Hydrogel-Based Cytokine Carrier for Oral cancer Therapy

用于口腔癌治疗的水凝胶细胞因子载体

• 批准号: 6817100
• 负责人: FANG-AN CHEN
• 金额: $ 28.25万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2004-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6817100
• 关键词: SCID mouse; biodegradable product; bioengineering /biomedical engineering; biomaterial development /preparation; biomaterial evaluation; biophysics; cellular immunity; chemical structure function; clinical research; cytokine; disease /disorder model; drug delivery systems; gel; human subject; interleukin 12; lymphocyte; mouth neoplasms; neoplasm /cancer immunotherapy; patient oriented research; pharmacokinetics; slow release drug

DESCRIPTION (provided by applicant): The goal of this project is to develop an innovative biodegradable hydrogel (BH) based cytokine carrier for intra-tumoral immunotherapy of human oral cancer (OC). Despite aggressive multimodality treatment, Ioco-regional recurrence is the principal pattern of treatment failure of oral cancer. We hypothesize that BH can be engineered for local sustained release of pro-inflammatory cytokines into the tumor microenvironment to mobilize tumor associated lymphocytes that will eradicate tumor cells. The potent antitumor effects of cytokines have already been established. However, toxicity associated with systemic administration of cytokine limits its clinical application. Intra-tumoral cytokine administration strategies have been shown to improve efficacy of cytokine treatment and minimize the toxicity. The essential criteria of such local cytokine administration are control of dose, release kinetics and preservation of cytokine bioactivity. Although gene therapy has provided proof of this principle, but has failed to meet all the requisite criteria. In this project a BH-based cytokine-delivery system will be developed as a collaborative project between Biomedical Engineering Program of Cornell University and Head and Neck Oncology Division of NYU Cancer Institute. In addition to its biocompatibility, versatility in formulation and technical simplicity, our preliminary results have demonstrated that BHs can be formulated for loading various proteins, controlling their release kinetics and preservation of cytokine bioactivity. In Aim 1, BH formulations will be engineered to optimize the cytokine release kinetics (amount, duration and pattern) and to confirm preservation of cytokine bioactivity. In Aim 2, this newly developed BH-delivery system will be investigated in a chimeric human/SCID mouse model of OC established in our laboratory. This tumor model allows co-engraftment of human tumor and autologous lymphocytes and proved to be effective for in vivo evaluation of intra-tumoral immunotherapy. The anti-tumor efficacy of BH mediated delivery of IL-12 alone or its synergistic combination will be optimized in this model. A preliminary lymphocyte subset depletion study will also be conducted to provide insight into cellular components responsible for anti-tumor activity with intra-tumoral cytokine treatment. This may serve as a basis for future complete and systematic anti-tumor mechanism study. The results from this study will establish a novel intratumoral immunotherapy for OC, which may be readily translated into clinical trials. This potential therapeutic strategy, hydrogel mediated controlled release of cytokine into tumor microenvironment, may be used in other solid tumors.

描述（由申请人提供）：该项目的目标是开发一种基于创新型可生物降解水凝胶（BH）的细胞因子载体，用于人类口腔癌（OC）的瘤内免疫治疗。尽管采取了积极的多学科治疗，局部区域复发仍然是口腔癌治疗失败的主要模式。我们假设 BH 可以被设计为促炎细胞因子局部持续释放到肿瘤微环境中，以动员肿瘤相关淋巴细胞，从而根除肿瘤细胞。 细胞因子的有效抗肿瘤作用已经被证实。然而，与细胞因子的全身施用相关的毒性限制了其临床应用。肿瘤内细胞因子施用策略已被证明可以提高细胞因子治疗的功效并最大限度地减少毒性。这种局部细胞因子施用的基本标准是控制剂量、释放动力学和细胞因子生物活性的保存。尽管基因治疗已经提供了这一原理的证明，但未能满足所有必要的标准。在该项目中，康奈尔大学生物医学工程项目和纽约大学癌症研究所头颈肿瘤科之间的合作项目将开发基于 BH 的细胞因子递送系统。除了其生物相容性、配方的多功能性和技术简单性之外，我们的初步结果还表明，BH 可以配制用于负载各种蛋白质、控制其释放动力学并保存细胞因子生物活性。在目标 1 中，BH 配方将被设计为优化细胞因子释放动力学（数量、持续时间和模式）并确认细胞因子生物活性的保留。在目标 2 中，这种新开发的 BH 递送系统将在我们实验室建立的 OC 嵌合人/SCID 小鼠模型中进行研究。该肿瘤模型允许人类肿瘤和自体淋巴细胞共同植入，并被证明可有效地评估肿瘤内免疫治疗的体内效果。 BH介导的IL-12单独递送或其协同组合的抗肿瘤功效将在该模型中得到优化。还将进行初步的淋巴细胞亚群去除研究，以深入了解肿瘤内细胞因子治疗中负责抗肿瘤活性的细胞成分。这可以为今后完整、系统的抗肿瘤机制研究奠定基础。 这项研究的结果将为 OC 建立一种新型瘤内免疫疗法，并可轻松转化为临床试验。这种潜在的治疗策略，即水凝胶介导的细胞因子受控释放到肿瘤微环境中，可用于其他实体瘤。