Cell Processing and Sample Collection: Core C This FHCRC Adult Leukemia Research Center (ALC) grant comprises proposals for three clinical trials: one trial of adoptive immunotherapy with WT1-specific T cell receptor (TCR) gene-modified T cells for acute myeloid leukemia (Project 1); one trial of adoptive immunotherapy using BCMA-specific chimeric antigen receptor (CAR)-modified T cells for multiple myeloma (Project 2); and one trial comparing methods of T cell depletion of donor grafts for allogeneic HCT (Project 3). Core C: Cell Processing and Sample Collection will support the activities of Projects 1-3. First, Core C will provide highly specialized facilities and expertise necessary to conduct current Good Manufacturing Practice (cGMP) production of TCR- and CAR-modified T cells for Projects 1-2 for treatment of patients enrolled in the clinical trials proposed in Projects 1-2. This effort will initially comprise validation cell processing runs (years 1-2) to qualify standard operating procedures for subsequent cGMP production, followed by cGMP production and release of genetically modified T cell products (years 1-5). Compared to decentralized cell processing managed by each separate project, consolidation of clinical cell processing within Core C will ensure that cGMP manufacturing is efficient and cost-effective, and performed with the optimal level of quality control (QC) and quality assurance (QA) oversight. Second, Core C will conduct studies to evaluate the effects of short-term storage in infusion medium or of cryopreservation on the potency of CAR- or TCR-modified T cells for clinical use. Although the potency of genetically modified T cells that are freshly formulated may be better than that of those that are stored, the ability to store and cryopreserve these products will be important for clinical logistics and for future delivery beyond phase 1 studies. We will conduct these studies using models in which human genetically modified T cells that have been stored under different conditions are administered to immunodeficient mice bearing human tumors, because we have found that data in these models of efficacy most accurately reflects outcomes in human engineered T cell clinical trials. Because the manufacturing processes may affect the capacity of genetically modified T cell products to tolerate storage, we will conduct these experiments using T cells that are manufactured using either a process involving multiple in vitro stimulations (Project 1) or a truncated process involving only a single stimulation (Project 2). The data will provide insight into whether important and frequently performed processing manipulations affect potency of genetically modified T cells. Third, Core C will provide a clinic-based facility to rapidly and efficiently process and distribute research samples from Projects 1-3 to FHCRC research laboratories and external collaborators. This will ensure data of the highest quality and uniformity is obtained from correlative research studies, maximizing the opportunity for bedside-to-bench research to guide new developments in adoptive immunotherapy and allogeneic HCT.
Cell Processing and Sample Collection: Core C Core C: Cell Processing and Sample Collection will serve Projects 1-3 of the Fred Hutchinson Cancer Research Center (FHCRC) Adult Leukemia Research Center (ALC) proposal in three main areas. First, Core C will supply the facilities and expertise to manufacture clinical-grade genetically modified T cell immunotherapy products to be used to treat patients with hematologic malignancies in Projects 1-2. Second, Core C will conduct studies to determine if storage or freezing of clinical-grade human T cell immunotherapy products causes loss of potency of the T cell products, by testing their anti-tumor efficacy in immunodeficient mice bearing human-derived tumors. These data will support studies in Projects 1 and 2. Finally, Core C will manage a system for collection of research blood samples and bone marrow aspirates from patients treated on the clinical trials in Projects 1-3 followed by rapid processing and distribution by a newly established Biomarker Research Laboratory located within the clinic. The activities of Core C will provide centralized, high quality manufacturing of clinical T cell therapies, insight into the optimization of storage and delivery of T cell products to patients, and a system for rapidly processing research samples that will ensure the highest sample integrity and maximize data quality from correlative studies to improve future treatments.
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