Donor Innate Lymphocyte Infusion Product for Immunotherapy of Glioblastoma Multif

用于多发性胶质母细胞瘤免疫治疗的供体先天淋巴细胞输注产品

• 批准号: 7772397
• 负责人: LAWRENCE S LAMB
• 金额: $ 18.31万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7772397
• 关键词: Adjuvant; Allogenic; Antigen-Presenting Cells; Autoantigens; Biological Assay; Blood; Brain Neoplasms; Cell Line; Cell Therapy; Cells; Clinical; Clinical Protocols; Data; Development; Diphosphates; Effector Cell; Glioblastoma; Human; Immune; Immune response; Immune system; Immunotherapeutic agent; Immunotherapy; In Vitro; Induction of Apoptosis; Infusion procedures; Interferon Type II; Interleukin-12; Interleukin-2; Laboratories; Lymphocyte; Malignant neoplasm of brain; Methods; Migration Assay; Minor; Mus; Natural Killer Cells; Nitrogen; Nude Mice; Patients; Peptides; Procedures; Process; Production; Protocols documentation; Publishing; Reagent; Regimen; Regulation; Reproducibility; Research; Resistance; Staging; Stress; T-Cell Activation; T-Lymphocyte; Testing; Therapy Clinical Trials; Translations; Tumor Burden; Tumor Cell Line; United States Food and Drug Administration; Work; Xenograft Model; Zoledronate; antigen processing; base; bisphosphonate; brain tissue; cancer therapy; cell growth; cell mediated immune response; clinical application; cytokine; cytotoxic; cytotoxicity; effective therapy; killings; manufacturing process; neoplastic cell; programs; public health relevance; scale up; tumor; tumor xenograft

DESCRIPTION (provided by applicant): Despite significant advances in the treatment of cancer over the past several decades, there are no long-term effective therapies for glioblastoma multiforme (GBM). Our laboratory has recently shown promising findings both in vitro and in mouse xenograft models that human GBM is vulnerable to locally delivered allogeneic innate lymphocyte therapy. These proposed studies will define a manufacturing regimen for an FDA-approvable cell therapy product that is principally composed of expanded/activated 34 T cells and a minor subset of NK cells for the adjuvant immunotherapy of GBM. Several potential methods for the large-scale expansion of 34 T cells for immunotherapeutic applications have been recently published. These include the use of clinically-approved nitrogen-containing bisphosphonates such as Zoledronate and bromohydrin pyrophosphate (BrHPP) in combination with IL-2 as well as an investigational two-stage method using CD2, IFN-3, IL-12, OKT-3, and IL-2. Effector cells generated by these methods have shown potent innate antitumor activity against a wide variety of human tumor cell lines. In this proposal, it is our objective to compare three FDA-approvable cell manufacturing processes for an innate lymphocyte cell therapy product for treatment of GBM. We will then scale-up and validate the optimal manufacturing regimen for IND submission to the FDA. The overall objectives of this program of which this proposal will serve to further develop is below in the following hypothesis. Hypothesis: Allogeneic innate immune cells, comprised principally of 34 T cells can be successfully manufactured in sufficient numbers for repetitive sequential administration to patients with brain tumors using at least one of three FDA-approvable processes We will compare the three clinically translatable methods discussed above for manufacturing of a donor innate lymphocyte cellular therapy product comprised principally of expanded/activated 34 T cells for therapy of glioblastoma multiforme (GBM). We will prioritize development of clinical-scale manufacturing protocols on (a) final composition of the cell product, (b) reproducibility of the procedure, (c) potency and (d) feasibility of rapid translation as described below and detailed in the Research Plan. The successful completion of this specific aim will result in a scalable procedure for cell therapy product manufacturing that can be approved by the US FDA for clinical use. Secondly, we will develop and validate manufacturing protocols for clinical scale cell therapy product(s) based on data from small scale work. Completion of this work will also include the development of a CMC section for IND application. PUBLIC HEALTH RELEVANCE: At present, there is no effective treatment for glioblastoma multiforme (GBM), the most common malignant brain tumor. GBM tumors are vulnerable to killing by a component of the immune system known as 34 T cells. These cells can be obtained from the blood of a healthy donor and, when exposed to reagents that promote cell growth and immune response, have been shown to kill GBM tumors. We will test promising methods for generating 34 T cells from healthy donor to determine the best method for clinical production and human therapeutic trials.

描述（由申请人提供）：尽管过去几十年来癌症治疗取得了显着进展，但多形性胶质母细胞瘤（GBM）尚无长期有效的治疗方法。我们的实验室最近在体外和小鼠异种移植模型中显示出有希望的发现，即人类 GBM 很容易受到局部递送的同种异体先天淋巴细胞疗法的影响。这些拟议的研究将确定 FDA 批准的细胞治疗产品的生产方案，该产品主要由扩增/活化的 34 T 细胞和一小部分 NK 细胞组成，用于 GBM 的辅助免疫治疗。最近发表了几种大规模扩增 34 T 细胞用于免疫治疗应用的潜在方法。其中包括使用临床批准的含氮双膦酸盐，例如唑来膦酸和焦磷酸溴醇 (BrHPP) 与 IL-2 组合，以及使用 CD2、IFN-3、IL-12、OKT-3 和 IL-2 的研究性两阶段方法。通过这些方法产生的效应细胞对多种人类肿瘤细胞系表现出强大的先天抗肿瘤活性。在本提案中，我们的目标是比较用于治疗 GBM 的先天淋巴细胞治疗产品的三种 FDA 批准的细胞制造工艺。然后，我们将扩大规模并验证向 FDA 提交 IND 的最佳生产方案。本提案将有助于进一步发展该计划的总体目标，如下假设。假设：主要由 34 个 T 细胞组成的同种异体先天免疫细胞可以使用 FDA 批准的三种工艺中的至少一种成功地制造出足够数量的重复序贯给药给脑肿瘤患者。我们将比较上面讨论的三种临床可转化方法，用于制造主要由扩增/活化的 34 个 T 细胞组成的供体先天淋巴细胞细胞治疗产品，用于治疗 多形性胶质母细胞瘤（GBM）。我们将优先开发临床规模的生产方案，包括 (a) 细胞产品的最终组成、(b) 程序的可重复性、(c) 效力和 (d) 快速转化的可行性，如下所述并在研究计划中详细说明。这一具体目标的成功实现将带来可扩展的细胞治疗产品制造程序，并获得美国 FDA 批准用于临床。其次，我们将根据小规模工作的数据开发和验证临床规模细胞治疗产品的生产方案。这项工作的完成还将包括开发用于 IND 申请的 CMC 部分。 公共卫生相关性：目前，多形性胶质母细胞瘤（GBM）是最常见的恶性脑肿瘤，尚无有效的治疗方法。 GBM 肿瘤很容易被免疫系统中称为 34 T 细胞的成分杀死。这些细胞可以从健康捐献者的血液中获得，当接触到促进细胞生长和免疫反应的试剂时，已被证明可以杀死 GBM 肿瘤。我们将测试从健康捐赠者中产生 34 个 T 细胞的有前途的方法，以确定临床生产和人体治疗试验的最佳方法。