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

• 批准号: 7894236
• 负责人: David Zaharoff
• 金额: $ 16.66万
• 依托单位: UNIVERSITY OF ARKANSAS AT FAYETTEVILLE
• 依托单位国家: 美国
• 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/7894236
• 关键词: Adjuvant; Antigen Presentation; Antigens; Arkansas; Biocompatible Materials; Biomedical Engineering; Biomedical Research; Biopolymers; Bladder; CD8B1 gene; Cancer Vaccines; Cells; Cessation of life; Chitosan; Clinical; Clinical Trials; Colorectal; 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

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）：白介素12（IL-12）是一种有效的抗肿瘤细胞因子，具有明显的临床毒性。为了降低临床毒性，并在维持或提高IL-12的抗肿瘤功效的同时，我们开发了一种新型的基于生物材料的递送系统，用于局部给药。我们已经证明，IL-12与粘性生物聚合物Chitosan的共同成型可以：（i）将IL-12保留在肿瘤微环境中； （ii）根除建立的结直肠，膀胱和胰腺肿瘤； （iii）产生持久的肿瘤复发保护。仅壳聚糖或IL-12不能复制这些效果。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通过在肿瘤微环境中IL-12的局部保留以及产生明显但互补的炎症过程的产生，从而消除肿瘤，从而消除肿瘤，从而引起肿瘤特异性的适应性免疫反应。提出了四个具体目标来研究这些机制，并定义了局部壳聚糖/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免疫疗法的临床翻译提供理由，以治疗多种癌症。 Zaharoff博士在杜克大学和国家癌症研究所的肿瘤免疫学方面接受了广泛的药物分娩应用培训。本应用程序利用了他独特的多学科技能，以研究壳聚糖在增强IL-12的免疫调节功能方面的作用。最近，Zaharoff博士加入了阿肯色大学的生物医学工程计划。生物医学工程是一项快速扩展的计划，致力于实现国家认可。阿肯色大学的生物医学研究界是一个充满活力的，高度协作的小组，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，该实验室将着重于开发用于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的要素包括知识产权保护方面的教学培训，由资助良好的调查员组成的顾问委员会以及通过会议和审查小组参与来增强专业网络。 公共卫生相关性：IL-12是一种有效的细胞因子，在临床前研究中既表现出巨大的抗肿瘤潜力，又在临床试验中具有严重毒性。 IL-12与生物聚合物壳聚糖的共同成型可以增强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翻译。