Glioma immunotherapy with strategies based on autonomous parvovirus MVMp

基于自主细小病毒 MVMp 的神经胶质瘤免疫治疗策略

• 批准号: 8634751
• 负责人: Justin Cobb Paglino
• 金额: $ 11.74万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8634751
• 关键词: Achievement; Am 80; Animals; Antibodies; Antigen-Presenting Cells; Award; Blocking Antibodies; Brain; C57BL/6 Mouse; CD8B1 gene; CTLA4 gene; Cancer Immunology Science; Capsid; Cell secretion; Cells; Clinic; Clinical; Clinical Pathology; Combined Modality Therapy; Complementary DNA; Cytolysis; Data; Dependence; Development; Development Plans; Diagnosis; Disease; Engineering; Epitopes; Faculty; Feedback; Genetic; Genome; Glioblastoma; Glioma; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Growth; Heterophile Antigens; Human; Immune; Immune Tolerance; Immune response; Immune system; Immunity; Immunobiology; Immunocompetent; Immunocompromised Host; Immunotherapeutic agent; Immunotherapy; In Vitro; Individual; Infection; Injection of therapeutic agent; Interleukin-12; Journals; K-Series Research Career Programs; Knowledge; Laboratories; Libraries; Lytic; Malignant Glioma; Malignant Neoplasms; Measures; Mediating; Mediator of activation protein; Medical; Medicine; Mentors; Mentorship; Modeling; Molecular; Molecular Mimicry; Molecular Virology; Mus; Neuroglia; Neurosurgeon; Oncolytic; Oncolytic viruses; Operative Surgical Procedures; Outcome; Paper; Parvovirus; Parvovirus Infections; Patients; Positioning Attribute; Prostate; Prostatic Neoplasms; Proteins; Publications; Publishing; Radiation; Recombinant adeno-associated virus (rAAV); Recombinants; Regulatory T-Lymphocyte; Reporting; Research; Research Personnel; Residencies; Resistance; Safety; Signal Transduction; Splenocyte; Structure; Survival Analysis; T-Cell Depletion; T-Cell Development; T-Lymphocyte; Techniques; Testing; Therapeutic; Time; TimeLine; Training; Transgenes; Tropism; Tumor Antigens; Tumor Biology; Tumor Immunity; United States; Vesicular stomatitis Indiana virus; Viral; Viral Vector; Virus; Virus Replication; Yale Cancer Center; adeno-associated viral vector; base; cancer immunotherapy; career; career development; chemotherapy; combinatorial; cytokine; design; experience; implantation; interest; killings; knowledge base; meetings; member; mouse model; neoplastic cell; neuro-oncology; neurosurgery; novel; novel strategies; oncology program; oncolysis; preference; professor; programs; research and development; responsible research conduct; sarcoma; skills; success; symposium; tumor; tumor microenvironment; vector; virology

DESCRIPTION (provided by applicant): 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.

描述（申请人提供）：此应用程序描述了一个计划，通过全职研究，结构化的指导，教学法，研讨会，在负责任的研究行为，在会议上演示的培训，以及实现目标的具体目标日期，包括完成和出版我的具体目标中所描述的数据，委员会的指导，以推进终身教职，并提交R 01提案。研究策略描述了我们尝试使用溶瘤性细小病毒联合治疗来治愈同基因原位恶性胶质瘤的方法，我们假设这些治疗将与细小病毒治疗协同作用，因为它们通过不同的机制起作用。细小病毒在原位同基因胶质瘤模型中的使用是新颖的，细小病毒与所选互补方法的组合也是新颖的，这些方法都具有显著的前景或已证明的功效。 我已经做好充分的准备去追求在这份申请中所列出的目标。我在临床病理学方面的医学培训和住院医师培训为我了解疾病及其治疗提供了全面的知识基础。我在耶鲁大学实验室医学系的Peter Tattersall博士（裁判）指导下进行的分子细小病毒学研究生培训使我掌握了各种分子病毒学技术，培养了我设计有效实验方法的能力，并在病毒学上发表了两篇关于溶瘤细小病毒向性的第一作者论文。在我随后与Anthony货车den Pol博士（这里是主要导师）的培训中，我获得了使用溶瘤性水泡性口炎病毒（VSV）、设计和生成许多重组腺相关病毒（AAV）载体以及在免疫受损小鼠模型中研究肿瘤溶瘤的能力。2011年，我在《病毒学杂志》上发表了一篇关于VSV治疗人类肉瘤的适用性的第一作者文章，其中我们证明了在某些肉瘤中，组成性先天免疫信号传导对VSV复制构成障碍;我发现了几种增强病毒靶向其他耐药肉瘤的方法。今年，我在《病毒学杂志》上发表了另一篇第一作者论文，内容是关于体外和免疫功能低下小鼠中神经胶质瘤的细小病毒溶瘤作用。我的研究兴趣从一开始我的培训一直是利用病毒作为癌症治疗。对我来说，这一领域最令人兴奋的进展是发现了病毒可以刺激有效的，甚至是治愈性的抗肿瘤免疫反应的方法。虽然我有免疫生物学和癌症免疫疗法的知识，但我试图在一定程度上理解它，使我能够在这一领域取得必要的进展。因此，我申请这个职业发展奖，以接受培训和开展研究，重点是免疫生物学，特别是使用病毒和病毒载体作为免疫治疗剂。 职业发展计划描述了每月与导师一对一会面，每季度与整个委员会会面，我的研究和职业发展活动将提交给他们以获得反馈。我在神经外科的情况和我的主要导师的经验使胶质瘤成为我研究的理想目标疾病。货车登波尔博士已经发表了关于使用多种病毒靶向神经胶质瘤的报告，包括我们最近调查细小病毒的报告。共同导师Joseph Piepmeier博士是一名执业神经外科医生，外科神经肿瘤学项目主任，并担任《神经肿瘤学杂志》主编八年。我会和皮普梅尔医生一起参加肿瘤会诊共同导师丹尼尔迪迈奥博士，遗传学教授和耶鲁大学癌症中心的科学主任，将是有价值的导师，因为他的专业知识，在分子病毒学和肿瘤生物学。由免疫生物学教授Alfred Bothwell博士共同指导是该应用程序的一个关键特征。作为耶鲁癌症中心癌症免疫学项目的成员和研究生研究主任，他的免疫生物学专业知识与出色的指导记录相结合，将对我来说是不可或缺的，因为我奋进扩大我在他的领域的研究。职业发展计划的其他重要组成部分包括免疫生物学课程，T细胞发育高级课程，参加相关研究和临床研讨会，年度会议报告，以及实现研究和职业目标的时间轴。 我们的方法是最密切地模仿临床胶质瘤，通过使用原位同基因免疫活性模型，我们已经确定了两个胶质瘤细胞系同基因C57 BL/6小鼠，细小病毒MVMp的裂解生长敏感。MVMp基因组与细小病毒LuIII的基因组有80%相同，LuIII是我们最近报道的在人类神经胶质瘤中生长最佳的病毒，然而LuIII的人类物种偏好排除了其在同基因小鼠模型中的使用。证据支持我们的观点，即细小病毒溶瘤作用增强了感染刺激的微环境中肿瘤抗原的释放，从而引发抗肿瘤免疫应答。我的方法的核心是，最佳疗效取决于通过不同机制协调促进抗肿瘤免疫应答的治疗方法的组合。因此，我测试的假设，组合策略，其中溶瘤细小病毒感染与不同的互补免疫刺激治疗相结合，将构成有效的免疫治疗胶质瘤。在目标1中，我测试了三种免疫刺激抗体。在目的2中，我测试了两种表达细胞因子的细小病毒载体。在目的3中，我测试了一个工程化到细小病毒载体中的“改变自身表位文库”。我期待着这里所描述的研究和培训活动。