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.

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.该研究策略描述了我们尝试使用溶瘤性侧病毒与我们假设的疗法结合使用的溶瘤性副病毒疗法来治疗合成性原位恶性神经胶质瘤的方法，因为它们通过不同的机制起作用，我们假设我们假设的疗法将与细小病毒疗法协同作用。在原位同性神经胶质瘤模型中使用细节性病毒是新颖的，细小病毒与所选互补方法的结合也是如此，这都是显着的希望或证明的功效。 我已经准备好追求本申请中概述的目标。我在临床病理学方面的医学培训和居住期为我提供了了解疾病及其治疗的全面知识库。 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.在此后，我随后对Anthony van den Pol博士进行了主要指导者的培训，我获得了使用肿瘤囊肿孔炎病毒（VSV）的设施，设计和生成许多与腺相关的病毒（AAV）载体（AAV）载体，并研究免疫原子质培养的肿瘤肿瘤模型。 2011年，我在《病毒学杂志》上发表了有关VSV对人类肉瘤的适用性的第一篇文章，其中我们证明，在某些肉瘤中，构成性的先天免疫信号传导构成了VSV复制的障碍。我发现了几种增强病毒靶向抗性肉瘤的方法。今年，我发表了另一篇关于胶质瘤的病毒学杂志和免疫功能低下的小鼠的第一论文。从培训开始开始，我的研究兴趣是将病毒用作癌症治疗剂。对我来说，该领​​域最令人兴奋的发展是发现了病毒可以刺激有效，治愈性抗肿瘤免疫反应的手段。尽管我对免疫生物学和癌症免疫疗法有了解，但我试图以使我能够在该领域取得必要的进步的水平来理解它。因此，我正在申请该职业发展奖，以接受培训和进行研究，重点是免疫生物学，尤其是使用病毒和病毒载体作为免疫治疗药。 职业发展计划描述了每月与导师一对一会议，并与整个委员会每季度举行会议，将向我的研究和职业发展活动提供反馈。我在神经外科部门和主要导师的经验中的状况使神经胶质瘤成为我研究的理想目标疾病。范·丹·波尔（Van den Pol）博士发表了有关使用多种病毒靶向神经胶质瘤的报告，其中包括我们对细小病毒的最新报告。同事Joseph Piepmeier博士是手术神经肿瘤计划主任的神经外科医生，并且是《神经肿瘤学杂志》的主编已有八年。我将与Piepmeier博士一起参加肿瘤板。鉴于他在分子病毒学和肿瘤生物学方面的专业知识，遗传学教授兼科学主任丹尼尔·迪马奥（Daniel Dimaio）博士将成为有价值的丹尼尔·迪马奥（Daniel Dimaio）博士。免疫生物学教授Alfred Bothwell博士的会议是该应用程序的关键特征。耶鲁癌症中心癌症免疫学计划的成员和研究生研究主任，他的免疫生物学专业知识与我努力将研究扩大到他的领域的研究对我来说是必不可少的。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细胞开发的高级课程，参加相关研究和临床研讨会，会议的年度演讲以及实现研究和职业目标的时间表。 我们的方法是使用原位合成性免疫能力模型来最紧密地模拟临床神经胶质瘤，并且我们已经确定了两种对C57BL/6小鼠的神经胶质瘤线的胶质瘤线，这些胶质瘤易受Parvovirus MVMP裂解的生长。 MVMP基因组与细小病毒LUIII相同，该病毒最近报告在人神经胶质瘤中最佳地生长，但是LUIII的人类偏好排除了其在Syngenic小鼠模型中的使用。证据支持我们的观点，即细节性肿瘤可以增强感染刺激的微环境中肿瘤抗原的释放，从而启动抗肿瘤免疫反应。我方法的核心是，最佳疗效取决于治疗剂的结合，这些治疗剂通过不同机制协调促进抗肿瘤免疫反应的组合。因此，我检验了以下假设：结合策略与溶瘤性细胞小伏病毒感染与不同的互补免疫刺激治疗相结合，将构成有效的神经胶质瘤免疫疗法。在AIM 1中，我测试了三种免疫刺激性抗体。在AIM 2中，我测试了表达细胞因子的两个细节矢量。在AIM 3中，我测试了设计为山视角矢量的“更改自我表位库”。我期待此处描述的研究和培训活动。