Recent advances in CAR-T cell engineering Huang, Ruihao; Li, Xiaoping; He, Yundi ...
Journal of hematology and oncology,
07/2020, Letnik:
13, Številka:
1
Journal Article
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Chimeric antigen receptor T (CAR-T) cell therapy is regarded as an effective solution for relapsed or refractory tumors, particularly for hematological malignancies. Although the initially approved ...anti-CD19 CAR-T therapy has produced impressive outcomes, setbacks such as high relapse rates and resistance were experienced, driving the need to discover engineered CAR-T cells that are more effective for therapeutic use. Innovations in the structure and manufacturing of CAR-T cells have resulted in significant improvements in efficacy and persistence, particularly with the development of fourth-generation CAR-T cells. Paired with an immune modifier, the use of fourth-generation and next-generation CAR-T cells will not be limited because of cytotoxic effects and will be an efficient tool for overcoming the tumor microenvironment. In this review, we summarize the recent transformations in the ectodomain, transmembrane domain, and endodomain of the CAR structure, which, together with innovative manufacturing technology and improved cell sources, improve the prospects for the future development of CAR-T cell therapy.
Abstract Hematopoietic stem cell transplantation (HSCT) is a highly effective and unique medical procedure for the treatment of most hematological malignancies. The first allogeneic transplantation ...was performed by E. Donnall Thomas in 1957. Since then, the field has evolved and expanded worldwide. The first successful allogenic HSCT (allo-HSCT) in China was conducted in 1981. Although the development of allo-HSCT in China lagged, China has since made considerable contributions to the process of HSCT worldwide, with more than 10,000 HSCTs performed annually. In particular, haploid HSCT (haplo-HSCT) technology represented in the Beijing Protocol has demonstrated similar efficacy to human leukocyte antigen-matched HSCT and has gradually become the pre-dominant choice for allo-HSCT in China. Currently, the number of haplo-HSCT procedures exceeds 5000 per year, and the Beijing Protocol has been greatly improved by implementing updated individualized strategies for controlling complications, relapse, and infection management. In addition, innovative haplo-HSCT technologies developed by different medical transplantation centers, such as Soochow, Zhejiang, Fujian, Chongqing, and Anhui, have emerged, providing inspiration for the refinement of global practice. This review will focus on the current activity in this field and highlight important trends that are vital in China's allo-HSCT process, examining the current viewpoint and future directions.
Recurrent neural network (RNN) has been demonstrated as a powerful tool for analyzing various types of time series data. There is limited knowledge about the application of the RNN model in the area ...of pharmacokinetic (PK) and pharmacodynamic (PD) analysis. In this paper, a specific variation of RNN, long short-term memory (LSTM) network, is presented to analyze the simulated PK/PD data of a hypothetical drug.
The plasma concentration and effect level under one dosing regimen were used to train the LSTM model. The developed LSTM model was used to predict the individual PK/PD data under other dosing regimens.
The optimized LSTM model captured temporal dependencies and predicted PD profiles accurately for the simulated indirect PK-PD relationship.
The results demonstrated that the generic LSTM model can approximate the complex underlying mechanistic biological processes.
Silver nanoclusters (Ag NCs) are nanoscale aggregates that possess molecular-like discrete energy levels, resulting in electronic configuration-dependent tunable luminescence spanning the entire ...visible range. Benefiting from the efficient ion exchange capacity, nanometer dimensional cages, and high thermal and chemical stabilities, zeolites have been employed as desirable inorganic matrices to disperse and stabilize Ag NCs. This paper reviewed the recent research progresses on the luminescence properties, spectral manipulation, as well as the theoretical modelling of electronic structure and optical transition of Ag NCs confined inside various zeolites with different topology structures. Furthermore, potential applications of the zeolite-encaged luminescent Ag NCs in lighting, gas monitoring and sensing were presented. This review concludes with a brief comment on the possible future directions in the study of zeolite-encaged luminescent Ag NCs.
Ocular graft-versus-host-disease (GVHD) remains a significant clinical complication after allogeneic hematopoietic stem cell transplantation. Impaired visual function, pain, and other symptoms ...severely affect affected individuals' quality of life. However, the diagnosis of and therapy for ocular GVHD involve a multidisciplinary approach and remain challenging for both hematologists and ophthalmologists, as there are no unified international criteria. Through an exploration of the complex pathogenesis of ocular GVHD, this review comprehensively summarizes the pathogenic mechanism, related tear biomarkers, and clinical characteristics of this disease. Novel therapies based on the mechanisms are also discussed to provide insights into the ocular GVHD treatment.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative treatment for patients with myeloid malignancies such as myelodysplastic syndrome (MDS) and acute myeloid ...leukemia (AML). However, relapse and graft-versus-host disease (GvHD) still affect the survival of patients who receive allo-HSCT, and more appropriate therapeutic strategies should be applied at all stages of transplantation to prevent these adverse events. The use of epigenetics agents, such as hypomethylating agents (HMAs), has been explored to decrease the risk of relapse by epigenetic modulation, which is especially effective among AML patients with poor mutations in epigenetic regulators. Furthermore, epigenetic agents have also been regarded as prophylactic methods for GvHD management without abrogating graft versus leukemia (GvL) effects. Therefore, the combination of epigenetic therapy and HSCT may optimize the transplantation process and prevent treatment failure. Existing studies have investigated the feasibility and effectiveness of using HMAs in the pretransplant, transplant and posttransplant stages among MDS and AML patients. This review examines the application of HMAs as a bridge treatment to reduce the tumor burden and the determine appropriate dose during allo-HSCT. Within this review, we also examine the efficacy and safety of HMAs alone or HMA-based strategies in posttransplant settings for MDS and AML. Finally, we provide an overview of other epigenetic candidates, which have been discussed in the nontransplant setting.
In this research, upconversion nanocrystals incorporated with MOR zeolite composites were synthesized using the desilicated MOR zeolite as a host for the in situ growth of NaREF4 (RE = Y, Gd) Yb/Er ...nanocrystals. The structure and morphology of the composites were studied with XRD, XPS, and TEM measurements, and the spectral studies indicated that the subsequent thermal treatment can effectively improve the upconversion emission intensity of Er3+. By using the NaYF4:Yb/Er@DSi1.0MOR-HT composite that holds the strongest upconversion emission, a probe of UCNC@DSiMOR/BPEI was constructed with the modification of branched poly ethylenimine for the detection of Cu2+. It was indicated that the integrated emission intensity of Er3+ shows a linear dependence with the logarithm value of the Cu2+ concentration ranging from 0.1 to 10 μM. This study offered a feasible method for the construction of UCNC@zeolite composites with enhanced upconversion emission, which may have a potential application as fluorescent probes for the detection of various metal ions by adjusting the doping luminescent center.
Abstract Background: Imatinib mesylate (IM) resistance is an emerging problem for chronic myeloid leukemia (CML). Previous studies found that connexin 43 (Cx43) deficiency in the hematopoietic ...microenvironment (HM) protects minimal residual disease (MRD), but the mechanism remains unknown. Methods: Immunohistochemistry assays were employed to compare the expression of Cx43 and hypoxia-inducible factor 1α (HIF-1α) in bone marrow (BM) biopsies of CML patients and healthy donors. A coculture system of K562 cells and several Cx43-modified bone marrow stromal cells (BMSCs) was established under IM treatment. Proliferation, cell cycle, apoptosis, and other indicators of K562 cells in different groups were detected to investigate the function and possible mechanism of Cx43. We assessed the Ca 2+ -related pathway by Western blotting. Tumor-bearing models were also established to validate the causal role of Cx43 in reversing IM resistance. Results: Low levels of Cx43 in BMs were observed in CML patients, and Cx43 expression was negatively correlated with HIF-1α. We also observed that K562 cells cocultured with BMSCs transfected with adenovirus-short hairpin RNA of Cx43 (BMSCs-shCx43) had a lower apoptosis rate and that their cell cycle was blocked in G0/G1 phase, while the result was the opposite in the Cx43-overexpression setting. Cx43 mediates gap junction intercellular communication (GJIC) through direct contact, and Ca 2+ is the key factor mediating the downstream apoptotic pathway. In animal experiments, mice bearing K562, and BMSCs-Cx43 had the smallest tumor volume and spleen, which was consistent with the in vitro experiments. Conclusions: Cx43 deficiency exists in CML patients, promoting the generation of MRD and inducing drug resistance. Enhancing Cx43 expression and GJIC function in the HM may be a novel strategy to reverse drug resistance and promote IM efficacy.
Antimicrobial peptides are a class of proteins with antibacterial functions. In this study, the anti-lipopolysaccharide factor isoform 3 gene (
), encoding an antimicrobial peptide from
with a super ...activity was expressed in
, which would develop a microalga strain that can be used for the antimicrobial peptide production. To construct the expression cluster, namely pH2A-Pm3, the codon optimized
gene was fused with the
reporter by 2A peptide and inserted into pH124 vector. The glass-bead method was performed to transform pH2A-Pm3 into
CC-849. In addition to 8 μg/mL zeocin resistance selection, the
transformants were further confirmed by genomic PCR and RT-PCR. Western blot analysis showed that the
-derived ALFPm3 (cALFPm3) was successfully expressed in
transformants and accounted for 0.35% of the total soluble protein (TSP). Furthermore, the results of antibacterial assay revealed that the cALFPm3 could significantly inhibit the growth of a variety of bacteria, including both Gram-negative bacteria and Gram-positive bacteria at a concentration of 0.77 μM. Especially, the inhibition could last longer than 24 h, which performed better than ampicillin. Hence, this study successfully developed a transgenic
strain, which can produce the active ALFPm3 driven from
, providing a potential strategy to use
as the cell factory to produce antimicrobial peptides.
Chimeric antigen receptor T (CAR-T) cell therapy has significantly improved the life expectancy for patients with refractory or relapse B cell lymphoma. As for B cell acute lymphoblastic leukemia ...(B-ALL), although the primary response rate is promising, the high incidence of early relapse has caused modest long-term survival with CAR-T cell alone. One of the main challenges is the limited persistence of CAR-T cells. To further optimize the clinical effects of CAR-T cells, many studies have focused on modifying the CAR structure and regulating CAR-T cell differentiation. In this review, we focus on CAR-T cell persistence and summarize the latest progress and strategies adopted during the in vitro culture stage to optimize CAR-T immunotherapy by improving long-term persistence. Such strategies include choosing a suitable cell source, improving culture conditions, combining CAR-T cells with conventional drugs, and applying genetic manipulations, all of which may improve the survival of patients with hematologic malignancies by reducing the probability of recurrence after CAR-T cell infusion and provide clues for solid tumor CAR-T cell therapy development.
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