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318 Building A Better CAR: Improving CAR-T Trafficking in Cancer Therapy
- Yeonsun Hong, Hye-Ran Kim, Brandon L. Walling, John Lozada, Andrea M. Amitrano, Cooper J. Sailer, Kihong Lim, Raj Kumar Mongre, Kyun-Do Kim, Tara Capece, Elena B. Lomakina, Nicholas S. Reilly, Richard E. Waugh, Patrick M. Reagan, Minsoo Kim, Patrick W. Oakes, Chang-Duk Jun
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- Journal:
- Journal of Clinical and Translational Science / Volume 6 / Issue s1 / April 2022
- Published online by Cambridge University Press:
- 19 April 2022, p. 57
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- Article
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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.
Study of a Needleless Intermittent Intravenous-Access System for Peripheral Infusions: Analysis of Staff, Patient, and Institutional Outcomes
- Meryl H. Mendelson, Louise J. Short, Clyde B. Schechter, Burt R. Meyers, Margarita Rodriguez, Sandra Cohen, John Lozada, Marvalyn DeCambre, Shalom Z. Hirschman
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- Journal:
- Infection Control & Hospital Epidemiology / Volume 19 / Issue 6 / June 1998
- Published online by Cambridge University Press:
- 02 January 2015, pp. 401-406
- Print publication:
- June 1998
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OBJECTIVE:
To assess the effect on staff- and patient-related complications of a needleless intermittent intravenous access system with a reflux valve for peripheral infusions.
DESIGN: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.
SETTING: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.
INTERVENTION: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.
RESULTS: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.
CONCLUSIONS: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.