Project 3: Measles virus based immunovirotherapy in the treatment of metastatic breast cancer

项目摘要 乳腺癌是世界上最常见的恶性肿瘤，也是女性癌症死亡率的第二大原因。 我们尽管内分泌治疗、化疗和生物制剂的可用性， 癌症仍然无法治愈。溶瘤病毒疗法缺乏与常规系统性治疗的交叉耐药性。 乳腺癌的干预措施，以及积累的临床前和临床证据表明， 诱导的抗肿瘤免疫可能有助于这些病毒载体的治疗效果。溶瘤 在发表了一些病例后，首次认识到野生型麻疹病毒（MV）的潜力 报告记录了自然MV感染后各种恶性血液病的消退。为了 为了避免与使用野生型MV菌株相关的潜在并发症，我们率先使用工程化的 Edmonston MV疫苗谱系菌株在癌症治疗中的应用。MV毒株编码的早期临床试验 钠碘同向转运体（NIS）标记基因（MV-NIS）在晚期显示临床活性， 恶性肿瘤伴抗肿瘤免疫应答的发展。乳腺MV菌株的平行工作检测 肿瘤细胞系和动物模型显示出显著的抗肿瘤活性，与肿瘤细胞感染相关 和病毒复制，不依赖于ER/PR和HER2受体状态， 为了证实这种溶瘤病毒治疗方法的潜力，我们对MV疫苗株进行了工程改造，使其表达一种 免疫刺激转基因，嗜中性粒细胞活化蛋白的H。幽门螺杆菌（NAP），一种有效的Toll样受体2 激动剂，并且我们证明了编码NAP的MV菌株的上级抗肿瘤功效。效应期免疫 免疫反应可能受到免疫抑制机制的抑制，其中PD-1/PD-L1轴起着重要作用。 突出的作用。随着越来越多的证据表明单药抗PD-1药物在难治性肿瘤中具有抗肿瘤活性， 对于乳腺癌患者，免疫检查点阻断有很大的潜力，以增加有希望的 溶瘤免疫病毒疗法在乳腺癌中的抗肿瘤活性。因此，我们假设， MV-s-NAP与PD-1阻断剂的组合将是协同的，并且在以下方面优于单独的任一种药剂： 乳腺癌的治疗在具体目标1中，我们将进行第一次人体I期临床试验， 转移性乳腺癌中的瘤内麻疹病毒（MV-s-NAP）制剂。在具体目标2中，我们将评估 MV病毒治疗与抗体联合的有效性、最佳顺序和作用机制 在免疫活性乳腺癌模型中阻断PD-1/PD-L1轴;并进行临床前 毒理学研究，以评估麻疹复制允许转基因患者联合治疗的安全性 模型和评估生物分布。在Aim Specific 3中，我们将进行第一个I期临床试验来测试 肿瘤内MV-s-NAP和PD-1阻断的组合在转移性乳腺癌患者中的应用。的 两项I期临床试验的主要临床终点是（a）评价安全性和耐受性和（B） 确定最大耐受剂量（MTD）;此外，将采集组织和血液样本以评估 用于单独使用MV和与检查点阻断组合的全身性抗肿瘤免疫应答。的 通过引入一种新的治疗方法，拟议的一系列临床前和临床研究将产生重大影响。 乳腺癌的治疗方法

Project Summary Breast cancer is the most common malignancy and the second leading cause of female cancer mortality in the US. Despite the availability of endocrine therapy, chemotherapeutics, and biologic agents, metastatic breast cancer remains incurable. Oncolytic virotherapy lacks cross resistance with conventional systemic interventions for breast cancer, and accumulating preclinical and clinical evidence suggests that viral cell death induced antitumor immunity may contribute to the therapeutic effects of these viral vectors. The oncolytic potential of wild type measles virus (MV) was first recognized following the publication of a number of case reports documenting regression of various hematologic malignancies after natural MV infection. In order to avoid potential complications associated with use of wild type MV strains, we pioneered the use of engineered strains of Edmonston MV vaccine lineage in cancer treatment. Early clinical testing of MV strains encoding for the sodium iodine symporter (NIS) marker gene (MV-NIS) by our group showed clinical activity in advanced malignancies with development of antitumor immune response. Parallel work testing of MV strains in breast cancer lines and animal models demonstrated significant antitumor activity, associated with tumor cell infection and viral replication, independent of ER/PR and HER2 receptor status, To enhance the immunotherapeutic potential of this oncolytic virotherapy approach, we engineered the MV vaccine strain to express an immunostimulatory transgene, the neutrophil activating protein of H. pylori (NAP), a potent toll-like receptor 2 agonist, and we demonstrated superior antitumor efficacy of NAP encoding MV strains. Effector phase immune responses may be dampened by immune-suppressive mechanisms among which the PD-1/PD-L1 axis plays a prominent role. With growing evidence of the antitumor activity of single agent anti-PD-1 agents in refractory breast cancer patients, there is significant potential for immune checkpoint blockade to augment the promising antitumor activity of oncolytic immunovirotherapy in breast cancer. We therefore hypothesize that combining MV-s-NAP with PD-1 blockade will be synergistic and superior to either agent alone in the treatment of breast cancer. In Specific Aim 1, we will conduct the first in-human phase I clinical trial of single- agent intratumoral measles virus (MV-s-NAP) in metastatic breast cancer. In Specific Aim 2, we will evaluate the efficacy, optimal sequence and mechanism of action of MV virotherapy in conjunction with antibody blockade of the PD-1/PD-L1 axis in immunocompetent breast cancer models; and conduct preclinical toxicology studies to evaluate the safety of combination therapy in measles replication permissive transgenic models and assess biodistribution. In Specific Aim 3, we will conduct the first phase I clinical trial to test the combination of intratumoral MV-s-NAP and PD-1 blockade in patients with metastatic breast cancer. The primary clinical endpoints of the two phase I clinical trials are to (a) evaluate safety and tolerability and (b) identify the maximum tolerated dose (MTD); in addition, tissue and blood samples will be collected to assess for systemic antitumor immune response with MV alone and in combination with checkpoint blockade. The proposed series of preclinical and clinical studies will have significant impact by introducing a novel therapeutic approach to the armamentarium against breast cancer.