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.
Thoracic malignancies including malignant pleural mesothelioma (MPM) are very common and extremely deadly diseases. In the absence of effective therapeutic options and novel treatment approaches are desperately needed. Virotherapy using a modified vaccine strain measles virus (MV) has shown some promise in a phase I trial enrolling patients with advanced ovarian cancer. The biological mechanisms of this therapeutic benefit is currently unclear and possibilities include direct viral oncolysis versus immune mediated tumor cell destruction remain. Our proposed studies offer a unique opportunity to enhance the understanding of the interactions between intrapleurally administered modified vaccine strain measles viruses and the patient's immune system in individuals with MPM. Furthermore we will gain information regarding the safety and clinical efficiency of one of these viruses, MV-NIS in patients with MPM. Consequently, we expect the proposed research to be of very high relevance for public health.
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