Dendritic Cell Subset for Enhanced Cancer Vaccine

用于增强型癌症疫苗的树突状细胞亚群

• 批准号: 6832676
• 负责人: DOUGLAS Matthew SMITH
• 金额: $ 10.96万
• 依托单位: AASTROM BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-07 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6832676
• 关键词: bioreactors; biotechnology; carcinoembryonal antigen; cell differentiation; cellular immunity; clinical research; deficient growth media; dendritic cells; helper T lymphocyte; human subject; immune response; method development; monocyte; neoplasm /cancer immunotherapy; neoplasm /cancer vaccine; tissue /cell culture; tryptophan 2,3 dioxygenase; vaccine development

DESCRIPTION (provided by applicant): Tumor antigen primed dendritic cells (DCs) are under widespread clinical evaluation for immunotherapy of multiple forms of cancer. Emerging evidence suggests that DCs are fundamental regulators of the immune response leading to potent cell mediated immunity or alternatively to negative regulation and tolerance induction. Conventional cytokine combinations and DC culture methodologies widely used to generate cancer vaccines for these human clinical trials produce a mixture of immunoactivating and immunoinhibitory DC subsets as defined by expression and mechanistic association of the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO). Aastrom Biosciences, Inc. has developed a novel clinical scale bioreactor system for production, antigen loading, maturation and harvest of monocyte-derived dendritic cells using closed system automation and continuous single-pass medium perfusion. The primary goal of this Phase I proposal is to enhance the immunostimulatory potency of dendritic cell based cancer vaccines by removal of immunosuppressive DC subsets while selectively enriching for activating IDO negative DC subsets at the time of harvest from the AastromReplicell TM Cell Production System. A procedure for fractionation of DC subpopulations to high purity based on differential plastic adherence of IDO-negative DCs to the bioreactor cell bed at the time of harvest will be developed, evaluated and automated. New maturation cytokine combinations which specifically promote differentiation of highly immunoactivating DCs while minimizing production of potentially tolerogenic DCs will be identified and evaluated under perfusion culture conditions. Well-defined and clinically applicable cytomegaloviral (CMV)and tumor-associated carcinoembryonic antigen (CEA) peptide epitopes will be used to characterize theCD4+ and CD8+ T-cell responses to these DC subpopulations in vitro as a prerequisite to evaluation of the vaccine for safety, immunological and clinical efficacy for immunotherapy of human patients with CEA positive malignancies at Duke University Medical Center and other clinical sites during the Phase II SBIR proposal. A closed automated bioreactor system will fulfill a large unmet clinical demand for consistent, reliable and reproducible DC vaccine production under stringent regulatory conditions with improved immunologic and therapeutic potency for immunotherapy of infectious diseases and cancer.

描述（由申请人提供）：肿瘤抗原致敏的树突状细胞（DC）正在广泛的临床评价中用于多种形式癌症的免疫治疗。新出现的证据表明，DC是免疫应答的基本调节剂，导致有效的细胞介导的免疫或可替代地导致负调节和耐受诱导。广泛用于产生用于这些人类临床试验的癌症疫苗的常规细胞因子组合和DC培养方法产生免疫活化性和免疫抑制性DC亚群的混合物，所述免疫活化性和免疫抑制性DC亚群由聚糖降解酶吲哚胺2，3-双加氧酶（IDO）的表达和机械缔合来定义。Aastrom Biosciences，Inc.开发了一种新型临床规模的生物反应器系统，用于使用封闭系统自动化和连续单程培养基灌注生产、抗原加载、成熟和收获单核细胞衍生的树突状细胞。该I期提案的主要目标是通过去除免疫抑制性DC亚群同时在从AastromReplicell TM细胞生产系统收获时选择性富集活化IDO阴性DC亚群来增强基于树突状细胞的癌症疫苗的免疫刺激效力。将开发、评价和自动化基于收获时IDO阴性DC对生物反应器细胞床的差异塑性粘附将DC亚群分级分离至高纯度的程序。新的成熟细胞因子组合，特别是促进高度免疫活化的DC的分化，同时最大限度地减少潜在的致耐受性DC的生产将被确定和灌注培养条件下进行评估。明确定义的和临床适用的巨细胞病毒（CMV）和肿瘤相关癌胚抗原（CEA）肽表位将用于体外表征对这些DC亚群的CD 4+和CD 8 + T细胞应答，作为评价疫苗安全性的先决条件，在本研究期间，在杜克大学医学中心和其他临床中心，第二阶段SBIR提案。封闭的自动化生物反应器系统将满足在严格的监管条件下一致、可靠和可再现的DC疫苗生产的大量未满足的临床需求，其具有用于感染性疾病和癌症的免疫治疗的改善的免疫学和治疗效力。