Donor Innate Lymphocyte Infusion Product for Immunotherapy of Glioblastoma Multif

描述（由申请人提供）：尽管在过去的几十年里，癌症的治疗取得了重大进展，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有希望的发现，即人类GBM对局部传递的异体先天淋巴细胞治疗易感。这些拟议的研究将确定一种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T细胞和少量NK细胞组成，用于GBM的辅助免疫治疗。最近发表了几种用于免疫治疗应用的大规模扩增34 T细胞的潜在方法。这些方法包括使用临床批准的含氮双磷酸盐，如唑来膦酸盐和焦磷酸溴丙醇（BrHPP）与IL-2联合使用，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显示出强大的先天抗肿瘤活性。在本提案中，我们的目标是比较fda批准的用于治疗GBM的先天淋巴细胞治疗产品的三种细胞制造工艺。然后，我们将扩大并验证向FDA提交IND的最佳生产方案。本提案将有助于进一步发展的该计划的总体目标如下假设。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，用于重复顺序给药脑肿瘤患者，使用fda批准的三种工艺中的至少一种。我们将比较上述三种临床可翻译的方法，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）。我们将优先开发以下方面的临床规模生产方案：(a)细胞产品的最终组成，(b)过程的可重复性，(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细胞治疗产品生产的可扩展程序，可以被美国FDA批准用于临床使用。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应用的CMC部分。

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.