PVSRIPO in melanoma

PVSRIPO 在黑色素瘤中的应用

基本信息

批准号：
10132265
负责人：
Georgia Beasley
金额：
$ 16.7万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10132265
关键词：
Aftercare Animal Model Antineoplastic Agents Antitumor Response Antiviral Agents Attenuated Award Biopsy Blood Cell Line Cells Cessation of life Clinical Clinical Trials Combined Modality Therapy Data Dendritic Cells Development Disease Disease Progression Doctor of Philosophy Genes Glioblastoma Goals Human Human poliovirus Immune Immune checkpoint inhibitor Immunocompetent Immunologics Immunologist Immunology In Vitro Incidence Infection Inflammation Inflammatory Innate Immune System Interferon Type II Interferons Laboratories Malignant Neoplasms Mediating Melanoma Cell Mentors Metastatic Melanoma Modeling Mus Oncolytic Operative Surgical Procedures PD-L1 blockade Patient Care Patients Phase I Clinical Trials Physicians Poliovirus Vaccines Positioning Attribute Principal Investigator Prognosis Program Development Proteins Publishing Recurrence Research Resistance Resistance development Risk Scientist Serotyping Skin Skin Cancer Specimen Surgeon Testing Therapeutic Time Toxic effect Translating Translations Treatment Failure Tumor Immunity Tumor Tissue United States Universities Viral Work adaptive immune response age group anti-tumor immune response base career career development clinical practice cytotoxic cytotoxicity disease diagnosis effective therapy experience experimental study immune activation immunogenic improved in vivo macrophage melanoma mouse model neoplastic cell neurovirulence novel novel therapeutics oncolytic virotherapy phase I trial pre-clinical professor programmed cell death ligand 1 programmed cell death protein 1 public health relevance research and development skills stem tool tumor tumor growth tumor microenvironment young adult

项目摘要

PROJECT SUMMARY This proposal presents a five-year research career development program focused on the translation of oncolytic modified poliovirus (PVSRIPO) into a novel treatment for patients with advanced melanoma. The candidate is currently an Assistant Professor of Surgery at Duke University. The candidate has previous research and clinical experience in the management of patients with advanced melanoma and has now chosen to focus on immunology-driven approaches with a mentor who is an accomplished immunologist, Smita Nair, PhD. The proposed experiments and didactic work will provide the candidate with a unique set of immunologic and laboratory skills that will enable her transition to independence as a physician scientist in the field of melanoma therapeutics. Melanoma has been dramatically increasing in incidence for the last 30 years and is the most common fatal skin malignancy. Programmed death protein 1 (PD-1) antagonists represent important recent advances in the care of patients with metastatic melanoma. However, 60% of patients fail to respond to PD-1 therapy and late resistance remains a problem. Oncolytic virotherapy has emerged as a promising treatment for advanced melanoma due to its ability to elicit anti-neoplastic effects stemming from combined direct viral cytotoxicity and innate antiviral activation. PVSRIPO, the live attenuated, serotype 1 poliovirus vaccine that was genetically modified to eliminate its neurovirulence, has shown unprecedented long-term survival in 20% of recurrent glioblastoma multiforme patients, otherwise a nearly uniformly fatal disease. Further development of PVSRIPO as treatment for advanced melanoma will fulfill a clinical need for more effective therapies for these patients. More specifically, the aims of this proposal are: 1) investigate PVSRIPO induced immune bioactivity in melanoma tumor tissue obtained from a Phase I trial of patients with advanced melanoma, 2) determine the efficacy of mouse PVSRIPO treatment, in conjunction with PD-1/PD-L1 blockade, on tumor growth in vivo, 3) determine PVSRIPO-mediated immune activation in vitro in a tumor explant model. The scientific objectives of this proposal are to 1) define how PVSRIPO treatment facilitates engagement of anti-tumor immune responses and 2) to determine if administration of mouse PVSRIPO with concurrent PD-1/PD-L1 antagonists will eliminate adaptive resistance and potentiate durable-anti-tumor responses.

项目摘要该建议提出了一项五年的研究职业发展计划，重点是溶瘤的翻译改良的脊髓灰质炎病毒（PVSRIPO）为晚期黑色素瘤患者的新型治疗方法。候选人是目前是杜克大学手术助理教授。候选人先前的研究和临床在患有晚期黑色素瘤患者的管理方面的经验，现在已选择专注于免疫学驱动的方法与一位有成就的免疫学家Smita Nair博士。这拟议的实验和教学工作将为候选人提供一套独特的免疫学和实验室技能将使她能够过渡到黑色素瘤领域的医生科学家的独立性疗法。在过去30年中，黑色素瘤的发病率一直大大增加，是最常见的致命皮肤恶性。程序性死亡蛋白1（PD-1）拮抗剂代表了护理的最新进展转移性黑色素瘤的患者。但是，有60％的患者无法对PD-1治疗和迟到阻力仍然是一个问题。溶瘤病毒疗法已成为一种有前途的晚期治疗方法黑色素瘤由于其能够引起直接病毒细胞毒性的抗可塑性作用的能力而引起的先天抗病毒激活。 PVSRIPO，活的减毒，血清型1脊髓灰质炎病毒疫苗，遗传上是遗传学上的修改以消除其神经动力学，在20％的复发中显示了前所未有的长期生存胶质母细胞瘤多形患者，否则几乎是致命的疾病。 PVSripo的进一步发展由于对晚期黑色素瘤的治疗将满足对这些患者更有效疗法的临床需求。更具体地说，该提案的目的是：1）研究PVSRIPO诱导的黑色素瘤免疫活性从晚期黑色素瘤患者的I期试验获得的肿瘤组织，2）确定小鼠PVSRIPO处理，与PD-1/PD-L1阻滞结合，体内肿瘤生长，3）确定 PVSRIPO介导的免疫激活在肿瘤外植体模型中。该提议的科学目标到1）定义PVSRIPO治疗如何促进抗肿瘤免疫反应的参与以及2）确定用并发的PD-1/PD-L1拮抗剂对小鼠PVSRIPO的施用是否会消除适应性电阻和增强耐用的脉冲响应。