Inclusion of an IgG1-Fc spacer abrogates efficacy of CD19 CAR T cells in a xenograft mouse model.

Cancer therapy with T cells expressing chimeric antigen receptors (CARs) has produced remarkable clinical responses in recent trials, but also severe side effects. Whereas most protocols use permanently reprogrammed T cells, we have developed a platform for transient CAR expression by mRNA electroporation. This approach may be useful for safe clinical testing of novel receptors, or when a temporary treatment period is desirable. Herein, we investigated therapy with transiently redirected T cells in vitro and in a xenograft mouse model. We constructed a series of CD19-specific CARs with different spacers and co-stimulatory domains (CD28, OX40 or CD28-OX40). The CAR constructs all conferred T cells with potent CD19-specific activity in vitro. Unexpectedly, the constructs incorporating a commonly used IgG1-CH2CH3 spacer showed lack of anti-leukemia activity in vivo and induced severe, partly CD19-independent toxicity. By contrast, identical CAR constructs without the CH2-domain eradicated leukemia in vivo, without notable toxicity. Follow-up studies demonstrated that the CH2CH3-spacer bound soluble mouse Fcγ-receptor I and mediated off-target T-cell activation towards murine macrophages. Our findings highlight the importance of non-signalling CAR elements and of in vivo studies. Finally, the results show that transiently redirected T cells control leukemia in mice and support the rationale for developing an mRNA-CAR platform.

First epidemiologic study in Argentina of the prevalence of BK viruria in kidney transplant patients.

BACKGROUND: The worldwide seroprevalence of human BK polyomavirus (BKV) in adults is 80%. About 10%-60% of renal transplant recipients experience BKV infection, nephropathy of the graft may occur in 5% of the cases, and up to 45% lose the graft. The aim of this work was to describe the prevalence of BK viruria during the 1st year after transplantation. METHODS: An epidemiologic multicenter cross-sectional study was carried out in consecutive patients at each site with kidney transplantation from August 2011 to July 2012. Clinically significant viruria was defined as >10(7) copies/mL. Viral DNA was extracted with the use of silica columns. Quantification was performed with the use of real-time polymerase chain reaction with primers that amplify a fragment of the large T-antigen gene and with a specific Taqman-MGB probe for BKV. For each assay, a standard curve with a quantified plasmid was included. RESULTS: Of 402 renal transplant recipients at 18 renal transplant sites, we analyzed 382; median age was 46.33 years, and 46.40% were female. The median of the temporal distribution for urine samples was 153 days. BK virus was detected in 50/382 samples (13%), 18 with values >10(7) copies/mL (4.7%). The median of the distribution of positive values was 123 days and the highest frequency of positive values was in months 3-7. The conditions of recipient older than 34 years and donor older than 41 years were the only ones that showed statistically significant association with BK viruria. No association with any specific immunosuppressive drug was observed. CONCLUSIONS: This is the first multicenter study conducted in Argentina to determine the prevalence of BK viruria in renal transplant recipients. Because of the growing number of the population susceptible to this infection, it is important to register and describe data about its epidemiology and associated risk factors.

[Study of prevalence of pain at the Juan Canalejo Hospital in La Coruña]. / Estudio de la prevalencia del dolor en el Hospital Juan Canalejo de La Coruña.

A study of prevalence of pain conducted in 812 patients admitted in the Juan Canalejo Hospital in La Coruña (Spain). This is primarily an adult hospital. Of the 650 patients whose replies were deemed valid, 35.69% were suffering pain. Other findings were that the sociocultural level of the patients affected their assessment of pain and that 46.12% of those who were suffering pain were not receiving analgesics at that time. Magnesium dipyrone, a combination of paracetamol and codeine and morphine were the most commonly used drugs, although there was clearunderuse of analgesic.

Trasplantectomias renales: nuestra experiencia / Renal transplants: our experience

Se presentan 10 trasplantectomías realizadas en 8 pacientes. La morbilidad fue en 2 casos leve y en 1 grave. Un paciente falleció. Se analizan las indicaciones, el tiempo transcurrido entre el trasplante y la nefrectomía, la técnica quirúrgica empleada y las complicaciones

Cirugía vascular en trasplante renal: nuestra experiencia / Vascular surgery in renal trasplant: our experience

Entre 1976 y 1989 se realizaron 80 trasplantes renales en nuestro hospital. La frecuencia de complicaciones vasculares fue de 3.75%. Un paciente (1.25%) falleció a consecuencia de la rotura de un aneurisma micótico. Se analiza la evolución de las complicaciones y las técnicas quirúrgicas empleadas

Is serum creatinine a reliable expression of an adequate cyclosporine immunosuppression?

In 13 renal transplant patients with an excellent graft function, but concomitant abnormal T6 CsA plasma levels (CsA plasma level, 6 hours after oral administration of the drug), dose adjustments of CsA were performed until a normal T6 was achieved. A significant decrease of serum creatinine values was obtained after dose modification. Prophylactic monitoring of CsA immunosuppression by T6 could be a means of avoiding nephrotoxicity or undertreatment in patients with acceptable serum creatinine levels and unsuspected drug related renal dysfunction.