Intravesical Chitosan/IL-12 Immunotherapy for Bladder Carcinoma

项目摘要 膀胱癌是美国第六大最常见的癌症诊断。 患者早期诊断为浅表（非侵入性）疾病，膀胱癌高度复发， 需要长期的维持治疗和昂贵的持续监测。新疗法，能够 诱导持久的抗肿瘤反应，以限制进行性复发和提高存活率。 基于免疫的疗法已经证明了引发持久的肿瘤特异性免疫的潜力。在 特别是促炎细胞因子白细胞介素-12（IL-12），已经显示出显著的抗肿瘤作用。 在许多临床前肿瘤模型中的活性和保护性免疫。先前的研究表明， 壳聚糖是一种天然多糖，来源于甲壳类动物的外泌体，可以增强抗- 膀胱内施用的IL-12的肿瘤功效。壳聚糖溶液和IL-12（壳聚糖/IL-12）的共制剂 12)消除已建立的原位膀胱肿瘤，并产生全身肿瘤特异性 保护性免疫 该项目将继续进行膀胱内注射壳聚糖/IL-12的临床前开发 免疫疗法提出了三个独立的目标。目的1是为了阐明机制， 该壳聚糖促进膀胱内IL-12递送。目标2将评估药代动力学、安全性和 使用临床相关终点的膀胱内壳聚糖/IL-12免疫疗法的耐受性。目标3将开始， 描述膀胱内免疫疗法如何产生系统性保护性免疫。 这个项目的总体目标是提高我们对壳聚糖增强的机理的理解， 膀胱内递送，同时提供关键的临床前数据，以支持翻译一种有前途的新的 免疫疗法用于治疗膀胱癌。同时，该项目将提高生物医学 在一个地区机构的研究能力，为2个新的研究生提供宝贵的研究机会 并让大约15-25名本科生接触生物医学研究。

Project Summary Bladder cancer is the sixth most common cancer diagnosis in the U.S. Although three-quarters of patients are diagnosed early with superficial (non-invasive) disease, bladder cancer is highly recurrent and requires long-term maintenance therapy and costly continuous surveillance. Novel therapies, capable of inducing durable anti-tumor responses, are needed to limit progressive recurrence and to improve survival. Immune-based therapies have demonstrated the potential to elicit, durable tumor-specific immunity. In particular, the pro-inflammatory cytokine, interleukin-12 (IL-12), has demonstrated remarkable anti-tumor activity and protective immunity in numerous preclinical tumor models. Previous research has demonstrated that chitosan, a natural polysaccharide derived from the exoskelatons of crustaceans, can enhance the anti- tumor efficacy of intravesically administered IL-12. Co-formulations of chitosan solution and IL-12 (chitosan/IL- 12) were found to eliminate established orthotopic bladder tumors and generate systemic tumor-specific protective immunity. The proposed project will continue the preclinical development of intravesical chitosan/IL-12 immunotherapy. Three independent aims are proposed. Aim 1 is designed to elucidate the mechanisms by which chitosan facilitates intravesical IL-12 delivery. Aim 2 will assess the pharmacokinetics, safety and tolerability of intravesical chitosan/IL-12 immunotherapy using clinically relevant endpoints. Aim 3 will begin to describe how an intravesical immunotherapy can generate systemic protective immunity. The overall goal of this project is to improve our mechanistic understanding of chitosan-enhanced intravesical delivery while providing critical preclinical data in support of translation of a promising new immunotherapy for the treatment of bladder cancer. At the same time, this project will enhance the biomedical research capacity at an AREA institution, provide valuable research opportunities for 2 new graduate students and expose approximately 15-25 undergraduate students to biomedical research.