Chitosan-based Delivery and Immunopotentiation of Cancer Vaccines

说明(申请人提供)：白介素12(IL-12)是一种具有显著临床毒性的有效抗肿瘤细胞因子。为了减少临床毒性，同时保持或提高IL-12的抗肿瘤疗效，我们开发了一种新型的生物材料局部给药系统。我们已经证明，IL-12与粘性生物聚合物壳聚糖的联合制剂可以：(I)将IL-12保留在肿瘤微环境中；(Ii)根除已建立的结直肠、膀胱和胰腺肿瘤；以及(Iii)产生持久的保护，防止肿瘤复发。仅用几丁糖或IL-12都不能复制这些效应。本研究的目的是阐明壳聚糖增强IL-12抗肿瘤活性的免疫学机制。核心假设是壳聚糖和IL-12通过在肿瘤微环境中局部滞留IL-12和产生不同但互补的炎症过程来协同作用，从而诱导肿瘤特异性适应性免疫反应。提出了四个具体的目标来研究这些机制，并确定了局部壳聚糖/IL-12免疫治疗的潜在临床作用。该项目的成功完成将为当地壳聚糖/IL-12免疫疗法的临床翻译提供理论基础，用于治疗多种癌症。 扎哈罗夫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的教职。生物医学工程是一个迅速发展的项目，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，专注于开发用于疫苗和癌症免疫疗法的新型递送系统。这项提议所包括的职业发展计划的内容包括知识产权保护教学培训、由资金充足的调查人员组成的咨询委员会以及通过参加会议和审查小组来加强专业网络。 与公共卫生相关：IL-12是一种强大的细胞因子，在临床前研究中显示出显著的抗肿瘤潜力，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共制剂可增强IL-12的抗肿瘤活性，同时降低全身毒性。本项目将研究壳聚糖增强IL-12抗肿瘤活性的机制，为壳聚糖/IL-12免疫治疗的临床应用提供支持。

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.