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Long-term safety of lentiviral or gammaretroviral gene-modified T cell therapies.
Nat Med
January 2025
Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Long-term risks of gene therapy are not fully understood. In this study, we evaluated safety outcomes in 783 patients over more than 2,200 total patient-years of observation from 38 T cell therapy trials. The trials employed integrating gammaretroviral or lentiviral vectors to deliver engineered receptors to target HIV-1 infection or cancer.
View Article and Find Full Text PDFIn vitro NIH3T3 mouse embryonic fibroblast cell model does not predict AAV2 or AAVdj-mediated cell transformation.
Toxicol Appl Pharmacol
January 2025
Drug Safety Research & Development, Pfizer, Inc., Groton, CT 06340, USA.
One of the potential risk factors of recombinant adeno-associated virus (rAAV)-based gene therapy is insertional mutagenesis, which has been associated with the development of hepatocellular carcinoma (HCC) in rAAV-treated neonatal mice. The objective of this study was to investigate if well-established in vitro cell transformation assays (CTA) in mouse cell lines can detect AAV2 or AAVdj-mediated cell transformation. Since AAV integration at the Rian locus in neonatal mice has been implicated in AAV-mediated HCC, an rAAV vector specifically targeting the mouse Rian locus and an additional rAAV vector previously shown to cause HCC in neonatal mice were both tested for the induction of cell transformation in NIH3T3 cells.
View Article and Find Full Text PDFHyperleukocytosis in a neuroblastoma patient after treatment with natural killer T cells expressing a GD2-specific chimeric antigen receptor and IL-15.
J Immunother Cancer
January 2025
Center for Advanced Innate Cell Therapy, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA
The ability of immune cells to expand numerically after infusion distinguishes adoptive immunotherapies from traditional drugs, providing unique therapeutic advantages as well as the potential for unmanageable toxicities. Here, we describe a case of lethal hyperleukocytosis in a patient with neuroblastoma treated on phase 1 clinical trial (NCT03294954) with autologous natural killer T cells (NKTs) expressing a GD2-specific chimeric antigen receptor and cytokine interleukin 15 (GD2-CAR.15).
View Article and Find Full Text PDFFocused Ultrasound and Microbubble-Mediated Delivery of CRISPR-Cas9 Ribonucleoprotein to Human Induced Pluripotent Stem Cells.
Mol Ther
January 2025
Department of Biology, Concordia University, 7141 Sherbrooke St. W H4B 1R6, Montreal, Canada; Department of Physics, Concordia University, 7141 Sherbrooke St. W H4B 1R6, Montreal, Canada. Electronic address:
CRISPR-Cas9 ribonucleoproteins (RNPs) have been heavily considered for gene therapy due to their high on-target efficiency, rapid activity and lack of insertional mutagenesis relative to other CRISPR-Cas9 delivery formats. Genetic diseases such as hypertrophic cardiomyopathy currently lack effective treatment strategies and are prime targets for CRISPR-Cas9 gene editing technology. However, current in-vivo delivery strategies for Cas9 pose risks of unwanted immunogenic responses.
View Article and Find Full Text PDFCAR T-cell-associated secondary malignancies challenge current pharmacovigilance concepts.
EMBO Mol Med
January 2025
Safety of Biomedicines and Diagnostics, Paul-Ehrlich-Institut, Langen, Germany.
Suspected adverse reactions following chimeric antigen receptor T-cell (CAR T) treatment include more and more cases of secondary T-cell malignancies. The causality assessment of such suspected reactions challenges established evaluation practices due to (i) patient and product-specific risk factors and (ii) incomplete data available with post-marketing reports submitted to competent authorities. This is of particular relevance for gene therapy products that integrate into the host genome.
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