Intravesical Chitosan/IL-12 Immunotherapy for Bladder Carcinoma

膀胱内壳聚糖/IL-12免疫治疗膀胱癌

基本信息

批准号：
8626563
负责人：
David Zaharoff
金额：
$ 41.69万
依托单位：
UNIVERSITY OF ARKANSAS AT FAYETTEVILLE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-03-01 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8626563
关键词：
Biomedical Research Bladder Neoplasm Blood Chemical Analysis Calmette-Guerin Bacillus Cancer Patient Cardiac Caring Cells Chemicals Chitosan Clinical Complete Blood Count Crustacea Cytotoxic T-Lymphocytes Data Deacetylation Dependence Development Disease Distant Drug Formulations Drug Kinetics Early Diagnosis Epithelial Event Excretory function Genus Mycobacterium Glycosaminoglycans Goals Immune Immune response Immunity Immunologic Memory Immunotherapy Infection Inflammatory Institution Interleukin-12 Intravesical Administration Investigation Knockout Mice Life Liver Maintenance Therapy Malignant neoplasm of urinary bladder Mediating Modeling Molecular Weight Mus Organ Patients Permeability Polysaccharides Population Pre-Clinical Model Recombinant Interleukin-12 Recombinants Recurrence Recurrent disease Recurrent tumor Relative (related person)Renal function Research Risk Safety Sepsis Serum Solutions Time Tissues Toxic effect Toxicology Translations Tumor Burden Urothelium Viscosity base bladder Carcinoma cancer diagnosis clinically relevant cytokine design exoskeleton graduate student improved in vitro Assay insight intravesical melanoma novel pre-clinical public health relevance response subcutaneous tumor undergraduate student

项目摘要

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.

项目概要膀胱癌是美国第六大最常见的癌症诊断，尽管四分之三的人患者早期被诊断患有浅表（非侵入性）疾病，膀胱癌复发率很高，需要长期维持治疗和昂贵的持续监测。新颖的疗法，能够需要诱导持久的抗肿瘤反应，以限制进行性复发并提高生存率。基于免疫的疗法已被证明具有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)，已显示出显着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源自甲壳类动物外骨骼的天然多糖，可以增强抗膀胱内施用IL-12的肿瘤功效。壳聚糖溶液和 IL-12 的复合制剂（壳聚糖/IL- 12）被发现可以消除已建立的原位膀胱肿瘤并产生系统性肿瘤特异性保护性免疫力。拟议项目将继续膀胱内壳聚糖/IL-12的临床前开发免疫疗法。提出了三个独立的目标。目标 1 旨在通过以下方式阐明其机制：其中壳聚糖促进膀胱内 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全身保护性免疫。该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给药，同时提供关键的临床前数据以支持有前途的新药物的转化免疫疗法用于治疗膀胱癌。同时，该项目将增强生物医学 AREA 机构的研究能力，为 2 名新研究生提供宝贵的研究机会让大约 15-25 名本科生接触生物医学研究。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Intravesical chitosan/interleukin-12 immunotherapy induces tumor-specific systemic immunity against murine bladder cancer.

膀胱内壳聚糖/白细胞介素 12 免疫疗法可诱导针对小鼠膀胱癌的肿瘤特异性全身免疫。

DOI：
10.1007/s00262-015-1672-x
发表时间：
2015
期刊：
Cancer immunology, immunotherapy : CII
影响因子：
0
作者：
Smith,SeanG;Koppolu,BhanuPrasanth;Ravindranathan,Sruthi;Kurtz,SamanthaL;Yang,Lirong;Katz,MatthewD;Zaharoff,DavidA
通讯作者：
Zaharoff,DavidA

Immunological mechanisms of intravesical chitosan/interleukin-12 immunotherapy against murine bladder cancer.