Abstract:
:Chimeric antigen receptors (CARs, immunoreceptors) are frequently used to redirect T cells with pre-defined specificity, in particular towards tumour cells for use in adoptive immunotherapy of malignant diseases. Specific targeting is mediated by an extracellularly located antibody-derived binding domain, which is joined to the transmembrane and intracellular CD3ζ moiety for T-cell activation. Stable CAR expression in T cells, however, requires a spacer domain interposed between the binding and the transmembrane domain and which is commonly the constant IgG1 Fc domain. We here revealed that CARs with Fc spacer domain bind to IgG Fc gamma receptors (FcγRs), thereby unintentionally activating innate immune cells, including monocytes and natural killer (NK) cells, which consequently secrete high amounts of pro-inflammatory cytokines. Engineered T cells, on the other hand, are likewise activated by FcγR binding resulting in cytokine secretion and lysis of monocytes and NK cells independently of the redirected specificity. To reduce FcγR binding, we modified the spacer domain without affecting CAR expression and antigen binding. Engineered with the modified CAR, T cells are not activated in presence of FcγR(+) cells, thereby minimizing the risk of off-target activation while preserving their redirected targeting specificity.
journal_name
Gene Therjournal_title
Gene therapyauthors
Hombach A,Hombach AA,Abken Hdoi
10.1038/gt.2010.91subject
Has Abstractpub_date
2010-10-01 00:00:00pages
1206-13issue
10eissn
0969-7128issn
1476-5462pii
gt201091journal_volume
17pub_type
杂志文章相关文献
GENE THERAPY文献大全abstract::There is currently an urgent need to develop efficient gene-delivery systems for the lung that are free of inflammatory effects. The LID vector is a synthetic gene delivery system, comprised of lipofectin (L), an integrin-targeting peptide (I) and DNA (D) that has previously been shown to have high transfection effici...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/sj.gt.3301963
更新日期:2003-06-01 00:00:00
abstract::To evaluate the use of HSV-based vectors for arthritis gene therapy we have constructed a first-generation, ICP4 deficient, replication defective herpes simplex virus (HSV) vector (S/0-) and a second-generation HSV vector derivative (T/0-) deficient for the immediate-early genes ICP4, 22 and 27, each carrying a solubl...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/sj.gt.3301014
更新日期:1999-10-01 00:00:00
abstract::The E1 deleted adenoviral vectors are efficient at gene transfer to cells in culture or in animals. However, their use is limited because of an immune-mediated loss of transduced cells. This immune response is believed to result from low-level production of viral antigens from these vectors after gene transfer. The ea...
journal_title:Gene therapy
pub_type: 杂志文章
doi:
更新日期:1995-06-01 00:00:00
abstract::We tested the influence of overexpression of arylsulfatase A (ASA) on the activity of other sulfatases in fibroblasts from patients with metachromatic leukodystrophy (MLD). We demonstrated that the overexpression of ASA reduces the activity of various sulfatases by a small amount but does not induce an accumulation of...
journal_title:Gene therapy
pub_type: 杂志文章
doi:
更新日期:1995-08-01 00:00:00
abstract::The clinical efficacy and safety as well as the application range of gene therapy will be broadened by developing systems capable of finely modulating the expression of therapeutic genes. Transgene regulation will be crucial for maintaining appropriate levels of a gene product within the therapeutic range, thus preven...
journal_title:Gene therapy
pub_type: 杂志文章,评审
doi:10.1038/sj.gt.3302251
更新日期:2004-04-01 00:00:00
abstract::Insulin gene therapy in clinical medicine is currently hampered by the inability to regulate insulin secretion in a physiological manner, the inefficiency with which the gene is delivered, and the short duration of gene expression. To address these issues, we injected the liver of streptozotocin-induced diabetic rats ...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/sj.gt.3302644
更新日期:2006-02-01 00:00:00
abstract::Synthetic oligonucleotides and DNA fragments of less than 1 kilobase (kb) have been shown to cause site-specific genetic alterations in mammalian cells in culture and in vivo. We have used a lacZ reporter gene system to compare the efficiency of episomal and chromosomal gene repair in human embryonic kidney epithelial...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/sj.gt.3302049
更新日期:2003-09-01 00:00:00
abstract::Gene transfer vectors encoding two or more genes are potentially powerful research tools and are poised to play an increasingly important role in gene therapy applications. Common strategies employed to express more than one transgene per vector include the use of multiple promoters, internal ribosome entry site (IRES...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/sj.gt.3303105
更新日期:2008-03-01 00:00:00
abstract::Cancer therapies that target a single protein or pathway may be limited by their specificity, thus missing key players that control cellular proliferation and contributing to the failure of the treatment. We propose that approaches to cancer therapy that hit multiple targets would limit the chances of escape. To this ...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/s41434-019-0096-1
更新日期:2020-02-01 00:00:00
abstract::Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in diverse cancers, which contributes to the proliferation and survival of cancer cells by upregulating apoptosis inhibitors and cell cycle regulators. Suppressor of cytokine signaling 1 (SOCS1) is an important negative regulator of...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/gt.2012.4
更新日期:2013-01-01 00:00:00
abstract::Defensins are small cationic proteins that harbor broad-spectrum microbicidal activity against bacteria, fungi and viruses. This study examines the effects on pathogens of the epidermis engineered to express human beta-defensin 3 (HBD3) to combat bacterial infections. First, we examined the localization of HBD3 in the...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/sj.gt.3302472
更新日期:2005-05-01 00:00:00
abstract::Silencing of gene expression by small interfering RNAs (siRNAs) is rapidly becoming a powerful tool for genetic analysis of mammalian cells. The use of DNA-based plasmid vectors to achieve transient and stable expression of siRNA has been developed to avoid the problems of double-stranded oligonucleotides transfection...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/sj.gt.3302878
更新日期:2007-03-01 00:00:00
abstract::Pancreatic cancer and chronic pancreatitis are clinical syndromes associated with severe pain that is difficult to manage. Thus, seeking additional pain reduction therapies is warranted. Excessive alcohol consumption over an extended period of time is the primary causal agent in pancreatitis. The efficacy of a replica...
journal_title:Gene therapy
pub_type: 杂志文章,评审
doi:10.1038/gt.2009.27
更新日期:2009-04-01 00:00:00
abstract::Intramuscular (i.m.) injection of plasmids followed by electropermeabilization is an efficient process to deliver genes into skeletal myofibers that permits proteins to be produced and secreted at therapeutically relevant levels. To further improve skeletal muscle as a bioreactor, we identified a formulation that elev...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/sj.gt.3301806
更新日期:2002-10-01 00:00:00
abstract::Galactose(alpha1,3)galactose on the surface of cells of non-primate organs is the major xenoantigen responsible for hyperacute rejection in xenotransplantation. The antigen is synthesised by (alpha1, 3)galactosyl transferase. Humans lack this enzyme and their serum contains high levels of pre-existing natural antibody...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/sj.gt.3300934
更新日期:1999-06-01 00:00:00
abstract::Prenatal gene therapy has been considered for Herlitz junctional epidermolysis bullosa (H-JEB), a lethal genodermatosis caused by the absence of any of the three subunits of laminin-5, resulting from birth in widespread blistering and erosions of skin and mucosae. To investigate this strategy in an animal model, adeno...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/sj.gt.3302832
更新日期:2006-12-01 00:00:00
abstract::Chimeric oligonucleotides have been used successfully to correct point and frameshift mutations in several cell types, as well as in animal and plant models. However, their application to primitive human blood cells has been limited. In this investigation, chimeric oligonucleotides designed to direct a site-specific n...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/sj.gt.3301610
更新日期:2002-01-01 00:00:00
abstract::Human adenovirus (Ad) vectors are extensively used as gene transfer vehicles. However, a serious obstacle for the use of these vectors in clinical applications is due to pre-existing immunity to human Ads affecting the efficacy of gene transfer. One of the approaches to circumvent host immune response could be the dev...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/sj.gt.3302146
更新日期:2004-01-01 00:00:00
abstract::A highly desirable feature for an human immunodeficiency virus type 1 (HIV-1) vaccine is the ability to induce broadly reactive anti-envelope antibodies that can neutralize primary HIV-1 isolates. Two immunizations with an HIV-1 envelope-encoding plasmid together with recombinant granulocyte-macrophage colony-stimulat...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/sj.gt.3302275
更新日期:2004-07-01 00:00:00
abstract::Selection of targeted vectors from virus display peptide libraries is a versatile and efficient approach to improve vector specificity and efficiency. This strategy has been used to target various cell types in vitro. Here, we report the screening of an adeno-associated virus type 2 (AAV2) display peptide library in v...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/gt.2010.44
更新日期:2010-08-01 00:00:00
abstract::The umbilical cord provides a rich source of primitive mesenchymal stem cells (human umbilical cord mesenchymal stem cells (HUMSCs)), which have the potential for transplantation-based treatments of Parkinson's Disease (PD). Our pervious study indicated that adenovirus-associated virus-mediated intrastriatal delivery ...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/gt.2010.152
更新日期:2011-04-01 00:00:00
abstract::Episomally maintained self-replicating systems present attractive alternative vehicles for gene therapy applications. Recent insights into the ability of chromosomal scaffold/matrix attachment regions (S/MARs) to mediate episomal maintenance of genetic elements allowed the development of a small circular episomal vect...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/sj.gt.3302593
更新日期:2006-01-01 00:00:00
abstract::We have designed new vectors for the construction of recombinant adenoviruses containing expression cassettes in the E1 and/or E3 regions. Using a versatile set of restriction enzymes, the cassettes are cloned into small bacterial vectors and subsequently introduced into large plasmids containing the adenoviral sequen...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/sj.gt.3301047
更新日期:2000-01-01 00:00:00
abstract::The potential of gene therapy for treatment of lung disease remains unrealised. Early model systems often resulted in promising efficiency of gene transfer, only to prove irreproducible in the clinic. While problems such as induction of host immune responses and duration of expression also need to be addressed, it is ...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/sj.gt.3301146
更新日期:2000-04-01 00:00:00
abstract::Successful keratinocyte gene therapy requires the development of efficient methods of gene transfer to keratinocytes. Jet injection of a solution containing DNA can be used to transfer genes to several tissues in vivo. In this article, we tried to introduce DNA into rat and human keratinocytes using this method. First...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/sj.gt.3301002
更新日期:1999-10-01 00:00:00
abstract::The insertion of suicide genes in donor T lymphocytes constitutes the basis of new approaches aiming at the treatment of the graft-versus-host disease (GVHD), a frequent complication in recipients of allogeneic haematopoietic grafts. In this study we investigated the impact that the ex vivo manipulation required for t...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/sj.gt.3302188
更新日期:2004-03-01 00:00:00
abstract::Choroidal neovascularization (CNV) leads to loss of vision in age-related macular degeneration (AMD), the leading cause of blindness in adult population over 50 years old. In this study, we developed intravenously administered, nanoparticulate, targeted nonviral retinal gene delivery systems for the management of CNV....
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/gt.2008.185
更新日期:2009-05-01 00:00:00
abstract::Bone morphogenetic protein (BMP) adenoviral vectors for the induction of osteogenesis are being developed for the treatment of bone pathology. However, it is still unknown which BMP adenoviral vector has the highest potential to stimulate bone formation in vivo. In this study, the osteogenic activities of recombinant ...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/sj.gt.3302075
更新日期:2003-09-01 00:00:00
abstract::Success of gene therapy for diseases affecting the T cell lineage depends on the thymic repopulation by genetically engineered hematopoietic progenitor cells (HPC). Although it has been shown that retrovirally transduced HPC can repopulate the thymus, little information is available on the effect of the culture protoc...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/sj.gt.3301176
更新日期:2000-05-01 00:00:00
abstract::Oligonucleotides (ODNs) show great promise in their ability to specifically inhibit single gene expression but must cross the cell membrane, escape the endosomal vesicle, and possibly traverse the nuclear membrane to arrive at their intracellular target molecules. In an attempt to improve the delivery of phosphodieste...
journal_title:Gene therapy
pub_type: 杂志文章
doi:
更新日期:1996-04-01 00:00:00