Selected Compilation: Car T-cell targeted therapy GBM with high efficiency specificity
Last Update: 2020-06-17
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There is still a lack of effective treatment for glioblastoma (GBM)In recent years, the expression chimeric antigen receptor (CAR) T cells obtained through the technological transformation of genetic engineering technology are expected to become a new means of treating GBMThe study found that chloramphenicol (CLTX) extracted from scorpion venom binds specifically to GBM cellsDongrui Wang of City of Hope Medical Center in the United States designed a CLTX-based CAR and evaluated the efficacy of CLTX-CAR T cells for GBM, published online in March 2020 in Science Translational Medicinethe results of the studythe authors' lead findings are as follows:1.CLTX and GBM cells are strongly bonded:CLTX can bind to more than 80% of tumor cells in the pathological specimens of most GBM patientsFurthermore, the binding of CLTX and GBM cells is not affected by the level of expression of IL13Ra2, HER2 and EGFRThe binding rate of CLTX to THE PBT-TS of the GBM progenitor cell line is more than 70%CLTX binds tumor cells more than IL13Ra2 and EGFRGBM is highly heterogeneous, in which glioma stem cells (GSC) have the potential to self-renew and form tumors, and are the target of CAR T-cell therapyThe study found that CLTX can be combined with GSC and non-GSC, and that CLTX binds to CD44 plus or CD133 plus GSC at a higher rate than differentiated CD44-or CD133-tumor cellsWith in vitro culture cell differentiation, the expression level of the GSC marker CD133 decreased gradually, but the CLTX combined with GBM cells did not decrease to show that THE CLTX and GBM cells were strongly bonded and were expected to be applied to CAR T-cell therapy2CLTX-CAR T-cell building ideas and in vitro anti-GBM cells ability testing:study to build CLTX-CAR using clTX-CAR with IgG4Fc (EQ) interval sequence and CD28 co-stimulated domain CLTX The cytotoxicity of CLTX-CAR T cells is assessed by THE PBT-TS of the GBM primary cell line PBT-TS Within 2 hours, CLTX-CAR T cells form an immune synaptic structure with PBT-TS Co-cultured with GBM cells, CLTX-CAR T cells are significantly activated, CD69 and 4-1BB (CD137) are increased, and there are departicles (cell surface CD107a) A total of 48 hours of culture, CLTX-CAR T cell killing GBM cell effective target ratio (E:T) is 1:4 In addition, CLTX-CAR T cells can identify and attack all types of PBT-TS compared to IL13Ra2 T cells that are ineffective against PBT-TS with low expression IL13Ra2 Thus, CLTX-CAR T cells can identify and attack GBM cells, and their cytotoxicity is consistent with the potential of CLTX to widely bind to GBM cells studies further compare multiple interval sequences and co-stimulating domains, and the results show that the EQ interval sequence and CD28 co-stimulation domain in CLTX are closely related to their target killer GBM cells In addition, CLTX-CAR T cells containing EQ interval sequences exhibit more long-lasting antitumor activity than CD8h interval sequences Anti-tumor activity of CLTX-CAR T cells in the animal model of growing GBM tumor: the researchers used animal models of PBT-TS intracranial implantation to assess the tumor-killing effect of CLTX-CAR T cells in the body It was found that CLTX-CAR T cells can control tumor growth and extend the survival of tumor-bearing animals However, the anti-tumor effects of CLTX-CAR T cells also varied from the animal models of different PBT-TS intracranial tumors The study found that the ability of tumors that relapsed after CLTX-CAR T cell therapy was similar to clTX binding to untreated tumors, indicating that antigen escape was not the cause of tumor recurrence In addition, CAR T cells expressing granulase B can still be detected 14 days after infusion during anti-tumor In contrast, the CLTX-CAR T cells that persist in recurrent tumors are low-expression granase B At the same time, the expression of the procedural cell death ligand 1 (PD-L1) in recurrent tumors increased significantly compared to untreated tumors PD-L1 expression can be induced by IFN gamma signals, resulting in tumor immunotherapy resistance After CAR intervention, the induction of PD-L1 in PBT-TS was associated with an increase in ifN-receptor A expression In addition, PBT-TS can be induced with a significant increase in PD-L1 expression when PBT-TS is treated with a conditional medium of CLTX-CAR T cells and tumor cell co-culture 4 Low off-target effect of CLTX-CAR T cells: the study did not detect CLTX binding to non-tumor cells Through cell departicleing and toxicity experiments, CLTX-CAR T cells were not found to target non-tumor cells In the GBM animal model of tumor-grown tumors, CLTX and GBM cell-specific binding were observed, not non-tumor cells CLTX-CAR T-cell immunotherapy did not have adverse reactions in animal experiments, including neurological symptoms or weight loss The above results show that CLTX-CAR T-cell-specific target ingress GBM cells, no obvious toxic side effects 5 Matrix metalloproteinase 2 is involved in the targeted therapy of CLTX-CAR T cells: studies have found that CLTX-CAR T cells have different effects on different GBM cells CLTX-CAR T-cell departicles are closely related to GBM cell expression matrix metalloproteinase 2 (MMP2) And CLTX binding GBM cells and its expression MMP2 are related, the results show that MMP2 is the main medium of CLTX binding GBM cells, and mediate CLTX-CAR T cell activation the PLM-CAR T cell activation and cytotoxicity can be significantly inhibited by lowering the Expression of MMP2 in GBM cells The Expression of MMP2 that interferes with the transplanted GBM tumor in the body also significantly inhibited the anti-tumor activity of CLTX-CAR T cells, and the results showed that MMP2 was an important medium necessary for the identification, activation and performance of CLTX-CAR T cells , the addition of soluble MMP2 does not activate CLTX-CAR T cells and does not reduce the toxicity of CLTX-CAR T cells to GBM cells Further research found that MMP2 involved in the formation of immunosyditis structure between CLTX-CAR T cells and GBM cells was necessary to co-locate with CLCN3 in tumor cells, and the results showed that MMP2 on the cell surface was necessary for CLTX-CAR T cells to activate, and the secretion mMP2 neither activated nor affected the function of CLTX-CAR Conclusions , the study found that the clTX-CAR T cells are highly safe, no obvious toxic side effects are seen inthepontoes to animals, CLTX-CAR T cells are strongly correlated with GBM, have strong and specific target-killing GBM activity, and have no antigen escape The researchers believe that CLTX-CAR T cells, unlike traditional CAR designs, are expected to be used in GBM treatments Copyright Notice the copyright of works published by Outside Information APP, including but not limited to text, pictures, videos, are owned by the sponsor/original author and of the God's Information , and no one may steal any content directly or indirectly by means of adaptation, cutting, 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