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(申请人提供)：尽管在过去的几十年里癌症的治疗有了很大的进步，但对于多形性胶质母细胞瘤(GBM)还没有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都显示出令人振奋的发现，即人的GBM对局部注射的同种异体先天淋巴细胞治疗很脆弱。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/激活的34T细胞和一小部分NK细胞组成，用于GBM的辅助免疫治疗。最近公布了几种大规模扩增34T细胞用于免疫治疗的潜在方法。这些措施包括使用临床批准的含氮双磷酸盐，如唑来膦酸盐和溴羟丙烷焦磷酸(BrHPP)与IL-2结合使用，以及使用CD2、干扰素-3、IL-12、OKT-3和IL-2的两阶段研究方法。通过这些方法产生的效应细胞对多种人类肿瘤细胞株显示出强大的天然抗肿瘤活性。在这项提案中，我们的目标是比较三种FDA批准的用于治疗GBM的固有淋巴细胞治疗产品的细胞制造工艺。然后，我们将扩大规模，并验证IND提交给FDA的最佳制造方案。这项计划的总体目标将在下面的假设中得到进一步发展。假设：同种异体先天免疫细胞，主要由34个T细胞组成，可以成功地制造足够数量的同种异体先天免疫细胞，以使用FDA批准的至少三种方法之一重复连续给药给脑瘤患者。我们将比较上面讨论的三种临床可翻译的方法，以制造主要由扩增/激活的34 T细胞组成的供体先天淋巴细胞治疗产品，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制造方案，重点是(A)细胞产品的最终成分，(B)程序的重复性，(C)效力和(D)快速翻译的可行性，如下所述并在研究计划中详细说明。这一特定目标的成功完成将导致一种可扩展的细胞治疗产品制造程序，该程序可被美国FDA批准用于临床。其次，我们将基于小规模工作的数据，开发和验证临床规模细胞治疗产品(S)的制造方案。这项工作的完成还将包括为IND应用编写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，目前还没有有效的治疗方法。GBM肿瘤很容易被免疫系统的一种成分34T细胞杀死。这些细胞可以从健康捐赠者的血液中获得，当暴露在促进细胞生长和免疫反应的试剂中时，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细胞的有前景的方法，以确定临床生产和人类治疗试验的最佳方法。