Fc receptor-like 5(FCRL5)-directed CAR-T cells exhibit antitumor activity against multiple myeloma

Multiple myeloma(MM)remains a challenging hematologic malignancy despite advancements in chimeric antigen receptor T-cell(CAR-T)therapy.Current targets of CAR-T cells used in MM immunotherapy have limitations,with a subset of patients experiencing antigen loss resulting in relapse.Therefore,novel targets for enhancing CAR-T cell therapy in MM remain needed.Fc receptor-like 5(FCRL5)is a protein marker with considerably upregulated expression in MM and has emerged as a promising target for CAR-T cell therapeutic interventions,offering an alternative treatment for MM.To further explore this option,we designed FCRL5-directed CAR-T cells and assessed their cytotoxicity in vitro using a co-culture system and in vivo using MM cell-derived xenograft models,specifically focusing on MM with gain of chromosome 1q21.Given the challenges in CAR-T therapies arising from limited T cell persistence,our approach incorporates interleukin-15(IL-15),which enhances the functionality of central memory T(TCM)cells,into the design of FCRL5-directed CAR-T cells,to improve cytotoxicity and reduce T-cell dysfunction,thereby promoting greater CAR-T cell survival and efficacy.Both in vitro and xenograft models displayed that FCRL5 CAR-T cells incorporating IL-15 exhibited potent antitumor efficacy,effectively inhibiting the proliferation of MM cells and leading to remarkable tumor suppression.Our results highlight the capacity of FCRL5-specific CAR-T cells with the integration of IL-15 to improve the therapeutic potency,suggesting a potential novel immunotherapeutic strategy for MM treatment.

Histones released by NETosis enhance the infectivity of SARS-CoV-2 by bridging the spike protein subunit 2 and sialic acid on host cells

Neutrophil extracellular traps(NETs)can capture and kill viruses,such as influenza viruses,human immunodeficiency virus(HIV),and respiratory syncytial virus(RSV),thus contributing to host defense.Contrary to our expectation,we show here that the histones released by NETosis enhance the infectivity of SARS-CoV-2,as found by using live SARS-CoV-2 and two pseudovirus systems as well as a mouse model.The histone H3 or H4 selectively binds to subunit 2 of the spike(S)protein,as shown by a biochemical binding assay,surface plasmon resonance and binding energy calculation as well as the construction of a mutant S protein by replacing four acidic amino acids.Sialic acid on the host cell surface is the key molecule to which histones bridge subunit 2 of the S protein.Moreover,histones enhance cell-cell fusion.Finally,treatment with an inhibitor of NETosis,histone H3 or H4,or sialic acid notably affected the levels of sgRNA copies and the number of apoptotic cells in a mouse model.These findings suggest that SARS-CoV-2 could hijack histones from neutrophil NETosis to promote its host cell attachment and entry process and may be important in exploring pathogenesis and possible strategies to develop new effective therapies for COVID-19.

Targeted protein degradation:mechanisms,strategies and application

Traditional drug discovery mainly focuses on direct regulation of protein activity.The development and application of protein activity modulators,particularly inhibitors,has been the mainstream in drug development.In recent years,PROteolysis TArgeting Chimeras(PROTAC)technology has emerged as one of the most promising approaches to remove specific disease-associated proteins by exploiting cells’own destruction machinery.In addition to PROTAC,many different targeted protein degradation(TPD)strategies including,but not limited to,molecular glue,Lysosome-Targeting Chimaera(LYTAC).

Administration of B7-H3 targeted chimeric antigen receptor-T cells induce regression of glioblastoma

Dear Editor,Nowadays,glioblastoma(GBM)was the most common and lethal form of primary intracranial tumor.Despite standard-of-care therapy,GBM still exhibited a poor prognosis with 5-years survival rate less than 5%.Recent years,adoptive CAR-T therapy came to be a novel immunotherapy in treating malignant tumors.Great progress has been made by CD19 targeted CAR-T cells against refractory B cell cancers.Recent studies also reported about the clinical potential of CAR-T therapy targeting IL13Ra2 and EGFRvlll in treating GBM.1,2 However,limited numbers of therapeutic targets in GBM may preclude it from progress and being popularized.B7-H3(CD276)has been found to be overexpressed by many tumors and tumor-infiltrating dendritic cell.3 Our previous studies suggested the potent anti-tumor effect of B7-H3 targeted CAR-T cells against GBM in preclinical models.

DCLK1 autoinhibition and activation in tumorigenesis

Doublecortin-like kinase 1(DCLK1)is upregulated in many tumors and is a marker for tumor stem cells.Accumulating evidence suggests DCLK1 constitutes a promising drug target for cancer therapy.However,the regulation of DCLK1 kinase activity is poorly understood,particularly the function of its autoinhibitory domain(AID),and,moreover,no physiological activators of DCLK1 have presently been reported.Here we determined the first DCLK1 kinase structure in the autoinhibited state and identified the neuronal calcium sensor HPCAL1 as an activator of DCLK1.The C-terminal AID functions to block the ATP-binding site and is competitive with ATP.HPCAL1 binds directly to the AID in a Ca^(2+)-dependent manner,which releases the autoinhibition.We also analyzed cancer-associated mutations occurring in the AID and elucidate how these mutations disrupt DCLK1 autoinhibition to elicit kinase activity upregulation.Our results present a molecular mechanism for autoinhibition and activation of DCLK1 kinase activity and provide insights into DCLK1-associated tumorigenesis.

Facile construction of targeted pH-responsive DNA-conjugated gold nanoparticles for synergistic photothermal-chemotherapy

Recently,stimuii-responsive DNA nano structure-based nanodevices have bee n applied for cancer therapy.In this study,pH-responsive i-motifDNA was modified on gold nanoparticles(AuNPs)via a facile,time-saving freeze-thaw method and utilized to construct stimuii-responsive drug nanocarriers.When the environment pH changes from 7.4 to 5.0,the i-motif DNA would be folded into four-stranded(C-quadruplex)that could be characterized by circular dichroism,and the characteristic of acid stimulate was verified by fluorescence resonanee energy transfer(FRET).To enhance specifical cellular uptake,MUC1 aptamer was employed as the targeting moiety.Doxorubicin(Dox)is an anticancer drug that can be efficiently intercalated into GC base pairs of DNA nanostructure to form drug-loaded nanovehicles(Dox@AuNP-MUCl).Additionally,owing to the excellent photothermal con version efficiency of AuNPs,the synergistic effect between chemotherapy and PTT can be readily achieved by 808 nm near-infrared(NIR)irradiation,which exhibits specifically and efficiently anticancer efficiency.Hence,this multifunctional drug carrier shows the potential for synergistic photothermal-chemotherapy.

Antimicrobial peptide DP7 with potential activity against SARS coronavirus infections

Dear Editor,The outbreak of the SARS-CoV-2 epidemic once again demonstrates that RNA viruses,through mutations,genetic recombination and cross-species transmission,can pose a serious threat to the health of people worldwide.Even after the severe acute respiratory syndrome(SARS)and middle east respiratory syndrome(MERS)outbreaks,the world still initially lacked effective means to control the current coronavirus disease 2019(COVID-19)outbreak.We must work together to develop effective drugs to treat existing and future potential coronavirus infections to reduce their impact on the global health system and human life.Due to time constraints,the'conventional drug in new use#method has become the main method of treating SARS-CoV-2 infections.However,long-term drug development goals should include treatments that can produce broad-spectrum effects on different coronaviruses,and provide the means to alleviate disease symptoms and prevent death.