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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.
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http://dx.doi.org/10.1038/nature21405 | DOI Listing |
Mol Ther
December 2024
Program for Cell and Gene Therapy and Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA, 98101, USA; Department of Pediatrics, University of Washington, Seattle, WA, 98105, USA; Department of Immunology, University of Washington, Seattle, WA, 98109, USA. Electronic address:
Pathogenic long-lived plasma cells (LLPCs) secrete autoreactive antibodies, exacerbating autoimmune diseases and complicating solid organ transplantation. Targeted elimination of the autoreactive B-cell pool represents a promising therapeutic strategy, yet current treatment modalities fall short in depleting mature plasma cells. Here, we demonstrate that chimeric antigen receptor (CAR) T cells, targeting BCMA utilizing a split-receptor design, offer a controlled and effective therapeutic strategy against LLPCs.
View Article and Find Full Text PDFMol Ther
December 2024
Translational Vectorology Research Unit, Children's Medical Research Institute, Faculty of Medicine and Health, The University of Sydney, Westmead, Australia; Australian Genome Therapeutics Centre, Children's Medical Research Institute and Sydney Children's Hospitals Network, Westmead, NSW 2145, Australia; Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine - National Research Institute, Warsaw, Poland. Electronic address:
Chimeric antigen receptor (CAR) T-cell (CAR-T) therapies present options for patients diagnosed with certain leukemias. Recent advances of the technology included a method to integrate the CAR into the T-cell receptor alpha constant (TRAC) locus to take advantage of the endogenous promoter and regulatory elements for CAR expression. This method used adeno-associated viral (AAV) vectors based on AAV6 to deliver the donor template encoding the CAR construct.
View Article and Find Full Text PDFBackground: Performance of a 16S rRNA analysis of the cervicovaginal microbiome of 220 participants recruited into the T Cell Response against Chlamydia (TRAC) cohort between February 2011 and August 2014 in Allegheny County, Pennsylvania USA detected DNA encoding chlamydial 16S rRNA in samples from seven participants whose tests were negative for Chlamydia trachomatis (CT) and DNA encoding gonococcal 16S rRNA from five participants whose tests were negative for Neisseria gonorrhoeae (NG) infection with the Aptima Combo2 assay (Hologic).
Methods: We used targeted PCR amplification followed by sequencing to characterize the chlamydial 23S rRNA locus and qPCR to detect gonococcal DNA in residual diagnostic swab eluates or DNA used to generate 16S rRNA libraries.
Results: Discrepant specimens that contained chlamydial DNA carried a diagnostic-avoidant, G1526A variant in the 23S rRNA locus identical to variants previously detected in Finland, Denmark, and the UK.
Sci Adv
November 2024
Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
CD8 T cell exhaustion hampers control of cancer and chronic infections and limits chimeric antigen receptor (CAR) T cell efficacy. Targeting in CAR T cells provides therapeutic benefit; however, TET2's role in exhausted T cell (T) development is unclear. In chronic lymphocytic choriomeningitis virus (LCMV) infection, TET2 drove conversion from stem cell-like T progenitors toward terminally differentiated and effector (T)-like T.
View Article and Find Full Text PDFNat Commun
May 2024
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 211198, China.
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