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

描述（由申请人提供）：我的长期职业目标是成为胸肿瘤学的独立翻译研究者。我计划将我的实验室研究重点放在胸部恶性肿瘤的免疫肿瘤微环境的表征和治疗修饰上。此外，我期待在临床试验中为这些患者研究新的有前途的治疗策略。本建议书中概述的职业发展和研究计划将为我提供实现这些目标所需的技能。胸部恶性肿瘤是非常常见和致命的疾病。然而，缺乏有效的治疗策略。溶瘤病毒，如改良的疫苗株麻疹病毒（MV），诱导肿瘤细胞破坏的治疗用途代表了一个非常有吸引力的替代方案。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。可能的作用包括直接的病毒溶瘤作用和靶向病毒和/或肿瘤抗原的免疫介导的肿瘤细胞破坏。次优的病毒复制和预先存在的中和抗病毒抗体涉及免疫介导的破坏而不是溶瘤。在此，我们提出了一个修改后的MV携带人类基因的钠碘同向转运体（NIS）的局部和全身抗肿瘤和抗病毒免疫的影响进行调查。我们将进行一项I期研究，在MPM患者中测试高达6个周期的MV-NIS胸膜内给药。次要终点，特别是无进展生存期将在扩展的MTD队列中测量，以初步评估MV-NIS对肿瘤进展的影响。相关研究将使用连续I123 SPECT/CT扫描非侵入性测量病毒复制，并在整个试验期间分析局部（通过永久性胸膜导管的胸腔积液）和全身（血液）抗肿瘤和抗MV免疫。我们预计，这些调查的结果将提高我们的MV病毒治疗胸部恶性肿瘤的机制的理解，导致改进的治疗方案，并有助于扩大从MPM到其他胸部恶性肿瘤的修饰疫苗的治疗用途。最重要的是，拟议的临床试验与相关的相关研究，指导和综合课程将为我提供临床试验经验，以实现我的职业目标，成为一名独立的翻译研究者在胸部肿瘤。

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.