Chitosan-based Delivery and Immunopotentiation of Cancer Vaccines

基于壳聚糖的癌症疫苗的递送和免疫增强

基本信息

批准号：
8277296
负责人：
David Zaharoff
金额：
$ 16.88万
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：
2010
资助国家：
美国
起止时间：
2010-06-01 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8277296
关键词：
Adjuvant Antigen Presentation Antigens Arkansas Biocompatible Materials Biomedical Engineering Biomedical Research Biopolymers Bladder Neoplasm CD8B1 gene Cancer Vaccines Cells Cessation of life Chitosan Clinical Clinical Trials Colorectal Neoplasms Combined Vaccines Commit Communities Crustacea Data Deacetylation Development Development Plans Distal Drug Delivery Systems Drug Formulations Elements Engineering Equipment Excision Faculty Flow Cytometry Funding Generations Goals Granulocyte-Macrophage Colony-Stimulating Factor ITGAM gene Immune Immune response Immunity Immunologic Adjuvants Immunologics Immunology Immunotherapy Inflammation Inflammatory Injection of therapeutic agent Intellectual Property Interleukin-12 K22 Award Laboratories Lymphoid Tissue Malignant Neoplasms Mediating Methods Microdialysis Molecular Weight National Cancer Institute Natural Killer Cells Neoadjuvant Therapy Neoplasm Metastasis Operative Surgical Procedures Polysaccharides Pre-Clinical Model Primary Neoplasm Process Property Proteins Publishing Recombinant Cytokines Recombinant Interleukin-12 Recurrence Relative (related person)Research Personnel Residual Neoplasm Role Solutions System T-Lymphocyte Testing Therapeutic Time Toxic effect Training Translations Tumor Antigens Universities Vaccines Viral Antigens base cancer immunotherapy career development cytokine design exoskeleton improved interest knowledge base multidisciplinary neoplastic cell novel pancreatic neoplasm paracrine preclinical study programs public health relevance response skills subcutaneous symposium tumor tumor immunology

项目摘要

DESCRIPTION (provided by applicant): Interleukin-12 (IL-12) is a potent antitumor cytokine with significant clinical toxicities. In an effort to reduce clinical toxicities and while maintaining or improving the antitumor efficacy of IL-12, we have developed a novel biomaterials-based delivery system for local administration. We have demonstrated that co-formulations of IL- 12 with a viscous biopolymer, chitosan, can: (i) retain IL-12 in the tumor microenvironment; (ii) eradicate established colorectal, bladder and pancreatic tumors; and (iii) generate durable protection from tumor recurrence. These effects could not be reproduced by either chitosan or IL-12 alone. The goal of this proposal is to elucidate the immunologic mechanisms by which chitosan potentiates the antitumor activity of IL-12. The central hypothesis is that chitosan and IL-12 act synergistically to eradicate tumors through local retention of IL-12 in the tumor microenvironment and the generation of distinct, but complementary inflammatory processes which combine to elicit tumor-specific adaptive immune responses. Four specific aims are proposed to study these mechanisms and define the potential clinical role of local chitosan/IL-12 immunotherapy. Successful completion of this project will provide rationale for clinical translation of local chitosan/IL-12 immunotherapies for the treatment of numerous cancers. Dr. Zaharoff has received extensive training in drug delivery applications at Duke University and tumor immunology at the National Cancer Institute. The present application exploits his unique multidisciplinary skill set to study the role of chitosan in enhancing the immunomodulatory functions of IL-12. Recently, Dr. Zaharoff joined the faculty in the Biomedical Engineering Program at the University of Arkansas. Biomedical Engineering is a rapidly expanding program that is committed to achieving national recognition. The biomedical research community at the University of Arkansas is a vibrant, highly collaborative group which provides ample opportunity for intellectual stimulation, collaborative interaction and equipment sharing. The K22 award will enable the candidate to establish an academic laboratory that will focus on the development of novel delivery systems for vaccines and cancer immunotherapies. Elements of the career development plan included in this proposal include didactic training in intellectual property protection, formation of an advisory board of well funded investigators and enhancing professional networks through conference and review panel participation. PUBLIC HEALTH RELEVANCE: IL-12 is a potent cytokine that has demonstrated both significant antitumor potential in preclinical studies and severe toxicities in clinical trials. Co-formulations of IL-12 with the biopolymer chitosan can enhance the antitumor activity of IL-12 while reducing systemic toxicity. This project will study the mechanisms by which chitosan enhances the antitumor activity of IL-12 and support the potential clinical translation of chitosan/IL- 12 immunotherapy.

描述（由申请人提供）：白细胞介素12（IL-12）是一种有效的抗肿瘤细胞因子，具有显着的临床毒性。为了减少临床毒性，同时维持或提高 IL-12 的抗肿瘤功效，我们开发了一种基于生物材料的新型局部给药递送系统。我们已经证明，IL-12 与粘性生物聚合物壳聚糖的复合制剂可以： (i) 将 IL-12 保留在肿瘤微环境中； (ii) 根除已形成的结直肠、膀胱和胰腺肿瘤； (iii) 产生持久的保护，防止肿瘤复发。单独使用壳聚糖或 IL-12 无法重现这些效应。该提案的目的是阐明壳聚糖增强 IL-12 抗肿瘤活性的免疫机制。中心假设是，壳聚糖和 IL-12 协同作用，通过 IL-12 在肿瘤微环境中的局部保留以及独特但互补的炎症过程的产生来根除肿瘤，这些炎症过程结合起来引发肿瘤特异性适应性免疫反应。提出了四个具体目标来研究这些机制并确定局部壳聚糖/IL-12 免疫疗法的潜在临床作用。该项目的成功完成将为局部壳聚糖/IL-12免疫疗法临床转化用于治疗多种癌症提供依据。 Zaharoff 博士在杜克大学接受了药物输送应用方面的广泛培训，并在国家癌症研究所接受了肿瘤免疫学方面的培训。本申请利用他独特的多学科技能来研究壳聚糖在增强 IL-12 免疫调节功能中的作用。最近，扎哈罗夫博士加入了阿肯色大学生物医学工程项目。生物医学工程是一个快速发展的项目，致力于获得国家认可。阿肯色大学的生物医学研究社区是一个充满活力、高度协作的团体，为智力刺激、协作互动和设备共享提供了充足的机会。 K22 奖将使候选人能够建立一个学术实验室，专注于开发疫苗和癌症免疫疗法的新型输送系统。该提案中包含的职业发展计划要素包括知识产权保护方面的教学培训、组建由资金充足的调查人员组成的咨询委员会以及通过会议和审查小组的参与加强专业网络。公共健康相关性：IL-12 是一种有效的细胞因子，在临床前研究中显示出显着的抗肿瘤潜力，在临床试验中显示出严重的毒性。 IL-12与生物聚合物壳聚糖的复合制剂可以增强IL-12的抗肿瘤活性，同时降低全身毒性。该项目将研究壳聚糖增强IL-12抗肿瘤活性的机制，并支持壳聚糖/IL-12免疫疗法的潜在临床转化。