Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection
Autor: | Michel Sadelain, Sjoukje J. C. van der Stegen, Mithat Gonen, Mohamad Hamieh, Theodoros Giavridis, Ashlesha Odak, Jorge Mansilla-Soto, Justin Eyquem, Kristen M. Cunanan |
---|---|
Rok vydání: | 2017 |
Předmět: |
Male
0301 basic medicine Receptors Antigen T-Cell alpha-beta T-Lymphocytes medicine.medical_treatment T cell Antigens CD19 Receptors Antigen T-Cell Lymphocyte Activation CD19 Translational Research Biomedical Mice 03 medical and health sciences Cancer immunotherapy Genome editing medicine Animals Humans CRISPR Gene silencing Promoter Regions Genetic Gene Editing Multidisciplinary biology Cas9 Cell Differentiation Precursor Cell Lymphoblastic Leukemia-Lymphoma Chimeric antigen receptor Disease Models Animal 030104 developmental biology medicine.anatomical_structure Gene Expression Regulation Genetic Loci Immunology biology.protein Cancer research Immunotherapy CRISPR-Cas Systems human activities |
Zdroj: | Nature. 543:113-117 |
ISSN: | 1476-4687 0028-0836 |
Popis: | 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. |
Databáze: | OpenAIRE |
Externí odkaz: |