Accommodating clinical trials and other externally manufactured cellular therapy products: challenges, lessons learned and creative solutions.

BACKGROUND AIMS: The Division of Transfusion Medicine and Cellular Therapy at New York-Presbyterian/Columbia University Irving Medical Center (NYPH-CUIMC) comprises the immunohematology laboratory and blood bank (transfusion service), hemotherapy/apheresis and the cellular therapy laboratory (CTL). The CTL processes and stores hematopoietic progenitor cells for bone marrow transplantation from all currently acceptable sources, including bone marrow, peripheral blood and umbilical cord blood. The laboratory provides services for the pediatric and adult blood and marrow transplant programs at both NYPH-CUIMC and the Morgan Stanley Children's Hospital of New York-Presbyterian. The laboratory processes and stores approximately 200 cellular therapy products per year, and the division participates in numerous clinical trials within the institution and with external pharmaceutical manufacturing facilities. As a licensed tissue bank, commercial chimeric antigen receptor T-cell products and other cellular-based therapies that are approved by the US Food and Drug Administration (FDA) are routed through the CTL for storage, processing, coordination of transportation, chain of custody and, eventually, thaw and distribution. Currently, we are distributing four such products from Kite Pharma, Novartis and Bristol Meyers Squid. In comparison to the amount of work, we employ a small staff of only four full-time clinical laboratory technologists, one technical specialist, one quality and operations manager and one medical director. In recent years, the growing use of the hematology/oncology service and the introduction of new immunotherapies have put significant pressure on our division to accommodate and scale up operations. Accompanying this growth is a mounting administrative burden and upsurge in regulatory and protocol-specific oversight. The purpose of this article is to share lessons learned and creative solutions to help better accommodate the surge in development of novel cellular therapies. METHODS: To handle this increase in demand, the CTL worked to standardize administrative procedures, implement comprehensive document control solutions, digitize data collection and implement lean design concepts to increase effectiveness and mitigate risk. RESULTS: Distribution of a standard operating procedure for clinical trial management improved the "on-boarding" process and allowed the laboratory to have more influence in the decision-making process. Implementation of digital workflows and a comprehensive document control system allowed for improved organization of critical documents and proved to be flexible enough to accommodate various protocol-specific requirements. Introduction of visual ques and reorganization of the workspace facilitated better organization, mitigated risk and assisted the laboratory in maintaining regulatory compliance. CONCLUSIONS: Better-defined, structured and controlled laboratory processes helped laboratory management implement new clinical trials and track critical data. Implementing digital solutions using widely available tools like Microsoft SharePoint has proven to be a very secure, low-cost and flexible solution to keeping us "up-to-date" and inspection-ready.

In vivo microdialysis sampling of cytokines from rat hippocampus: comparison of cannula implantation procedures.

Cytokines are signaling proteins that have been of significant importance in the field of immunology, since these proteins affect different cells in the immune system. In addition to their immune system significance, these proteins have recently been referred to as a third chemical communication network within the CNS. The role that cytokines play in orchestrating the immune response within tissues after a mechanical injury leads to potential complications if the source of cytokines (i.e., trauma vs disease) is of interest. Microdialysis sampling has seen wide use in collection of many different solutes within the CNS. Yet, implantation of microdialysis guide cannulas and the probes creates tissue injury. In this study, we compared the differences in cytokine levels in dialysates from 4 mm, 100 kDa molecular weight cutoff (MWCO) polyethersulfone membrane microdialysis probes implanted in the hippocampus of male Sprague-Dawley rats. Comparisons were made between animals that were dialyzed immediately after cannula implantation (day 0), 7 days post cannula implantation (day 7), and repeatedly sampled on day 0 and day 7. Multiplexed bead-based immunoassays were used to quantify CCL2 (MCP-1), CCL3 (MIP-1α), CCL5 (RANTES), CXCL1 (KC/GRO), CXCL2 (MIP-2), IL-1ß, IL-6, and IL-10 in dialysates. Differences in cytokine concentrations between the different treatment groups were observed with higher levels of inflammatory cytokines measured in day 7 cannulated animals. Only CCL3 (MIP-1α), CXCL1 (KC/GRO), CXCL2 (MIP-2), and IL-10 were measured above the assay limits of detection for a majority of the dialysates, and their concentrations were typically in the low to high (10-1000) picogram per milliliter range. The work described here lays the groundwork for additional basic research studies with microdialysis sampling of cytokines in rodent CNS.