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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Fountain, Jane W
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University of Alabama Birmingham
Internal Medicine/Medicine
Schools of Medicine
United States
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