Provoking anti-tumor immune responses with Fas ligand

项目摘要/摘要：我们已经证明Fas配体（FasL）基因治疗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数据的精确外推。因此，我们使用狗的自发性癌症作为转译研究的中介。狗的大小和生理，以及这些物种的同源肿瘤的自然历史，比在实验室中创建的啮齿动物肿瘤模型更接近于人类。在这个项目中，我们将使用犬阑尾骨肉瘤（OS）模型来确定FasL基因治疗的腺病毒传递载体的安全性。犬OS是一种不治之症，与儿童OS的分子特征和临床表现相似，适合肿瘤内基因治疗。然而，这种疾病在狗身上更为普遍，这为测试新疗法和机制假设提供了一个有效和临床相关的机会。公共卫生意义的一个主要方面是，该项目将在该SBIR的第二阶段为人类治疗的发展提供原则证明。在这里，我们将使用现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。这种方法可以适应三元或二元二元结果，以及可能是非单调剂量的疗效概率。模拟可用于跟踪剂量-结果情景，以帮助制定有关剂量治疗的决策，同时实现理想的疗效-毒性权衡。这项研究将包括在18个月内招募的30只狗；受试者将接受瘤内腺病毒FasL治疗，随后在10天后进行标准护理（截肢和辅助化疗）。主要结果指标将是局部和全身毒性，而疗效（与采用相同护理标准治疗的240只狗的当代对照群的无病间隔进行比较）被认为是次要指标。项目描述：免疫系统的设计是为了保护个体免受癌症或传染病的侵害。当它失效时，疾病就会发生。这个项目将测试一种通常被称为免疫疗法的方法，通过这种方法，病人的免疫系统得到加强，现在可以成功地做出反应并预防疾病。这个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，而不是让他们服用有毒药物。

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.