Chitosan-based Delivery and Immunopotentiation of Cancer Vaccines

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，具有显著的临床毒性。为了减少临床毒性，同时保持或提高IL-12的抗肿瘤功效，我们开发了一种新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）根除结肠、膀胱和胰腺肿瘤；(3)对肿瘤复发产生持久的保护作用。壳聚糖或IL-12不能单独复制这些效果。本研究旨在阐明壳聚糖增强IL-12抗肿瘤活性的免疫机制。核心假设是壳聚糖和IL-12协同作用，通过肿瘤微环境中IL-12的局部保留和不同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。研究这些机制和确定局部壳聚糖/IL-12免疫治疗的潜在临床作用，提出了四个具体目标。该项目的成功完成将为局部壳聚糖/IL-12免疫疗法治疗多种癌症的临床转化提供依据。

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.