Genetically Engineered Viruses for Brain Tumor Therapy

用于脑肿瘤治疗的基因工程病毒

基本信息

批准号：
10066369
负责人：
ROBERT L MARTUZA
金额：
$ 54.84万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-05-01 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10066369
关键词：
Angiopoietin-2 Applications Grants Brain Brain Neoplasms CD4 Positive T Lymphocytes CD47 gene Cancer Vaccines Cells Clinical Clinical Trials Competence Development Distant Environment Event FDA approved Future Genes Genetic Genome Glioblastoma Glioma Goals Grant HSV vector Hand Health Human Immune Immune checkpoint inhibitor Immune response Immune system Immunization Immunosuppression Immunotherapy In Situ In complete remission Interleukin-12 Invaded Japan Length Ligands Medical Device Morbidity - disease rate Mus Oncolytic Oncolytic viruses Patients Pharmaceutical Preparations Pharmacologic Substance Phase Phase I Clinical Trials Process Public Health Refractory Reporting Research Research Design Resistance Role Safety Simplexvirus Solid Neoplasm T-Cell Activation Technology Testing Therapeutic Toxic effect Treatment Efficacy Tumor Immunity Viral Virus Work anti-tumor immune response antigen processing antigenic peptide transporter base cancer therapy cancer vaccination checkpoint inhibition cost cytokine design expression vector gene product genetically engineered virus immune checkpoint blockade immunoregulation immunotherapeutic virotherapy improved improved outcome inhibitor/antagonist interest lymphoid neoplasm macrophage neoplastic cell novel oncolysis oncolytic herpes simplex virus oncolytic virotherapy preclinical study preservation programs standard of care stem cell model stem cell population stem cells synergism therapy outcome tumor tumor growth tumor microenvironment tumor-immune system interactions vaccine response vector virtual welfare

项目摘要

PROJECT SUMMARY The overall goal of our program has been to improve the standard of care for brain tumor patients with a specific emphasis on glioblastoma multiforme (GBM). Towards this end, we initially developed oncolytic herpes simplex virus vectors (oHSV) to kill glioma cells, including the so-called glioblastoma stem cells (GSCs), and revealed the synergistic importance of viral oncolysis combined with immune stimulation (in situ oncolytic tumor vaccination). We demonstrated the advantage of blocking tumor-induced immune suppression and inducing anti-tumor immune responses during the process of in situ oncolytic tumor vaccination. Our studies of immune mechanisms demonstrated synergy of an oncolytic virus expressing a cytokine (IL12) with immune checkpoint inhibitors that forms an exciting avenue of research exploration for our next grant cycle, as well as for improved future clinical trials. Therefore, in this next grant cycle, we have designed studies to answer several important unmet needs in the immunovirotherapy of GBM: 1, How can a virus be better designed to stimulate an immune response to the tumor; 2, How can an oncolytic virus be used to overcome tumor-induced immunosuppression; and, 3, How can understanding tumor lymphocyte actions and macrophage reprogramming be utilized to improve therapeutic efficacy. We are taking advantage of this iterative process of oHSV development to continually improve outcomes. In the novel studies we have proposed, we are exploring the combined use of uniquely designed oHSV to overcome the current limitations of immune therapy by combined local intra-tumoral expression of co- stimulatory ligands in concert with cytokine stimulation of an in-situ oncolytic tumor vaccine response. This approach should eliminate distant tumor cells, while minimizing toxicity and be amenable to additional combinations. Our studies explore several hypotheses leading to improvement in vector design and efficacy. These studies will then be used to make novel oncolytic viruses incorporating the advantageous features learned from each of the aims in this grant proposal. We expect that this will lead to an improved immunovirotherapy approach to take into clinical trial for GBM. This strategy is not only novel and unique but we emphasize that it could save costs by shortening the length of treatment and also would apply to other tumors both in the brain and in the periphery.

项目概要我们计划的总体目标是提高脑肿瘤患者的护理标准特别强调多形性胶质母细胞瘤（GBM）。为此，我们最初开发了溶瘤药物单纯疱疹病毒载体（oHSV）杀死神经胶质瘤细胞，包括所谓的胶质母细胞瘤干细胞（GSC），并揭示了病毒溶瘤与免疫刺激（原位溶瘤肿瘤疫苗接种）。我们证明了阻断肿瘤诱导的免疫抑制的优势在原位溶瘤肿瘤疫苗接种过程中诱导抗肿瘤免疫反应。我们的免疫机制研究证明表达细胞因子（IL12）的溶瘤病毒与免疫检查点抑制剂为我们的下一个资助周期形成了令人兴奋的研究探索途径，如以及改进未来的临床试验。因此，在下一个资助周期中，我们设计了研究解答GBM免疫病毒治疗中几个重要的未满足需求：1、病毒如何更好旨在刺激对肿瘤的免疫反应； 2、如何利用溶瘤病毒来攻克肿瘤引起的免疫抑制； 3、如何了解肿瘤淋巴细胞的作用和利用巨噬细胞重编程来提高治疗效果。我们正在利用 oHSV 开发的迭代过程来不断改进结果。在我们提出的新颖研究中，我们正在探索独特设计的组合使用 oHSV 通过联合局部肿瘤内表达来克服目前免疫治疗的局限性刺激配体与原位溶瘤肿瘤疫苗反应的细胞因子刺激相配合。这方法应消除远处的肿瘤细胞，同时最大限度地减少毒性并适合额外的治疗组合。我们的研究探索了几种有助于改进载体设计和功效的假设。这些研究将用于制造具有优势特征的新型溶瘤病毒从该赠款提案中的每个目标中汲取教训。我们预计这将导致改善免疫病毒疗法纳入 GBM 临床试验。这一策略不仅新颖独特，而且我们强调，它可以通过缩短治疗时间来节省成本，并且也适用于其他大脑和周围的肿瘤。