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OBJECTIVES/GOALS: #NAME? METHODS/STUDY POPULATION: Cell culture & protein identification: human T cells were purified from healthy blood, then activated & cultured for 5d. CAR-T cells were collected from infusion bags of cancer patients undergoing CAR-T. Silver staining of naive & activated healthy T-cell lysates was compared; B-II spectrin was upregulated and confirmed by Western blot. Migration assays: naive & activated T-cells were imaged during migration on ICAM-1 and ICAM-1 + CXCL12 coated plates. T-cells were transfected with BII-spectrin cDNA & the chemokine dependence of migration was compared with controls. In-vivo studies: in a melanoma mouse model, BII-spectrin transfected or control T-cells were injected; tumors were followed with serial imaging. Human patient records were examined to correlate endogenous BII-spectrin levels and CAR-T response. RESULTS/ANTICIPATED RESULTS: Activated T-cells downregulate the cytoskeletal protein B-II spectrin compared to naive cells, leading to chemokine-independent migration in in vitro assays and off-target trafficking when CAR-T cells are given in vivo. Restoration of B-II spectrin levels via transfection restores chemokine-dependence of activated T-cells. In a mouse melanoma model, control mice injected with standard activated T-cells showed fewer cells in the tumor site and more cells in the off-target organs (spleen, lungs) when compared to mice injected with B-II spectrin transfected cells. Furthermore, among 3 human patients undergoing CAR-T therapy, those with higher endogenous B-II spectrin levels experienced fewer side-effects, measured by the neurotoxicity and cytokine release syndrome grades. DISCUSSION/SIGNIFICANCE: A major hurdle to widespread CAR-T therapy for cancer is significant, often fatal side-effects. Our work shows that the protein B-II spectrin is downregulated during CAR-T production, and that restoring B-II spectrin levels decreases side-effects while increasing tumor clearance--hopefully translating to better CAR-T regimens for the future.
To assess the effect on staff- and patient-related complications of a needleless intermittent intravenous access system with a reflux valve for peripheral infusions.
A 6-month cross-over clinical trial (phase I, 13 weeks; phase II, 12 weeks) of a needleless intermittent intravenous access system (NL; study device) compared to a conventional heparin-lock system (CHL, control device) was performed during 1991 on 16 medical and surgical units. A random selection of patients was assessed for local intravenous-site complications; all patients were assessed for the development of nosocomial bacteremia and device-related complications. Staff were assessed for percutaneous injuries and participated in completion of product evaluations. A cost analysis of the study compared to the control device was performed.
A 1,100-bed, teaching, referral medical center.
PATIENTS AND STAFF PARTICIPANTS:
594 patients during 602 patient admissions, comprising a random sample of all patients with a study or control device inserted within a previous 24-hour period on study and control units, were assessed for local complications. The 16 units included adult inpatient general medicine, surgical, and subspecialty units. Pediatrics, obstetrics-gynecology, and intensive-care units were excluded. All patients on study and control units were assessed for development of nosocomial bacteremia and device-related complications. All staff who utilized, manipulated, or may have been exposed to sharps on study and control units were assessed for percutaneous injuries. Nursing staff completed product evaluations.
The study device, a needleless intermittent intravenous access system with a reflux valve, was compared to the control device, a conventional heparin lock, for peripheral infusions.
During the study, 35 percutaneous injuries were reported. Eight injuries were CHL-related; no NL-related injuries were reported (P=.007). An evaluation of 602 patient admissions, 1,134 intermittent access devices, and 2,268 observed indwelling device days demonstrated more pain at the insertion site for CHL than NL; however, no differences in objective signs of phlebitis were noted. Of 773 episodes of positive blood cultures on study and control units, 6 (0.8%) were device-related (assessed by blinded investigator), with no difference between NL and CHL. Complications, including difficulty with infusion (P<.001) and disconnection of intravenous tubing from device (P<.001), were reported more frequently with CHL than with NL. Of nursing staff responding to a product evaluation survey, 95.2% preferred the study over control device. The projected annual incremental cost to our institution for hospitalwide implementation of NL for intermittent access for peripheral infusions was estimated at $82,845, or $230 per 1,000 patient days.
A needleless intermittent intravenous access system with a reflux valve for peripheral infusions is effective in reducing percutaneous injuries to staff and is not associated with an increase in either insertion-site complications or nosocomial bacteremia. Institutions should consider these data, available institutional resources, and institution-specific data regarding the frequency and risk of intermittent access-device-related injuries and other types of sharps injuries in their staff when selecting the above or other safety devices.
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