Bioreactor for Enhanced T-cell Based Therapy of Melanoma

用于增强 T 细胞黑色素瘤治疗的生物反应器

• 批准号: 6791918
• 负责人: DOUGLAS Matthew SMITH
• 金额: $ 12.42万
• 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: 2004-04-01 至 2005-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6791918
• 关键词: T lymphocyte; antibody specificity; antitumor antibody; bioengineering /biomedical engineering; bioreactors; clinical research; cytotoxic T lymphocyte; flow cytometry; high throughput technology; human tissue; immunologic substance development /preparation; immunologic substance resource /registry /referral center; immunopharmacology; interleukin 2; melanoma; method development; neoplasm /cancer vaccine; perfusion; plasmapheresis; tumor antigens; tumor infiltrating lymphocyte

DESCRIPTION (provided by applicant): Malignant melanoma is a significant and deadly form of cancer worldwide. Emerging evidence has shown that melanoma cells express tumor-associated antigens that are specifically recognized by the immune system. Melanoma antigen-specific T-lymphocytes can be isolated from the tumors of late stage cancer patients or induced by active vaccination using well-characterized tumor peptide epitope vaccines. Adoptive transfer therapy of autologous tumor infiltrating lymphocytes (TILs) has been shown to mediate durable regression of malignant melanoma in particular patients. Furthermore, ex vivo antigen-specific expansion of autologous T-cells from vaccinated patients is a promising approach to increase the potency and frequency of tumor antigen specific T-cells for adoptive immunotherapy. However, current culture methods for ex vivo lymphocyte expansion to produce billions of T-cells for patient therapy are costly, labor intensive and consist of multiple manual open-process steps which are difficult to implement for wider patient delivery without specialized facilities under increasingly stringent regulatory requirements. In addition, prolonged culture of T-cells leads to replicative senescence with loss of biological function and therapeutic activity. Aastrom Biosciences, Inc. is developing a novel clinical scale bioreactor system for production of cells for human cell therapy using closed system automation and continuous single-pass perfusion technologies. The primary goal of this Phase I proposal is to demonstrate the feasibility of using the AastromReplicell/TM Cell Production System to expand highly active melanoma tumor antigen specific T-lymphocytes from patients' tumors or apheresis cells of vaccinated donors for immunotherapy against malignant melanoma. Multiple culture parameters for both antigen-independent and selective melanoma peptide driven T-cell expansion processes will be implemented and evaluated in the clinical scale bioreactor system. The beneficial effect of single-pass perfusion for potentially improved biological function and replicative capabilities of T-lymphocytes when compared to conventional methods will be defined. A closed automated bioreactor system will fulfill a large unmet clinical demand for consistent, reliable and reproducible T-cell production under stringent regulatory conditions with improved immunologic and therapeutic potency for immunotherapy of cancer.

描述（由申请人提供）：恶性黑色素瘤是世界范围内一种重要且致命的癌症。新出现的证据表明，黑色素瘤细胞表达免疫系统特异性识别的肿瘤相关抗原。黑色素瘤抗原特异性T淋巴细胞可以从晚期癌症患者的肿瘤中分离或通过使用充分表征的肿瘤肽表位疫苗的主动接种来诱导。自体肿瘤浸润淋巴细胞（TIL）的连续转移治疗已被证明可介导特定患者恶性黑色素瘤的持久消退。此外，来自接种疫苗的患者的自体T细胞的离体抗原特异性扩增是一种很有前途的方法，可以提高肿瘤抗原特异性T细胞用于过继免疫治疗的效力和频率。然而，目前用于离体淋巴细胞扩增以产生数十亿T细胞用于患者治疗的培养方法是昂贵的、劳动密集型的，并且由多个手动开放过程步骤组成，在日益严格的监管要求下，在没有专门设施的情况下，难以实施用于更广泛的患者递送。此外，T细胞的长期培养导致复制性衰老，丧失生物学功能和治疗活性。Aastrom Biosciences，Inc.正在开发一种新的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灌注技术生产用于人类细胞治疗的细胞。该I期提案的主要目标是证明使用AastromReplicell/TM细胞生产系统从患者肿瘤或接种供体的单采细胞术细胞扩增高活性黑素瘤肿瘤抗原特异性T淋巴细胞用于恶性黑素瘤免疫治疗的可行性。将在临床规模生物反应器系统中实施和评价抗原非依赖性和选择性黑素瘤肽驱动的T细胞扩增工艺的多个培养参数。与传统方法相比，单程灌注对T淋巴细胞的生物学功能和复制能力的潜在改善的有益作用将被定义。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T细胞生产的大量未满足的临床需求，并具有用于癌症免疫治疗的改善的免疫学和治疗效力。