Chimeric antigen receptors (CARs) are synthetic receptors that redirect and reprogram T cells to mediate tumour rejection. The most successful CARs used to date are those targeting CD19 (ref. 2), ...which offer the prospect of complete remission in patients with chemorefractory or relapsed B-cell malignancies. CARs are typically transduced into the T cells of a patient using γ-retroviral vectors or other randomly integrating vectors, which may result in clonal expansion, oncogenic transformation, variegated transgene expression and transcriptional silencing. Recent advances in genome editing enable efficient sequence-specific interventions in human cells, including targeted gene delivery to the CCR5 and AAVS1 loci. Here we show that directing a CD19-specific CAR to the T-cell receptor α constant (TRAC) locus not only results in uniform CAR expression in human peripheral blood T cells, but also enhances T-cell potency, with edited cells vastly outperforming conventionally generated CAR T cells in a mouse model of acute lymphoblastic leukaemia. We further demonstrate that targeting the CAR to the TRAC locus averts tonic CAR signalling and establishes effective internalization and re-expression of the CAR following single or repeated exposure to antigen, delaying effector T-cell differentiation and exhaustion. These findings uncover facets of CAR immunobiology and underscore the potential of CRISPR/Cas9 genome editing to advance immunotherapies.
An efficient basket trial design Cunanan, Kristen M.; Iasonos, Alexia; Shen, Ronglai ...
Statistics in medicine,
10 May 2017, Letnik:
36, Številka:
10
Journal Article
Chimeric antigen receptors (CARs) are synthetic antigen receptors that reprogram T cell specificity, function and persistence
. Patient-derived CAR T cells have demonstrated remarkable efficacy ...against a range of B-cell malignancies
, and the results of early clinical trials suggest activity in multiple myeloma
. Despite high complete response rates, relapses occur in a large fraction of patients; some of these are antigen-negative and others are antigen-low
. Unlike the mechanisms that result in complete and permanent antigen loss
, those that lead to escape of antigen-low tumours remain unclear. Here, using mouse models of leukaemia, we show that CARs provoke reversible antigen loss through trogocytosis, an active process in which the target antigen is transferred to T cells, thereby decreasing target density on tumour cells and abating T cell activity by promoting fratricide T cell killing and T cell exhaustion. These mechanisms affect both CD28- and 4-1BB-based CARs, albeit differentially, depending on antigen density. These dynamic features can be offset by cooperative killing and combinatorial targeting to augment tumour responses to immunotherapy.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers in the United States with a five-year survival rate of 7.2% for all stages. Although surgical resection is the only curative ...treatment, currently we are unable to differentiate between resectable patients with occult metastatic disease from those with potentially curable disease. Identification of patients with poor prognosis via early classification would help in initial management including the use of neoadjuvant chemotherapy or radiation, or in the choice of postoperative adjuvant therapy. PDAC ranges in appearance from homogeneously isoattenuating masses to heterogeneously hypovascular tumors on CT images; hence, we hypothesize that heterogeneity reflects underlying differences at the histologic or genetic level and will therefore correlate with patient outcome. We quantify heterogeneity of PDAC with texture analysis to predict 2-year survival. Using fuzzy minimum-redundancy maximum-relevance feature selection and a naive Bayes classifier, the proposed features achieve an area under receiver operating characteristic curve (AUC) of 0.90 and accuracy (Ac) of 82.86% with the leave-one-image-out technique and an AUC of 0.80 and Ac of 75.0% with three-fold cross-validation. We conclude that texture analysis can be used to quantify heterogeneity in CT images to accurately predict 2-year survival in patients with pancreatic cancer. From these data, we infer differences in the biological evolution of pancreatic cancer subtypes measurable in imaging and identify opportunities for optimized patient selection for therapy.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Consensus has not been reached on what constitutes an optimal diet in individuals with prediabetes and type 2 diabetes mellitus (T2DM), especially between low-carbohydrate options.
We compared 2 ...low-carbohydrate diets with 3 key similarities (incorporating nonstarchy vegetables and avoiding added sugars and refined grains) and 3 key differences (incorporating compared with avoiding legumes, fruits, and whole, intact grains) for their effects on glucose control and cardiometabolic risk factors in individuals with prediabetes and T2DM.
Keto-Med was a randomized, crossover, interventional trial. Forty participants aged ≥18 years with prediabetes or T2DM followed the well-formulated ketogenic diet (WFKD) and the Mediterranean-plus diet (Med-Plus) for 12 weeks each, in random order. The diets shared the 3 key similarities noted above. The Med-Plus incorporated legumes, fruits, and whole, intact grains, while the WFKD avoided them. The primary outcome was the percentage change in glycated hemoglobin (HbA1c) after 12 weeks on each diet. Secondary and exploratory outcomes included percentage changes in body weight, fasting insulin, glucose, and blood lipids; average glucose from continuous glucose monitor (CGM), and nutrient intake.
The primary analysis was of 33 participants with complete data. The HbA1c values did not differ between diets at 12 weeks. Triglycerides decreased more for the WFKD percentage changes, –16% (SEM, 4%) compared with –5% (SEM, 6%) for the Med-Plus; P = 0.02 and LDL cholesterol was higher for the WFKD percentage changes, +10% (SEM, 4%) compared with –5% (SEM, 5%) for the Med-Plus; P = 0.01. Weight decreased 8% (SEM, 1%) compared with 7% (SEM, 1%) and HDL cholesterol increased 11% (SEM, 2%) compared with 7% (SEM, 3%) for the WFKD compared with the Med-Plus, respectively; however, there was a significant interaction of diet × order for both. Participants had lower intakes of fiber and 3 nutrients on the WFKD compared with the Med-Plus. Twelve-week follow-up data suggest the Med-Plus is more sustainable.
HbA1c values were not different between diet phases after 12 weeks, but improved from baseline on both diets, likely due to several shared dietary aspects. The WFKD led to a greater decrease in triglycerides, but also had potential untoward risks from elevated LDL cholesterol and lower nutrient intakes from avoiding legumes, fruits, and whole, intact grains, as well as being less sustainable. This trial was registered at clinicaltrials.gov as NCT03810378.
The Notch ligand DLL3 has emerged as a novel therapeutic target expressed in small cell lung cancer (SCLC) and high-grade neuroendocrine carcinomas. Rovalpituzumab teserine (Rova-T; SC16LD6.5) is a ...first-in-class DLL3-targeted antibody-drug conjugate with encouraging initial safety and efficacy profiles in SCLC in the clinic. Here we demonstrate that tumor expression of DLL3, although orders of magnitude lower in surface protein expression than typical oncology targets of immunoPET, can serve as an imaging biomarker for SCLC. We developed
Zr-labeled SC16 antibody as a companion diagnostic agent to facilitate selection of patients for treatment with Rova-T based on a noninvasive interrogation of the
status of DLL3 expression using PET imaging. Despite low cell-surface abundance of DLL3, immunoPET imaging with
Zr-labeled SC16 antibody enabled delineation of subcutaneous and orthotopic SCLC tumor xenografts as well as distant organ metastases with high sensitivity. Uptake of the radiotracer in tumors was concordant with levels of DLL3 expression and, most notably, DLL3 immunoPET yielded rank-order correlation for response to SC16LD6.5 therapy in SCLC patient-derived xenograft models.
.
Weight change trajectory from diet and lifestyle interventions typically involves rapid weight loss followed by a weight plateau after approximately 6 months. Changing from one weight-loss diet to ...another at the time of the plateau could instigate renewed weight loss. Therefore, our secondary analysis aimed to assess trajectory of weight loss in a 12-month, randomized, cross-over study. Forty-two adults were randomized to eat a healthy low-fat or healthy low-carbohydrate diet for 6 months then switched to the opposite diet for an additional 6 months. Regardless of diet assignment, participants experienced rapid initial weight loss, which slowed between 3 to 6 months. After switching diets at 6 months, weight modestly decreased until 9 months, but at a rate slower than the initial 3 months and slower than the rate from 3 to 6 months. This suggests that the weight loss plateau typically seen at 6 months is physiological and cannot be overcome by simply switching to a different weight-loss diet.
Reply to T Kalayjian and EC Westman Gardner, Christopher D; Landry, Matthew J; Aronica, Lucia ...
The American journal of clinical nutrition,
10/2022, Letnik:
116, Številka:
4
Journal Article
Pretargeting offers a way to enhance target specificity while reducing off-target radiation dose to healthy tissue during payload delivery. We recently reported the development of an 18F-based ...pretargeting strategy predicated on the inverse electron demand Diels–Alder reaction as well as the use of this approach to visualize pancreatic tumor tissue in vivo as early as 1 h postinjection. Herein, we report a comprehensive structure: pharmacokinetic relationship study of a library of 25 novel radioligands that aims to identify radiotracers with optimal pharmacokinetic and dosimetric properties. This investigation revealed key relationships between molecular structure and in vivo behavior and produced two lead candidates exhibiting rapid tumor targeting with high target-to-background activity concentration ratios at early time points. We believe this knowledge to be of high value for the design and clinical translation of next-generation pretargeting agents for the diagnosis and treatment of disease.
PDF
