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World Journal of Gastroenterology Jul 2023The estimated world prevalence of hepatitis B virus (HBV) infection is 316 million. HBV infection was identified in 1963 and nowadays is a major cause of cirrhosis and... (Review)
Review
The estimated world prevalence of hepatitis B virus (HBV) infection is 316 million. HBV infection was identified in 1963 and nowadays is a major cause of cirrhosis and hepatocellular carcinoma (HCC) despite universal vaccination programs, and effective antiviral therapy. Long-term administration of nucleos(t)ide analogues (NA) has been the treatment of choice for chronic hepatitis B during the last decades. The NA has shown a good safety profile and high efficacy in controlling viral replication, improving histology, and decreasing the HCC incidence, decompensation, and mortality. However, the low probability of HBV surface antigen seroclearance made necessary an indefinite treatment. The knowledge, in recent years, about the different phases of the viral cycle, and the new insights into the role of the immune system have yielded an increase in new therapeutic approaches. Consequently, several clinical trials evaluating combinations of new drugs with different mechanisms of action are ongoing with promising results. This integrative literature review aims to assess the knowledge and major advances from the past of hepatitis B, the present of NA treatment and withdrawal, and the future perspectives with combined molecules to achieve a functional cure.
Topics: Humans; Hepatitis B virus; Antiviral Agents; Carcinoma, Hepatocellular; Liver Neoplasms; Hepatitis B, Chronic; Hepatitis B Surface Antigens; Hepatitis B; DNA, Viral
PubMed: 37476586
DOI: 10.3748/wjg.v29.i25.3964 -
Science Advances Nov 2023Ovarian cancer (OC) is a lethal gynecologic malignancy, with modest responses to CPI. Engagement of additional immune arms, such as NK cells, may be of value. We focused...
Ovarian cancer (OC) is a lethal gynecologic malignancy, with modest responses to CPI. Engagement of additional immune arms, such as NK cells, may be of value. We focused on Siglec-7 as a surface antigen for engaging this population. Human antibodies against Siglec-7 were developed and characterized. Coculture of OC cells with PBMCs/NKs and Siglec-7 binding antibodies showed NK-mediated killing of OC lines. Anti-Siglec-7 mAb (DB7.2) enhanced survival in OC-challenged mice. In addition, the combination of DB7.2 and anti-PD-1 demonstrated further improved OC killing in vitro. To use Siglec-7 engagement as an OC-specific strategy, we engineered an NK cell engager (NKCE) to simultaneously engage NK cells through Siglec-7, and OC targets through FSHR. The NKCE demonstrated robust in vitro killing of FSHR OC, controlled tumors, and improved survival in OC-challenged mice. These studies support additional investigation of the Siglec-7 targeting approaches as important tools for OC and other recalcitrant cancers.
Topics: Female; Humans; Mice; Animals; Biological Products; Killer Cells, Natural; Ovarian Neoplasms; Antigens, CD; Sialic Acid Binding Immunoglobulin-like Lectins
PubMed: 37910620
DOI: 10.1126/sciadv.adh4379 -
Current Opinion in Immunology Aug 2023Peptide ligands presented by cell-surface MHC class-I molecules enable T cells to eradicate intracellular pathogens and cancers. The presented peptide repertoire, the... (Review)
Review
Peptide ligands presented by cell-surface MHC class-I molecules enable T cells to eradicate intracellular pathogens and cancers. The presented peptide repertoire, the class-I immunopeptidome, is generated from each cell's translatome in a highly biased manner to avoid overrepresenting highly abundant translation products. The immunopeptidome can only be defined by mass spectrometry (MS). Here, we review recent advances in immunopeptidomics, focusing on using ribosome profiling as the optimal MS database to optimize the false- and failed-discovery rates and relate these findings to the contribution of defective ribosomal products and cellular quality control mechanisms to MHC class-I antigen processing and presentation.
Topics: Humans; Ribosome Profiling; Histocompatibility Antigens Class I; Peptides; Neoplasms; Mass Spectrometry; Antigen Presentation
PubMed: 37247567
DOI: 10.1016/j.coi.2023.102342 -
Journal of Translational Medicine Oct 2023Chimeric antigen receptor NK (CAR-NK) cell therapy is one of the most promising immunotherapies. Although it has shown a significant therapeutic effect in hematologic...
BACKGROUND
Chimeric antigen receptor NK (CAR-NK) cell therapy is one of the most promising immunotherapies. Although it has shown a significant therapeutic effect in hematologic malignancies, few successes have been obtained in solid tumors including esophageal squamous cell carcinoma (ESCC). The major reasons are lack of specific cell surface antigens and complex tumor microenvironment. Here we identify CD22, a well-known tumor surface marker in hematologic malignancies, is expressed in ESCC, possibly serving as a potential target of CAR-NK cell therapy.
METHODS
The expression of 13 tumor cell surface antigens used clinically was analyzed in patients from The Cancer Genome Atlas (TCGA) database. Also, mRNA expression were detected in 2 ESCC cell lines and 2 patients samples by qCPR. Then according to Venn diagram, CD22 was selected for further investigation. Following this, the expression of CD22 by immunofluorescence (IF) in ESCC cell lines and by immunohistochemistry (IHC) in 87 cases of human ESCC samples was detected respectively. On the basis of H-score results, the correlation between CD22 expression and clinical parameters was analyzed. As a proof, the efficacy of CD22-targeted CAR-NK cells against ESCC cell lines was performed by a real-time cell analyzer (RTCA) platform.
RESULTS
KYSE-140 and KYSE-150 cell lines displayed surface expression of CD22. IHC showed an 80.46% (70/87) positive rate in ESCC patient samples. Among these, cell membranous expression of CD22 was observed in 27.59% (24/87) patient samples. Through chi-square test, expression of CD22 in ESCC was associated with lymph node metastasis while it was no related to the depth of tumor invasion and clinical stage. Engineered CD22-targeted CAR-NK cells exhibited inhibitory growth capability against ESCC cell lines (p < 0.0001).
CONCLUSIONS
CD22 is a potential tumor surface antigen capable of being targeted by CAR-NK cells in ESCC. And potential therapeutics for ESCC may be developed based on immune cells expressing anti-CD22 CAR. The study also indicates that CD22 CAR-NK cells could be used in other cancers and more in vivo experiments are needed.
Topics: Humans; Esophageal Squamous Cell Carcinoma; Esophageal Neoplasms; Carcinoma, Squamous Cell; Biomarkers, Tumor; Killer Cells, Natural; Hematologic Neoplasms; Antigens, Surface; Cell- and Tissue-Based Therapy; Cell Line, Tumor; Tumor Microenvironment; Sialic Acid Binding Ig-like Lectin 2
PubMed: 37817249
DOI: 10.1186/s12967-023-04409-8 -
Journal of Medical Virology Sep 2023Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA), the transcription template for all viral mRNAs, is highly stable and current treatment options...
Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA), the transcription template for all viral mRNAs, is highly stable and current treatment options cannot effectively induce its clearance. Previously, we established an HBV persistence mouse model based on a clinical isolate (termed BPS) and identified interleukin-21 (IL-21) as a potent inducer of HBV clearance. Lipid nanoparticle (LNP) mediated delivery of mRNA has proven to be a highly safe and effective delivery platform. This work explored the applicability and effectiveness of the mRNA-LNP platform in IL-21-based HBV therapies. First, LNP-encapsulated murine IL-21 mRNA (LNP-IL-21) was prepared, characterized, and demonstrated to engender IL-21 expression in vitro and in vivo. Next, LNP-IL-21 was shown to induce clearance of both serum and intrahepatic HBV antigen and DNA in two HBV persistence mouse models based on BPS and recombinant cccDNA (rcccDNA), respectively, which was associated with HBV-specific humoral and cellular immune responses. Furthermore, peripheral blood mononuclear cells from BPS persistence mice treated ex vivo with LNP-IL-21 and HBV surface antigen (HBsAg) could induce similar HBV clearance upon infusion into recipient mice. These findings indicated that IL-21 combined with mRNA-LNP platform represents a valid and promising strategy for developing novel therapeutics against chronic HBV infection.
Topics: Animals; Mice; Hepatitis B virus; Leukocytes, Mononuclear; Hepatitis B Surface Antigens; Disease Models, Animal; RNA, Messenger
PubMed: 37665238
DOI: 10.1002/jmv.29062 -
Nature Chemical Biology Aug 2023Mammalian cell surface and secreted glycoproteins exhibit remarkable glycan structural diversity that contributes to numerous physiological and pathogenic interactions....
Mammalian cell surface and secreted glycoproteins exhibit remarkable glycan structural diversity that contributes to numerous physiological and pathogenic interactions. Terminal glycan structures include Lewis antigens synthesized by a collection of α1,3/4-fucosyltransferases (CAZy GT10 family). At present, the only available crystallographic structure of a GT10 member is that of the Helicobacter pylori α1,3-fucosyltransferase, but mammalian GT10 fucosyltransferases are distinct in sequence and substrate specificity compared with the bacterial enzyme. Here, we determined crystal structures of human FUT9, an α1,3-fucosyltransferase that generates Lewis and Lewis antigens, in complex with GDP, acceptor glycans, and as a FUT9-donor analog-acceptor Michaelis complex. The structures reveal substrate specificity determinants and allow prediction of a catalytic model supported by kinetic analyses of numerous active site mutants. Comparisons with other GT10 fucosyltransferases and GT-B fold glycosyltransferases provide evidence for modular evolution of donor- and acceptor-binding sites and specificity for Lewis antigen synthesis among mammalian GT10 fucosyltransferases.
Topics: Animals; Humans; Fucosyltransferases; Glycosyltransferases; Lewis Blood Group Antigens; Polysaccharides; Mammals
PubMed: 37202521
DOI: 10.1038/s41589-023-01345-y -
International Journal of Molecular... Dec 2023Cancer management still requires more potent and safer treatments, of which immunomodulatory receptors on the lymphocyte surface have started to show promise in new... (Review)
Review
Cancer management still requires more potent and safer treatments, of which immunomodulatory receptors on the lymphocyte surface have started to show promise in new cancer immunotherapies (e.g., CTLA-4 and PD-1). CD6 is a signal-transducing transmembrane receptor, mainly expressed by all T cells and some B and NK cell subsets, whose endogenous ligands (CD166/ALCAM, CD318/CDCP-1, Galectins 1 and 3) are overexpressed by malignant cells of different lineages. This places CD6 as a potential target for novel therapies against haematological and non-haematological malignancies. Recent experimental evidence for the role of CD6 in cancer immunotherapies is summarised in this review, dealing with diverse and innovative strategies from the classical use of monoclonal antibodies to soluble recombinant decoys or the adoptive transfer of immune cells engineered with chimeric antigen receptors.
Topics: Activated-Leukocyte Cell Adhesion Molecule; Antigens, CD; Antigens, Differentiation, T-Lymphocyte; Immunotherapy; Neoplasms; T-Lymphocytes
PubMed: 38139340
DOI: 10.3390/ijms242417510 -
Expert Opinion on Investigational Drugs 2023Chronic hepatitis B infection is a major global health issue associated with significant liver-related morbidity and mortality. While existing treatments can suppress... (Review)
Review
INTRODUCTION
Chronic hepatitis B infection is a major global health issue associated with significant liver-related morbidity and mortality. While existing treatments can suppress the virus effectively, they are incapable of inducing functional cure, as defined by hepatitis B surface antigen (HBsAg) seroclearance. Currently, numerous novel compounds are being developed, including bepirovirsen, an antisense oligonucleotide (ASO).
AREAS COVERED
This review summarizes the mechanism of action, pharmacokinetics, clinical efficacy and safety data collected from phase I and II studies of bepirovirsen. The data were extracted from publications relevant to the pivotal trials of bepirovirsen, in either full manuscript or conference abstracts.
EXPERTOPINION
Bepirovirsen, a 20-mer ASO, has already entered phase III clinical evaluation using the optimal dosing regimen of 300 mg subcutaneous injection weekly for 24 weeks in nucleoside analogue-treated HBeAg-negative non-cirrhotic patients with low (<3000 IU/mL) baseline HBsAg. The durability and long-term clinical outcomes among Bepirovirsen responders will need to be evaluated. The stop-to-cure approach in those reaching HBsAg < 100 IU/mL should also be explored. In the long run, Bepirovirsen has the potential to facilitate viral hepatitis elimination.
Topics: Humans; Hepatitis B, Chronic; Hepatitis B Surface Antigens; Hepatitis B e Antigens; Antiviral Agents; Oligonucleotides, Antisense; Hepatitis B virus; Clinical Trials, Phase II as Topic
PubMed: 37902953
DOI: 10.1080/13543784.2023.2277389 -
Molecular Therapy : the Journal of the... Oct 2023Hematopoietic stem cell (HSC) gene therapy is currently performed on CD34 hematopoietic stem and progenitor cells containing less than 1% true HSCs and requiring a...
Hematopoietic stem cell (HSC) gene therapy is currently performed on CD34 hematopoietic stem and progenitor cells containing less than 1% true HSCs and requiring a highly specialized infrastructure for cell manufacturing and transplantation. We have previously identified the CD34CD90 subset to be exclusively responsible for short- and long-term engraftment. However, purification and enrichment of this subset is laborious and expensive. HSC-specific delivery agents for the direct modification of rare HSCs are currently lacking. Here, we developed novel targeted viral vectors to specifically transduce CD90-expressing HSCs. Anti-CD90 single chain variable fragments (scFvs) were engineered onto measles- and VSV-G-pseudotyped lentiviral vectors that were knocked out for native targeting. We further developed a custom hydrodynamic titration methodology to assess the loading of surface-engineered capsids, measure antigen recognition of the scFv, and predict the performance on cells. Engineered vectors formed with minimal impairment in the functional titer, maintained their ability to fuse with the target cells, and showed highly specific recognition of CD90 on cells ex vivo. Most important, targeted vectors selectively transduced human HSCs with secondary colony-forming potential. Our novel HSC-targeted viral vectors have the potential to significantly enhance the feasibility of ex vivo gene therapy and pave the way for future in vivo applications.
Topics: Humans; Antigens, CD34; Genetic Therapy; Genetic Vectors; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells
PubMed: 37550965
DOI: 10.1016/j.ymthe.2023.08.003 -
Current Opinion in Rheumatology Mar 2024Chimeric antigen receptor T-cell therapy (CAR-T) has revolutionized cancer treatment by harnessing the immune system's power to target malignancies. CD19, a B-cell... (Review)
Review
PURPOSE OF REVIEW
Chimeric antigen receptor T-cell therapy (CAR-T) has revolutionized cancer treatment by harnessing the immune system's power to target malignancies. CD19, a B-cell surface antigen, a key target for CAR-T cell therapy in hematological malignancies, displayed remarkable clinical responses. Recently, there has been a growing interest in exploring the application of CD19 CAR-T cell therapy beyond oncology. The rationale for investigating CD19 CAR-T cells in Rheumatology stems from their ability to selectively target B cells, which play a central pathogenic role through autoantibody-dependent and independent mechanisms.
RECENT FINDINGS
Preclinical and five completed clinical studies have shown remarkable efficacy and safety in diseases such as systemic lupus erythematosus, antisynthetase syndrome, and systemic sclerosis. It is thus not surprising that 17 active clinical trials exploring CAR-T cells in Rheumatology are in progress.
SUMMARY
Although CAR-T therapy holds great promise in Rheumatology, many challenges loom. Whether this new way to deplete B-cells is superior to conventional antibody-based B-cell depletion in rheumatic diseases will be closely watched in the coming years.
Topics: Humans; Receptors, Chimeric Antigen; Receptors, Antigen, T-Cell; T-Lymphocytes; Rheumatology; Antigens, CD19; Cell- and Tissue-Based Therapy
PubMed: 38099466
DOI: 10.1097/BOR.0000000000000994