定我们的方法的免疫机制。预期 临床和免疫学发现将显着推进发展辐射和免疫 检查点疗法。 1

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