Oncolytic Immunotherapy using Chimeric HSV C134: A Phase I Trial and Establishment of Response Indicators in Recurrent Glioma Patients

胶质瘤是最常见的原发性恶性脑肿瘤， 多形性胶质母细胞瘤（GBM）是所有癌症中最致命和最难治疗的癌症之一。新 急需治疗。第一代溶瘤单纯疱疹病毒（第一代oHSV）用于 I期临床试验是安全的，产生了50%的反应率，然而，只有少数患者 持久的抗肿瘤反应。对第一代oHSV治疗的胶质瘤标本的分析显示， 肿瘤中的抗病毒和免疫刺激活性与Ib期的较长生存期直接相关 study.第一代oHSV旨在限制病毒复制，因此不能维持感染 或维持抗病毒免疫反应。为了提高oHSV的抗肿瘤活性，我们开发了下一个- 代oHSV，C134，具有增强的免疫刺激活性。C134被设计为激活抗病毒 细胞途径对于放大免疫应答和改善肿瘤细胞中的病毒复制是重要的。 虽然它与第一代oHSV具有相似的安全性特征，但C134在前肿瘤中具有上级抗肿瘤疗效。 临床模型小鼠研究还表明，C134更有效地诱导T细胞和抗原呈递细胞 在Ib期研究中与改善患者生存相关的缓解。 我们将测试我们的假设，即“C134是安全的，并诱导免疫活性，增强抗肿瘤作用， 复发性恶性胶质瘤患者的反应”，目的如下： 目的1：进行I期临床试验，以确定C134（IND 17296）在以下患者中的安全剂量： 复发性恶性胶质瘤假设：C134瘤内给药在复发性乳腺癌患者中是安全的 恶性神经胶质瘤我们已经准备好开始第一阶段的试验。我们的临床级C134已获得监管 NIH-重组DNA理事会（RAC）和FDA-研究新药（IND #17296）的批准。 C134将采用持续再评估方法（CRM）设计，对患者进行瘤内给药 并将监测C134的安全性和耐受性。 目的2监测oHSV介导的抗肿瘤免疫应答的变化 在C134治疗的患者中。假设：C134诱导的抗病毒和Th 1免疫活性有助于抗 肿瘤功效，并且可以从外周血样品推断。我们过去的临床试验结果表明， oHSV诱导的免疫活性与存活率提高相关。因此，我们将监测患者的 C134治疗后的外周血（免疫表型和细胞因子），并确定免疫应答 变化与抗肿瘤反应有关。研究还将研究持续的病毒活性和T细胞克隆 这些变化有助于C134抗肿瘤反应。 影响：成功完成这些研究是建立有效治疗的第一步。 这将提供一种监测和潜在增强病毒治疗反应的方法。

PROJECT SUMMARY: Gliomas are the most frequently occurring primary malignant brain tumors, with glioblastoma multiforme (GBM) being one of the most fatal and treatment-refractory of all cancers. New treatments are urgently needed. First-generation oncolytic Herpes Simplex Viruses (1st gen oHSVs) used in Phase I clinical trials were safe and produced a 50% response rate however, only a minority of patients had a durable anti-tumor response. Analysis of the 1st gen oHSV-treated glioma specimens shows that increased antiviral and immunostimulatory activity in the tumor directly correlates with longer survival in the Phase Ib study. The 1st Gen oHSVs were designed to restrict viral replication and therefore could not maintain infection or sustain an antiviral immune response. To improve oHSV antitumor activity, we have developed a next- generation oHSV, C134, with enhanced immunostimulatory activity. C134 is designed to activate antiviral cellular pathways important for amplifying the immune response and to improve viral replication in tumor cells. While it shares a similar safety profile as the 1st gen oHSVs, C134 has superior anti-tumor efficacy in pre- clinical models. Murine studies also show that C134 more effectively induces T cell and antigen presenting cell responses that are associated with improved patient survival in the Phase Ib studies. We will test our hypothesis that “C134 is safe and induces immune activity that enhances the anti-tumor response in patients with recurrent malignant glioma” by the following aims: Aim 1: To conduct a Phase I clinical trial to determine a safe C134 (IND 17296) dose in patients with recurrent malignant glioma. Hypothesis: Intratumoral administration of C134 is safe in patients with recurrent malignant gliomas. We are ready to start our Phase I trial. Our clinical grade C134 has received regulatory approval from the NIH-Recombinant DNA Council (RAC) and FDA-Investigational New Drug (IND#17296). C134 will be intratumorally-administered to patients using a Continual Reassessment Method (CRM) design and will be monitored for C134 safety and tolerability. AIM 2 To monitor immune response changes associated with oHSV mediated anti-tumor responses among C134-treated patients. Hypothesis: C134-induced antiviral and Th1 immune activity contribute to anti- tumor efficacy and can be inferred from peripheral blood samples. Our past clinical trial results indicate that oHSV-induced immune activity is associated with improved survival. We will therefore monitor patient's peripheral blood (immunophenotyping and cytokine) after C134-treatment and define how immune response changes relate to anti-tumor response. Studies will also examine how sustained viral activity and T cell clonal changes contribute to the C134-anti-tumor response. Impact: Successful completion of these studies is the first step in establishing an effective therapy for an incurable tumor and would provide a way to monitor and potentially enhance the virotherapeutic response.