TUMOR IMMUNOTHERAPY WITH BIODEGRADABLE MICROSPHERES

描述(由申请人提供)： 我们的专有肿瘤疫苗策略的可行性的原则证据已经在第一阶段研究中得到证明，该策略涉及使用白介素12包裹的微球。一次瘤内注射白介素12包裹的生物可降解微球可诱导小的原发肿瘤完全消退，促进长期全身抗肿瘤免疫的发展，并导致在小鼠肿瘤模型中根除已建立的播散性疾病。在这一第二阶段的申请中，我们建议进行广泛的产品开发工作，完成毒理学/药理学研究，并制定临床治疗方案，为IND备案做准备。为此，在目标1、2和3中，我们将侧重于产品开发研究，包括分析测试开发(目标1)、扩大规模和稳定性分析的工艺开发(目标2)以及提高产品稳定性的配方开发工作(目标3)。该产品的药代动力学和毒理学特性将在目标4中进行。在目标5中，优化的处方将用于在临床前的常规肿瘤模型中评估剂量、治疗方案和加强疫苗接种对播散性疾病长期治愈的影响。AIM 5中确定的最佳治疗策略将为I期临床试验方案提供蓝图。这些研究预计将产生IND批准所需的数据。

DESCRIPTION (provided by applicant): Proof of principle for the feasibility of our proprietary tumor vaccination strategy involving the use of Interleukin-12-encapsulated microspheres has been demonstrated in Phase I studies. A single intra-tumoral injection of Interleukin-12-encapsulated biodegradable microspheres induces the complete regression of small primary tumors, promotes the development of long-term systemic anti-tumor immunity and results in the eradication of established disseminated disease in murine tumor models. In this Phase II application, we propose to perform extensive product development work, complete the toxicology/pharmacology studies and develop a clinical treatment protocol in preparation for IND filing. To this end, in Aims 1, 2 and 3, we will focus on product development studies including analytical assay development (Aim 1), process development for scale-up and stability analysis (Aim 2) and formulation development work to improve product stability (Aim 3). Pharmacokinetic and toxicological characterization of the product will be performed in Aim 4. In Aim 5, the optimized formulation will be used to evaluate the effect of dose, treatment schedule and booster vaccinations on long-term cure of disseminated disease in a pre-clinical routine tumor model. The optimal treatment strategy identified in Aim 5 will provide the blueprint for a Phase I clinical trial protocol. These studies are expected to generate the data that is necessary for IND approval.