Presentation_1_Reprogramming of IL-12 secretion in the PDCD1 locus improves the anti-tumor activity of NY-ESO-1 TCR-T cells.pptx

IntroductionAlthough the engineering of T cells to co-express immunostimulatory cytokines has been shown to enhance the therapeutic efficacy of adoptive T cell therapy, the uncontrolled systemic release of potent cytokines can lead to severe adverse effects. To address this, we site-specifically inserted the interleukin-12 (IL-12) gene into the PDCD1 locus in T cells using clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9)-based genome editing to achieve T-cell activation-dependent expression of IL-12 while ablating the expression of inhibitory PD-1.MethodsNew York esophageal squamous cell carcinoma 1(NY-ESO-1)-specific TCR-T cells was investigated as a model system. We generated ΔPD-1-IL-12 -edited NY-ESO-1 TCR-T cells by sequential lentiviral transduction and CRISPR knock-in into activated human primary T cells.ResultsWe showed that the endogenous PDCD1 regulatory elements can tightly control the secretion of recombinant IL-12 in a target cell-dependent manner, at an expression level that is more moderate than that obtained using a synthetic NFAT-responsive promoter. The inducible expression of IL-12 from the PDCD1 locus was sufficient to enhance the effector function of NY-ESO-1 TCR-T cells, as determined by upregulation of effector molecules, increased cytotoxic activity, and enhanced expansion upon repeated antigen stimulation in vitro. Mouse xenograft studies also revealed that PD-1-edited IL-12-secreting NY-ESO-1 TCR-T cells could eliminate established tumors and showed significantly greater in vivo expansion capacity than control TCR-T cells.DiscussionOur approach may provide a way to safely harness the therapeutic potential of potent immunostimulatory cytokines for the development of effective adoptive T cell therapies against solid tumors.</p

Effect of post-transplant glycemic control on long-term clinical outcomes in kidney transplant recipients with diabetic nephropathy: A multicenter cohort study in Korea

<div><p>Purpose</p><p>Diabetic nephropathy is the leading cause of end stage renal disease. The number of kidney transplantation (KT) due to diabetic nephropathy is increasing and there is debate on glycemic control after KT. In this study, we used a multi-center database to determine the relationship between post-transplant glycemic control and the outcomes of KT in patients with diabetic nephropathy.</p><p>Methods</p><p>We conducted a retrospective chart review of kidney transplant recipients (KTRs) with diabetic nephropathy from three tertiary hospitals to analyze the association between post-transplant glycemic control and the clinical outcomes of graft failure, including patient death and biopsy-proven acute rejection (BPAR). We assessed time-averaged glucose level and hemoglobin A1c (HbA1c) for 36 months after KT.</p><p>Results</p><p>Among 3,538 KTRs, a total of 476 patients received kidney transplantation because of diabetic nephropathy. Mean time-averaged glucose and HbA1c levels were 147 ± 46 mg/dl and 7.7 ± 1.5%, respectively. Patients with diabetic nephropathy had poor graft and patient survival rate compared with non-diabetic nephropathy. Among KTRs with diabetic nephropathy, the highest quartile of time-averaged glucose was related to poor graft outcomes and the 3^rd quartile of time-averaged HbA1c was associated with significantly better graft outcomes than the 1^st, 2^nd or 4^th quartiles. There were no significant differences in the risk of BPAR across the 4 quartiles of glucose and HbA1c.</p><p>Conclusions</p><p>Strict glycemic control before KT might not be related to successful outcomes but poor glycemic control after KT is associated with poor graft outcomes. There was no significant relationship between pre- or post-transplant glycemic control and BPAR.</p></div

Effect of post-transplant glycemic control on long-term clinical outcomes in kidney transplant recipients with diabetic nephropathy: A multicenter cohort study in Korea - Fig 2

<p><b>Patient survival (A) and graft survival (B) for kidney transplant patients.</b> DN, diabetic nephropathy.</p

Transition of post-transplant glycemic control by serum glucose level and HbA1c.

<p>Transition of post-transplant glycemic control by serum glucose level and HbA1c.</p

Baseline characteristics by quartiles of time-averaged HbA1c levels.

<p>Baseline characteristics by quartiles of time-averaged HbA1c levels.</p

Lower serum potassium associated with increased mortality in dialysis patients: A nationwide prospective observational cohort study in Korea - Fig 3

<p><b>Cumulative mortality incidence in patients with end-stage renal disease undergoing hemodialysis (A) or peritoneal dialysis (B).</b> Mortality incidence was plotted according to the level of serum potassium.</p

Effect of post-transplant glycemic control on long-term clinical outcomes in kidney transplant recipients with diabetic nephropathy: A multicenter cohort study in Korea - Fig 5

<p>Hazard ratios of graft failure by serum glucose using standard Cox proportional hazards regression (A) and a time-averaged model (B). Hazard ratios of graft failure by HbA1c using standard Cox proportional hazards regression (C) and a time-averaged model (D). Model 1 is adjusted for age and gender. Model 2 is adjusted for age, gender, comorbidities (hypertension, ischemic heart disease), donor age, donor type, baseline hemoglobin level, and BPAR.</p

Effect of post-transplant glycemic control on long-term clinical outcomes in kidney transplant recipients with diabetic nephropathy: A multicenter cohort study in Korea - Fig 1

<p><b>Number (A) and proportion (B) of patients with diabetic nephropathy among total kidney transplantations from 1997 to 2011 in three hospitals (SNUH, AMC and KNUH).</b> DN, diabetic nephropathy; SNUH, Seoul National University Hospital; AMC, Asan Medical Center; KNUH; Kyungpook National University Hospital.</p

Baseline characteristics of non-DN versus DN.

<p>Baseline characteristics of non-DN versus DN.</p

Log hazard ratio for overall mortality in relation to serum potassium in patients with end-stage renal disease.

<p>A) entire study cohort, B) patients undergoing hemodialysis, C) patients undergoing peritoneal dialysis. The solid line and dotted lines represent the central risk estimate and 95% confidence intervals, respectively.</p