TUMOR IMMUNOTHERAPY WITH BIODEGRADABLE MICROSPHERES

描述（由申请人提供）： 我们专有的肿瘤疫苗接种策略（包括使用白细胞介素-12包封的微球）的可行性原理证明已在I期研究中得到证实。单次瘤内注射白细胞介素-12包封的生物可降解微球诱导小原发性肿瘤的完全消退，促进长期全身抗肿瘤免疫的发展，并导致小鼠肿瘤模型中已建立的播散性疾病的根除。在本次II期申请中，我们计划开展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申报做准备。为此，在目标1、2和3中，我们将重点关注产品开发研究，包括分析测定开发（目标1）、用于规模扩大和稳定性分析的工艺开发（目标2）以及用于提高产品稳定性的处方开发工作（目标3）。将在目标4中进行产品的药代动力学和毒理学表征。在目的5中，优化的制剂将用于在临床前常规肿瘤模型中评价剂量、治疗方案和加强疫苗接种对播散性疾病长期治愈的影响。目标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。预计这些研究将生成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.