A5052541853- CAR-T cell therapy research
- Acute Lymphoblastic Leukemia research
- Virus-based gene therapy research
- Immune Cell Function and Interaction
- Viral Infectious Diseases and Gene Expression in Insects
- RNA Interference and Gene Delivery
- Neuroblastoma Research and Treatments
- Biosimilars and Bioanalytical Methods
- CRISPR and Genetic Engineering
- Chronic Myeloid Leukemia Treatments
- Statistical Methods in Clinical Trials
- Cancer Genomics and Diagnostics
- Lymphoma Diagnosis and Treatment
- Advancements in Semiconductor Devices and Circuit Design
- Acute Myeloid Leukemia Research
- Cancer Immunotherapy and Biomarkers
- Safe Handling of Antineoplastic Drugs
- Integrated Circuits and Semiconductor Failure Analysis
- Chronic Lymphocytic Leukemia Research
- Gene Regulatory Network Analysis
- Immunotherapy and Immune Responses
- Hematopoietic Stem Cell Transplantation
- Childhood Cancer Survivors' Quality of Life
- Nanowire Synthesis and Applications
- Pluripotent Stem Cells Research
University of Pennsylvania
2016-2025
Children's Hospital of Philadelphia
2016-2025
Philadelphia University
2018-2024
California University of Pennsylvania
2017-2024
Pediatrics and Genetics
2015-2020
University of Colorado Denver
2012
Memorial Sloan Kettering Cancer Center
2012
Penn State Milton S. Hershey Medical Center
2012
The University of Texas Southwestern Medical Center
2012
St. Jude Children's Research Hospital
2012
Relapsed acute lymphoblastic leukemia (ALL) is difficult to treat despite the availability of aggressive therapies. Chimeric antigen receptor–modified T cells targeting CD19 may overcome many limitations conventional therapies and induce remission in patients with refractory disease.
In a single-center phase 1-2a study, the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel produced high rates of complete remission and was associated with serious but mainly reversible toxic effects in children young adults relapsed or refractory B-cell acute lymphoblastic leukemia (ALL).We conducted 2, single-cohort, 25-center, global study pediatric adult patients CD19+ ALL. The primary end point overall rate (the incomplete hematologic recovery) within 3...
The CD19 antigen, expressed on most B-cell acute lymphoblastic leukemias (B-ALL), can be targeted with chimeric antigen receptor-armed T cells (CART-19), but relapses epitope loss occur in 10% to 20% of pediatric responders. We detected hemizygous deletions spanning the locus and de novo frameshift missense mutations exon 2 some relapse samples. However, we also discovered alternatively spliced mRNA species, including one lacking 2. Pull-down/siRNA experiments identified SRSF3 as a splicing...
Chimeric antigen receptor (CAR)-modified T cells with anti-CD19 specificity are a highly effective novel immune therapy for relapsed/refractory acute lymphoblastic leukemia. Cytokine release syndrome (CRS) is the most significant and life-threatening toxicity. To improve understanding of CRS, we measured cytokines clinical biomarkers in 51 CTL019-treated patients. Peak levels 24 cytokines, including IFNγ, IL6, sgp130, sIL6R, first month after infusion were associated severe CRS. Using...
Initial success with chimeric antigen receptor-modified T cell therapy for relapsed/refractory acute lymphoblastic leukemia is leading to expanded use through multicenter trials. Cytokine release syndrome, the most severe toxicity, presents a novel critical illness syndrome limited data regarding diagnosis, prognosis, and therapy. We sought characterize timing, severity, intensive care management of cytokine after therapy.Retrospective cohort study.Academic children's hospital.Thirty-nine...
Primary resistance to CD19-directed chimeric antigen receptor T-cell therapy (CART19) occurs in 10% 20% of patients with acute lymphoblastic leukemia (ALL); however, the mechanisms this remain elusive. Using a genome-wide loss-of-function screen, we identified that impaired death signaling ALL led rapidly progressive disease despite CART19 treatment. This was mediated by an inherent cytotoxicity permitted persistence and subsequently magnified induction CAR functional impairment. These...
The anti-CD19 chimeric antigen receptor T-cell therapy tisagenlecleucel (CTL019) has an 81% response rate in children with relapsed or chemotherapy refractory (r/r) B-cell acute lymphoblastic leukemia (ALL). Cytokine release syndrome (CRS) is a life-threatening treatment-related toxicity that limits the full therapeutic potential adults. We report outcomes for adults r/r ALL treated optimized CTL019 dosing and CRS management strategy.
Immune effector cell (IEC) therapies offer durable and sustained remissions in significant numbers of patients with hematological cancers. While these unique immunotherapies have improved outcomes for pediatric adult a number disease states, as 'living drugs,' their toxicity profiles, including cytokine release syndrome (CRS) immune cell-associated neurotoxicity (ICANS), differ markedly from conventional cancer therapeutics. At the time article preparation, US Food Drug Administration (FDA)...
Abstract Purpose: Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR19) T-cell therapy approved for the treatment of children and young adults with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL). Patients Methods: We evaluated cellular kinetics tisagenlecleucel, effect patient factors, humoral immunogenicity, manufacturing attributes on its kinetics, exposure-response analysis efficacy, safety pharmacodynamic endpoints in 79 patients across two studies...
Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary point, may be published when key planned co-primary or secondary analyses are not yet available. Trial Updates provide an opportunity to disseminate additional results from studies, in JCO elsewhere, for which point has already been reported. In analysis of global phase II ELIANA trial (ClinicalTrials.gov identifier: NCT02435849), tisagenlecleucel provided...
Tisagenlecleucel, a chimeric antigen receptor (CAR) T-cell product targeting CD19 is approved for relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). However, the impact of pretreatment variables, such as expression level, on leukemic blasts, presence CD19- subpopulations, and especially prior CD19-targeted therapy, response to CAR therapy has not been determined. We analyzed 166 patients treated with at our institution. Eleven did achieve minimal residual disease (MRD)- deep...
PURPOSE To prospectively evaluate the effectiveness of risk-adapted preemptive tocilizumab (PT) administration in preventing severe cytokine release syndrome (CRS) after CTL019, a CD19 chimeric antigen receptor T-cell therapy. METHODS Children and young adults with CD19-positive relapsed or refractory B-cell acute lymphoblastic leukemia were assigned to high- (≥ 40%) low- (< tumor burden cohorts (HTBC LTBC) based on bone marrow aspirate biopsy before infusion. HTBC patients received single...