Chitosan-based Delivery and Immunopotentiation of Cancer Vaccines

描述（申请人提供）：白细胞介素-12（IL-12）是一种强效抗肿瘤细胞因子，具有显着的临床毒性。为了减少临床毒性，同时保持或改善IL-12的抗肿瘤疗效，我们开发了一种新型的基于生物材料的局部给药系统。我们已经证明，IL- 12与粘性生物聚合物壳聚糖的共制剂可以：（i）将IL-12保留在肿瘤微环境中;（ii）根除已建立的结肠直肠、膀胱和胰腺肿瘤;和（iii）产生持久的保护以防止肿瘤复发。这些效果不能再现由壳聚糖或IL-12单独。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。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和不同但互补的炎症过程的产生来根除肿瘤，所述炎症过程联合收割机引发肿瘤特异性适应性免疫应答。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当地壳聚糖/IL-12免疫疗法治疗多种癌症的临床转化提供理论基础。 博士Zaharoff曾在杜克大学接受过药物输送应用方面的广泛培训，并在国家癌症研究所接受过肿瘤免疫学方面的培训。本申请利用其独特的多学科技能来研究壳聚糖在增强IL-12的免疫调节功能中的作用。最近，Zaharoff博士加入了阿肯色州大学生物医学工程项目的教师队伍。生物医学工程是一个迅速扩大的计划，致力于实现国家认可。阿肯色州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。本提案中的职业发展计划包括知识产权保护方面的教学培训、成立一个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。 公共卫生相关性：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的共制剂可以增强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，并支持壳聚糖/IL- 12免疫治疗的潜在临床转化。

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.