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

项目摘要 乳腺癌是我国最常见的恶性肿瘤，也是女性癌症死亡的第二大原因。 我们。尽管有内分泌治疗、化疗药物和生物制剂，转移性乳房 癌症仍然是无法治愈的。溶瘤病毒治疗与常规全身治疗缺乏交叉耐药性 对乳腺癌的干预，以及积累的临床前和临床证据表明，病毒细胞死亡 诱导的抗肿瘤免疫可能有助于这些病毒载体的治疗作用。溶瘤术 在一些病例公布后，人们首次认识到野生型麻疹病毒(MV)的潜在可能性 关于自然感染MV后各种恶性血液病消退的报道。为了 避免了与使用野生型MV毒株相关的潜在并发症，我们率先使用了 埃德蒙斯顿MV疫苗谱系在癌症治疗中的应用。编码猪瘟病毒毒株的早期临床检测 本课题组发现的钠碘转运体(NIS)标志基因(MV-NIS)在晚期具有临床活性。 发生抗肿瘤免疫反应的恶性肿瘤。乳房中MV毒株的平行检测 癌细胞株和动物模型显示出显著的抗肿瘤活性，与肿瘤细胞感染有关 和病毒复制，独立于ER/PR和HER2受体状态，增强免疫治疗 这种溶瘤病毒治疗方法的潜力，我们设计了MV疫苗株来表达 免疫刺激性转基因幽门螺杆菌中性粒细胞激活蛋白(NAP)是一种有效的Toll样受体2 激动剂，我们证明了编码MV毒株的NAP具有良好的抗肿瘤效果。效应期免疫 反应可能受到免疫抑制机制的抑制，其中PD-1/PD-L1轴起作用 作用突出。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的抗肿瘤活性 乳腺癌患者存在免疫检查点阻断的巨大潜力，以增加前景 溶瘤免疫病毒疗法在乳腺癌中的抗肿瘤作用。因此，我们假设 MV-S-NAP与PD-1拮抗剂联合应用具有协同作用，优于单独使用任何一种药物 乳腺癌的治疗。在具体目标1中，我们将进行第一个人体内I期临床试验， 瘤内麻疹病毒(MV-S-NAP)在转移性乳腺癌中的作用在具体目标2中，我们将评估 MV病毒联合抗体治疗的疗效、最佳顺序及作用机制 在免疫活性乳腺癌模型中阻断PD-1/PD-L1轴；并进行临床前研究 评价麻疹复制允许性转基因联合治疗安全性的毒理学研究 建立模型并评估生物分布。在具体目标3中，我们将进行第一阶段临床试验，以测试 MV-S-NAP联合PD-1阻断治疗转移性乳腺癌这个 两个I期临床试验的主要临床终点是：(A)评估安全性和耐受性；(B) 确定最大耐受量(MTD)；此外，将收集组织和血液样本以评估 单用MV和联合检查点阻断的全身抗肿瘤免疫反应。这个 拟议的一系列临床前和临床研究将通过引入一种新的治疗方法产生重大影响 探讨乳腺癌的治疗方法。

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.