This application describes a plan to develop my career through fully-time research, structured mentoring, didactics, seminars, training in the responsible conduct of research, presentation at conferences, and specific target dates for the achievement of goals that include completion and publication of data described in my specific aims, committee guidance for moving forward to a tenure-track faculty position, and submission of an R01 proposal. The research strategy describes our approach to attempting to cure syngeneic orthotopic malignant glioma using an oncolytic parovirus combined with therapies that we hypothesize will synergize with parvovirus therapy because they operate by different mechanisms. The use of parvovirus in an orthotopic syngeneic glioma model is novel, as is the combination of parvovirus with the chosen complementary approaches, which are all of significant promise or demonstrated efficacy. I am well prepared to pursue the goals outlined in this application. My medical training and residency in clinical pathology give me a comprehensive knowledge base for understanding disease and its treatment. My graduate training in molecular parvovirology, under Dr. Peter Tattersall (referee) in the department of Laboratory Medicine at Yale equipped me with skills in a variety of molecular virology techniques, developed my ability to design an effective experimental approach, and resulted in two first-author publications in Virology on the tropism of oncolytic parvoviruses. In my subsequent training with Dr. Anthony van den Pol, here the primary mentor, I have gained facility in using oncolytic vesicular stomatitis virus (VSV), designing and generating a number of recombinant adeno-associated virus (AAV) vectors, and studying tumor oncolysis in immunocompromised mouse models. In 2011, I published a first-author article in the Journal of Virology on the applicability of VSV to treatment of human sarcomas, in which we demonstrate that in some sarcomas, constitutive innate immune signaling poses a barrier to VSV replication;I found several ways in which to enhance viral targeting to otherwise resistant sarcomas. This year, I published another first-author paper in the Journal of Virology on parvoviral oncolysis of gliomas in vitro and in immunocompromised mice. My research interest from the start of my training has been to employ viruses as cancer therapeutics. To me, the most exciting developments in this field have been the discovery of means by which viruses can stimulate an effective, even curative, anti-tumor immune response. Although I have knowledge of immunobiology and cancer immunotherapy, I seek to understand it on a level that will allow me to make needed advances in this field. Therefore I am applying for this career development award to receive training and undertake research with an emphasis on immunobiology, particularly the use of viruses and viral vectors as immunotherapeutics. The career development plan describes meeting monthly with mentors one-on-one, and quarterly with the entire committee, to whom my research and career development activities will be presented for feedback. My situation within the department of neurosurgery and the experience of my primary mentor make glioma the ideal target disease for my research. Dr. van den Pol has published reports on the use of a number viruses to target glioma, including our most recent report investigating parvoviruses. Co-mentor Dr. Joseph Piepmeier is a practicing neurosurgeon, director of the Surgical Neuro-Oncology Program, and was editor-in-chief of the Journal of Neuro-Oncology for eight years. I will attend tumor-board with Dr. Piepmeier. Co- mentor Dr. Daniel DiMaio, professor of Genetics and scientific director of the Yale Cancer Center, will be valuable as a mentor given his expertise in both molecular virology and tumor biology. Co-mentorship by Dr. Alfred Bothwell, Professor of Immunobiology, is a critical feature of this application. A member of the Yale Cancer Center's Cancer-Immunology Program, and Director of Graduate Studies, his immunobiology expertise combined with an excellent track record of mentoring will be indispensable to me as I endeavor to broaden my research into his field. Other important components of the career development plan include an immunobiology course, an advanced course in T-cell development, attending relevant research and clinical seminars, annual presentation at conferences, and a timeline for achievement of research and career goals. Our approach is to most closely mimic clinical glioma by using an orthotopic syngeneic immunocompetent model, and we have identified two glioma lines syngeneic to C57BL/6 mice that are susceptible to lytic growth of parvovirus MVMp. The MVMp genome is 80% identical to that of parvovirus LuIII, the virus we recently reported to grow optimally in human gliomas, however the human species preference of LuIII precludes its use in syngenic mouse models. Evidence supports our view that parvoviral oncolysis enhances release of tumor antigens in an infection-stimulated microenvironment, thereby priming an anti- tumor immune response. Central to my approach is the perspective that optimal efficacy depends on a combination of therapeutics that coordinately promote an anti-tumor immune response by different mechanisms. Therefore, I test the hypothesis that combinatorial strategies, in which oncolytic parvovirus infection is combined with different complementary immune stimulatory treatments, will constitute effective immunotherapy for glioma.
In Aim 1 I test three immunostimulatory antibodies.
In Aim 2 I test two parvoviral vectors expressing cytokines.
In Aim 3 I test an 'altere self epitope library'engineered into parvoviral vector. I look forward to the research and trainin activities described herein.

Public Health Relevance

Relevance: Malignant glioma is a highly aggressive cancer developing in the brain, and virtually 100% of the approximately 14,000 patients diagnosed each year in the United States will die from their disease, despite currently available surgical, radiation, and chemotherapy treatments. One promising novel approach to glioma therapy is the use of viruses engineered to be safe and effective at killing tumors and/or at stimulating the body's immune system to reject tumors. This award is to support the career development and research of a new investigator in this field whose research goal is to develop novel viral therapeutic approaches that stimulate immune rejection of glioma.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Clinical Investigator Award (CIA) (K08)
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Subcommittee G - Education (NCI)
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Jakowlew, Sonia B
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Yale University
Schools of Medicine
New Haven
United States
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