Provoking anti-tumor immune responses with Fas ligand

通过 Fas 配体激发抗肿瘤免疫反应

基本信息

批准号：
7291653
负责人：
DONALD BELLGRAU
金额：
$ 33.54万
依托单位：
APOPLOGIC PHARMACEUTICALS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-30 至 2009-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7291653
关键词：
Adenoviruses Adjuvant Adjuvant Chemotherapy Affect Amputation Animals Antitumor Response Apoptosis Bayesian Method Behavior Biological Cancer Patient Canis familiaris Caring Cessation of life Child Clinical Clinical Trials Collaborations Condition Data Decision Making Defense Mechanisms Development Disease Disease regression Disease-Free Survival Distant Metastasis Dog Diseases Dose Doxorubicin Drug Kinetics Feasibility Studies Gene Transfer Generations Genes Genetic Markers Goals Histologic Human Human Resources Immune Immune response Immune system Immunologics Immunotherapeutic agent Immunotherapy In Vitro Individual Infectious Agent Inflammation Knowledge Laboratories Laboratory Animals Laboratory mice Legal patent Limb structure Malignant Bone Neoplasm Malignant Neoplasms Measures Mediating Methods Modality Modeling Molecular Natural History Necrosis Neoplasm Metastasis Outcome Outcome Measure Patients Performance Pharmaceutical Preparations Phase Phase I Clinical Trials Physiology Population Control Population Study Predictive Value Predisposition Principal Investigator Probability Public Health Purpose Quality of life Radiation Range Recruitment Activity Research Resistance Rights Rodent Rodent Model Route Safety Score Secure Small Business Funding Mechanisms Small Business Innovation Research Grant Staging Standards of Weights and Measures Study Section Testing Toxic effect Translating Treatment Efficacy Tumor Burden Tumor Necrosis Factor Ligand Superfamily Member 6 Work abstracting base cancer cell cell killing chemotherapy clinical effect clinically relevant cohort cooking day design gene therapy improved indexing neoplastic cell osteosarcoma outcome forecast pre-clinical prognostic programs response simulation size therapy development translational study tumor two-dimensional vector

项目摘要

DESCRIPTION (provided by applicant): Project Summary/Abstract: We have shown that Fas ligand (FasL) gene therapy induces protective immune responses in rodent models. Yet, despite these unquestioned benefits to study mechanistic questions, various factors preclude precise extrapolation of safety data from rodent gene therapy studies to human trials. Hence, we have used spontaneous cancers of dogs as intermediaries for translational studies. The size and physiology of dogs, as well as the natural history of homologous tumors in these species, resemble those of humans more closely than rodent tumor models created in the laboratory. For this project, we will use a model of canine appendicular osteosarcoma (OS) to establish the safety of an adenovirus delivery vector for FasL gene therapy. Canine OS is an incurable disease that resembles the molecular features and the clinical presentation of OS in children, and which is amenable to intratumoral gene therapy. However, the disease is more prevalent in dogs, offering an efficient and clinically relevant opportunity to test new therapies and mechanistic hypotheses. A major aspect of public health significance is that this project will provide proof of principle for the development of this therapy in humans in the Phase II of this SBIR. Here, we will use a contemporary Bayesian method for dose finding that is designed to determine the differences between the probabilities of treatment efficacy and toxicity. This method can accommodate trinary or bivariate binary outcomes, as well as efficacy probabilities that may be nonmonotone in dose. Simulations can be produced to track dose-outcome scenarios that can assist in making decisions regarding dose treatment while achieving desirable efficacy-toxicity trade-offs. The study will consist of 30 dogs recruited over 18 months; subjects will be treated with intratumoral adenovirus FasL, followed by standard of care (limb amputation and adjuvant chemotherapy) after a 10 day delay. Major outcome measures will be local and systemic toxicity, with efficacy (disease free interval compared against a contemporary control population of 240 dogs treated with the same standard of care) considered as a secondary measure. Project Narrative: The immune system is designed to protect an individual from cancer or infectious agents. When it fails, disease can occur. This project will test an approach, generally termed immunotherapy, whereby a patient's immune system is strengthened such that it can now successfully respond and protect against disease. The relevance of this project to public health is that it offers an approach to treat cancer that utilizes enhancement of the patient's own defense mechanisms to fend off disease rather than subjecting them to toxic drugs.

描述（由申请人提供）：项目摘要/摘要：我们已经证明 Fas 配体 (FasL) 基因治疗可在啮齿动物模型中诱导保护性免疫反应。然而，尽管研究机制问题有这些毋庸置疑的好处，但各种因素阻碍了从啮齿动物基因治疗研究到人体试验的安全性数据的精确外推。因此，我们使用狗的自发性癌症作为转化研究的中介。狗的体型和生理学，以及这些物种中同源肿瘤的自然史，比实验室创建的啮齿动物肿瘤模型更接近人类。在这个项目中，我们将使用犬阑尾骨肉瘤 (OS) 模型来确定腺病毒递送载体用于 FasL 基因治疗的安全性。犬OS是一种无法治愈的疾病，其分子特征和临床表现与儿童OS相似，适合瘤内基因治疗。然而，这种疾病在狗中更为普遍，为测试新疗法和机制假设提供了有效且具有临床相关性的机会。公共卫生意义的一个主要方面是，该项目将为 SBIR 第二阶段的人类疗法的开发提供原理证明。在这里，我们将使用当代贝叶斯方法进行剂量发现，旨在确定治疗效果和毒性概率之间的差异。该方法可以适应三元或二元二元结果，以及剂量上可能非单调的功效概率。可以进行模拟来跟踪剂量结果场景，这可以帮助做出有关剂量治疗的决策，同时实现理想的功效-毒性权衡。该研究将招募 30 只狗，历时 18 个月；受试者将接受瘤内腺病毒 FasL 治疗，延迟 10 天后接受标准护理（截肢和辅助化疗）。主要结果指标将是局部和全身毒性，疗效（与接受相同护理标准治疗的 240 只狗的当代对照群体相比的无病间隔）被视为次要指标。项目叙述：免疫系统旨在保护个体免受癌症或传染源的侵害。当它失败时，就会发生疾病。该项目将测试一种通常称为免疫疗法的方法，通过该方法可以增强患者的免疫系统，使其能够成功地做出反应并预防疾病。该项目与公共卫生的相关性在于，它提供了一种治疗癌症的方法，利用增强患者自身的防御机制来抵御疾病，而不是让他们接受有毒药物。