This Program Project Grant (PO1) explores the enhancement of cord blood transplantation (CBT) by employing ex-vivo expansion of CB stem/progenitors, natural killer (NK) cells and T cells engineered to express chimeric antigen receptors (CARs), and virus-specific T cells in preclinical studies and clinical trials. All four projects will undertake clinical trials during the course of the studies. These rely on the availability of a GMP manufacturing facility for the preparation of the cellular therapy products. Projects 1, 3 and 4 will use on the Good Manufacturing Practice (GMP) Facility at MD Anderson Cancer Center (MDACC) and Project 2 will rely on the GMP Facility at Children's National Medical Center (CNHS)-Cell Enhancement and Technologies for Immunotherapy (CETI). The GMP Facility at MDACC has been in operation for more than 15 years and the GMP at CNHS-CETI is a new facility, which opened in 2013. The Cell Processing Facilities at both institutions have considerable experience in the preparation of a wide variety of cellular products and both received more- than-minimal cell therapy accreditation from the Foundation for the Accreditation of Cellular Therapy (FACT). Both Facilities are well equipped to operate under GMP conditions, with extensive documentation systems, barcoding, environmental monitoring, and quality assurance, control and improvement programs. An independent and validated alarm system is provided in both facilities to monitor, log and alarm the temperature in all incubators, refrigerators and freezers; the airflow in each biosafety cabinet; and differential pressure across doors between the ISO 7 and ISO 8 laboratories. Additional components of the Core are the Quality Control Laboratories at CNHS-CETI and MDACC, which perform in-house testing of cellular products, and are responsible for routine monitoring of the GMP Laboratory and Quality Assurance Group to ensure compliance with cGMP regulations and provides independent overview of all aspects of manufacturing and release. The GMP personnel at both institutions have extensive regulatory experience that will facilitate the translational of laboratory studies into clinical trials. In this proposal, MDACC will manufacture five cellular therapy products. For Project 1: expanded CB cells that have been fucosylated to enhance engraftment, and fucosylated mesenchymal stromal cells (MSCs) to treat graft versus host disease. For Project 3: CB NK cells genetically modified to express a chimeric antigen receptor (CAR) targeting CD19+ lymphoid cancers which expresses IL- 15, and an inducible caspase 9 suicide gene. For Project 4: CB T cells expressing a CAR targeting Pr1+ myeloid cancers. For Project 2: CNHS-CETI will manufacture CB multi-virus-specific T cells targeting CMV, EBV, adenovirs and BK virus, as well as the novel HIV-specific T cell product which will be used for patients with HIV disease.. In summary, the GMP Laboratory Core is a vital component of the P01 that will provide essential services to the implementation of the clinical studies in Projects 1, 2, 3 and 4.
While cord blood (CB) has emerged as an important source of stem cells for patients lacking HLA-matched donors, the major disadvantage of using CB is low stem and progenitor cell dose, which delays engraftment and immune reconstitution. In this PO1 we propose new strategies, including ex vivo expansion of CB stem/progenitor and CB-derived natural killer cells and T-cells, genetically engineered to express chimeric antigen receptors. The goal of this core is to manufacture, in a safe manner with appropriate quality control, all the cellular products that will be administered to patients in the clinical trials in projects 1-4.
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