Anti-Tumor Immunity in Response to a Modified Vaccine Strain Measles Virus

职位描述(申请人提供)：我的长期职业目标是成为一名胸腔肿瘤学的独立翻译研究员。我计划将我的实验室研究重点放在胸腔恶性肿瘤免疫肿瘤微环境的特征和治疗改进上。此外，我预计将在临床试验中为这些患者研究新的有希望的治疗策略。本提案中概述的CAREE开发和研究计划将为我提供实现这些目标所需的技能。胸部恶性肿瘤是一种非常常见和致命的疾病。然而，缺乏高效的治疗策略。在治疗上使用溶瘤病毒，如改良疫苗株麻疹病毒(MV)，以诱导肿瘤细胞的破坏是一个非常有吸引力的选择。尽管在难治性卵巢癌患者中有一些非常有希望的临床结果，但MV限制肿瘤生长的机制仍然知之甚少。可能的作用包括针对病毒和/或肿瘤抗原的直接病毒溶瘤和免疫介导的肿瘤细胞破坏。不理想的病毒复制和预先存在的中和抗病毒抗体意味着免疫介导的破坏，而不是溶瘤。在此，我们建议研究一种携带人类钠碘转运体(NIS)基因的改良MV对局部和全身抗肿瘤和抗病毒免疫的影响。我们将进行一项I期研究，测试MPM患者胸腔内最多6个周期的MV-NIS给药。次级终点，特别是无进展生存期将在扩大的MTD队列中进行测量，以初步评估MV-NIS对肿瘤进展的影响。相关研究将使用I123 SPECT/CT顺序扫描来非侵入性地测量病毒复制，并在整个试验过程中分析局部(通过永久性胸膜导管)和全身(血液)抗肿瘤和抗MV免疫。我们期待这些研究的结果将加深我们对MV病毒治疗胸部恶性肿瘤的机制的了解，导致治疗方案的改进，并有助于将改良疫苗的治疗应用从MPM扩大到其他胸部恶性肿瘤。最重要的是，拟议的临床试验以及相关的相关研究、指导和综合课程工作将为我提供临床试验经验，以实现我成为胸部肿瘤学独立翻译研究员的职业目标。

DESCRIPTION (provided by applicant): My long-term career goal is to become an independent translational investigator in thoracic oncology. I am planning to focus my laboratory-based research on the characterization and therapeutic modification of the immunological tumor microenvironment of thoracic malignancies. Moreover, I anticipate investigating new promising therapeutic strategies for these patients in clinical trials. The caree development and research plans outlined in this proposal will provide me with the skill set necessary to accomplish these goals. Thoracic malignancies are very common and deadly diseases. However, highly effective treatment strategies are lacking. The therapeutic use of oncolytic viruses, such as modified vaccine strain measles viruses (MV), to induce tumor cell destruction represents a very attractive alternative. Despite some very promising clinical outcomes in patients with refractory ovarian cancer the mechanisms by which MV limits tumor growth remain poorly understood. Possible effects include direct viral oncolysis and immune mediated tumor cell destruction targeting viral and/or tumor antigens. Suboptimal viral replication and pre-existing neutralizing anti-viral antibodies implicate immune mediated destruction rather than oncolysis. Herein we propose to investigate the effects of a modified MV carrying the human gene for the sodium iodine symporter (NIS) on local and systemic anti-tumor and antiviral immunity. We will conduct a phase I study testing the intrapleural administration of up to six cycles of MV-NIS in patients with MPM. Secondary endpoints, specifically progression free survival will be measured in an expanded MTD cohort for the preliminary assessment of the effect of MV-NIS on tumor progression. Correlative studies will non-invasively measure viral replication using sequential I123 SPECT/CT scanning and analyze the local (pleural fluid via permanent pleural catheter) and systemic (blood) anti-tumor and anti-MV immunity throughout the trial. We anticipate that the results of these investigations will enhance our understanding of the mechanisms of MV virotherapy in thoracic malignancies, result in improved treatment protocols and help to expand the therapeutic use of modified vaccine from MPM to other thoracic malignancy. Most importantly, the proposed clinical trial with the associated correlative studies, mentorship and integrated coursework will provide me with the clinical trial experience to accomplish my career goal of becoming an independent translational investigator in thoracic Oncology.