Provoking anti-tumor immune responses with Fas ligand

通过 Fas 配体激发抗肿瘤免疫反应

• 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
• 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

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）基因治疗诱导啮齿动物模型的保护性免疫反应。然而，尽管研究机制问题有这些毋庸置疑的好处，但各种因素妨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，我们使用犬的自发性癌症作为转化研究的中介。狗的大小和生理学，以及这些物种中同源肿瘤的自然史，比实验室中创建的啮齿动物肿瘤模型更接近人类。在这个项目中，我们将使用一个模型，犬apapapellular骨肉瘤（OS），以建立一个安全的腺病毒载体的FasL基因治疗。犬OS是一种无法治愈的疾病，其分子特征和儿童OS的临床表现相似，并且适于肿瘤内基因治疗。然而，这种疾病在狗中更普遍，这为测试新疗法和机制假设提供了有效和临床相关的机会。公共卫生意义的一个主要方面是，该项目将为SBIR第II阶段的人类治疗提供原则证明。在这里，我们将使用当代贝叶斯方法进行剂量发现，旨在确定治疗疗效和毒性概率之间的差异。该方法可以适应三变量或双变量二元结局，以及剂量可能非单调的疗效概率。可以产生模拟来跟踪剂量-结果情景，其可以帮助做出关于剂量治疗的决策，同时实现期望的功效-毒性权衡。该研究将包括在18个月内招募的30只犬;受试者将接受肿瘤内腺病毒FasL治疗，然后在延迟10天后接受标准治疗（截肢和辅助化疗）。主要结局指标为局部和全身毒性，疗效（与接受相同标准治疗的240只犬的同期对照群体相比的无病间期）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性病原体的侵害。当它失败时，疾病就会发生。该项目将测试一种通常称为免疫疗法的方法，通过这种方法，患者的免疫系统得到加强，使其现在能够成功地应对和预防疾病。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，该方法利用增强患者自身的防御机制来抵御疾病，而不是使他们接受有毒药物。