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Frontiers in Medicine 2021Herpes zoster (HZ) has raised public concern. An increasing incidence of HZ can be seen in the immunocompromised population, such as the psoriasis patients taking...
Herpes zoster (HZ) has raised public concern. An increasing incidence of HZ can be seen in the immunocompromised population, such as the psoriasis patients taking biologics. Real-world evidences are still needed to investigate the risks of HZ among patients receiving different biologics treatments. This study aims to summarize the findings from cohort studies. Herein, we performed a meta-analysis of cohort studies. We included studies referred to seven biologics (adalimumab, alefacept, efalizumab, etanercept, infliximab, rituximab, and ustekinumab) as well as methotrexate for psoriasis. We estimated summary relative risks (RRs) for HZ using pairwise and network meta-analysis. Overall, five studies were included for analysis. A total of 32827.6 patient-years were observed. The result of the meta-analysis showed that the pooled HZ incidence rate of adalimumab, which accounts for the most patient-years in our analysis, is 2.6 per 1,000 patient-years. Our analysis based on several cohorts showed an insignificant difference among the patients receiving adalimumab, alefacept, efalizumab, etanercept, infliximab, rituximab, ustekinumab, and methotrexate. Based on this analysis, the type of mono-biologic treatment contributes little to the risk of HZ among psoriasis patients. Of note, the negative findings of our study do not mean the unnecessity of vaccination. More efforts must be taken to further determine HZ risk of different therapeutic strategies.
PubMed: 34150802
DOI: 10.3389/fmed.2021.665559 -
Journal of Fungi (Basel, Switzerland) Mar 2021Since 1985 when the first agent targeting antigens on the surface of lymphocytes was approved (muromonab-CD3), a multitude of such therapies have been used in children... (Review)
Review
Invasive Fungal Diseases in Children with Hematological Malignancies Treated with Therapies That Target Cell Surface Antigens: Monoclonal Antibodies, Immune Checkpoint Inhibitors and CAR T-Cell Therapies.
Since 1985 when the first agent targeting antigens on the surface of lymphocytes was approved (muromonab-CD3), a multitude of such therapies have been used in children with hematologic malignancies. A detailed literature review until January 2021 was conducted regarding pediatric patient populations treated with agents that target CD2 (alefacept), CD3 (bispecific T-cell engager [BiTE] blinatumomab), CD19 (denintuzumab mafodotin, B43, BiTEs blinatumomab and DT2219ARL, the immunotoxin combotox, and chimeric antigen receptor [CAR] T-cell therapies tisagenlecleucel and axicabtagene ciloleucel), CD20 (rituximab and biosimilars, Y-ibritumomab tiuxetan, ofatumumab, and obinutuzumab), CD22 (epratuzumab, inotuzumab ozogamicin, moxetumomab pasudotox, BiTE DT2219ARL, and the immunotoxin combotox), CD25 (basiliximab and inolimomab), CD30 (brentuximab vedotin and iratumumab), CD33 (gemtuzumab ozogamicin), CD38 (daratumumab and isatuximab), CD52 (alemtuzumab), CD66b (Y-labelled BW 250/183), CD248 (ontuxizumab) and immune checkpoint inhibitors against CTLA-4 (CD152; abatacept, ipilimumab and tremelimumab) or with PD-1/PD-L1 blockade (CD279/CD274; atezolizumab, avelumab, camrelizumab, durvalumab, nivolumab and pembrolizumab). The aim of this narrative review is to describe treatment-related invasive fungal diseases (IFDs) of each category of agents. IFDs are very common in patients under blinatumomab, inotuzumab ozogamicin, basiliximab, gemtuzumab ozogamicin, alemtuzumab, and tisagenlecleucel and uncommon in patients treated with moxetumomab pasudotox, brentuximab vedotin, abatacept, ipilimumab, pembrolizumab and avelumab. Although this new era of precision medicine shows promising outcomes of targeted therapies in children with leukemia or lymphoma, the results of this review stress the necessity for ongoing surveillance and suggest the need for antifungal prophylaxis in cases where IFDs are very common complications.
PubMed: 33807678
DOI: 10.3390/jof7030186 -
JCI Insight Feb 2021Clinical trials of biologic therapies in type 1 diabetes (T1D) aim to mitigate autoimmune destruction of pancreatic β cells through immune perturbation and serve as... (Randomized Controlled Trial)
Randomized Controlled Trial
Clinical trials of biologic therapies in type 1 diabetes (T1D) aim to mitigate autoimmune destruction of pancreatic β cells through immune perturbation and serve as resources to elucidate immunological mechanisms in health and disease. In the T1DAL trial of alefacept (LFA3-Ig) in recent-onset T1D, endogenous insulin production was preserved in 30% of subjects for 2 years after therapy. Given our previous findings linking exhausted-like CD8+ T cells to beneficial response in T1D trials, we applied unbiased analyses to sorted CD8+ T cells to evaluate their potential role in T1DAL. Using RNA sequencing, we found that greater insulin C-peptide preservation was associated with a module of activation- and exhaustion-associated genes. This signature was dissected into 2 CD8 memory phenotypes through correlation with cytometry data. These cells were hypoproliferative, shared expanded rearranged TCR junctions, and expressed exhaustion-associated markers including TIGIT and KLRG1. The 2 phenotypes could be distinguished by reciprocal expression of CD8+ T and NK cell markers (GZMB, CD57, and inhibitory killer cell immunoglobulin-like receptor [iKIR] genes), versus T cell activation and differentiation markers (PD-1 and CD28). These findings support previous evidence linking exhausted-like CD8+ T cells to successful immune interventions for T1D, while suggesting that multiple inhibitory mechanisms can promote this beneficial cell state.
Topics: Adolescent; Adult; Alefacept; C-Peptide; CD57 Antigens; CD8-Positive T-Lymphocytes; Child; Diabetes Mellitus, Type 1; Double-Blind Method; Female; Humans; Immunologic Factors; Immunologic Memory; Immunophenotyping; Killer Cells, Natural; Lectins, C-Type; Lymphocyte Activation; Male; Programmed Cell Death 1 Receptor; RNA-Seq; Receptors, Immunologic; Young Adult
PubMed: 33351781
DOI: 10.1172/jci.insight.142680 -
JCI Insight Jan 2021Transient partial remission, a period of low insulin requirement experienced by most patients soon after diagnosis, has been associated with mechanisms of immune...
Transient partial remission, a period of low insulin requirement experienced by most patients soon after diagnosis, has been associated with mechanisms of immune regulation. A better understanding of such natural mechanisms of immune regulation might identify new targets for immunotherapies that reverse type 1 diabetes (T1D). In this study, using Cox model multivariate analysis, we validated our previous findings that patients with the highest frequency of CD4+CD25+CD127hi (127-hi) cells at diagnosis experience the longest partial remission, and we showed that the 127-hi cell population is a mix of Th1- and Th2-type cells, with a significant bias toward antiinflammatory Th2-type cells. In addition, we extended these findings to show that patients with the highest frequency of 127-hi cells at diagnosis were significantly more likely to maintain β cell function. Moreover, in patients treated with alefacept in the T1DAL clinical trial, the probability of responding favorably to the antiinflammatory drug was significantly higher in those with a higher frequency of 127-hi cells at diagnosis than those with a lower 127-hi cell frequency. These data are consistent with the hypothesis that 127-hi cells maintain an antiinflammatory environment that is permissive for partial remission, β cell survival, and response to antiinflammatory immunotherapy.
Topics: Adolescent; Adult; Alefacept; CD4-Positive T-Lymphocytes; Child; Child, Preschool; Diabetes Mellitus, Type 1; Disease Progression; Female; Humans; Immunotherapy; Infant; Interleukin-2 Receptor alpha Subunit; Interleukin-7 Receptor alpha Subunit; Male; Multivariate Analysis; Proportional Hazards Models; T-Lymphocyte Subsets; Young Adult
PubMed: 33301420
DOI: 10.1172/jci.insight.136114 -
Diabetes Technology & Therapeutics Dec 2020Several immunotherapies have demonstrated endogenous insulin preservation in recent-onset type 1 diabetes (T1D). We considered the primary results of rituximab,...
Several immunotherapies have demonstrated endogenous insulin preservation in recent-onset type 1 diabetes (T1D). We considered the primary results of rituximab, abatacept, teplizumab, alefacept, high-dose antithymocyte globulin (ATG), low-dose ATG, and low-dose ATG ± granulocyte-colony-stimulating factor trials in an attempt to rank the effectiveness of the agents studied. C-peptide 2-h area under the curve means were modeled using analysis of covariance. The experimental treatment group effect for each study, compared with its internal control, was estimated after adjusting for baseline C-peptide and age. Percentage increase in C-peptide over placebo and the absolute difference within study were calculated to compare and contrast effect size among interventions. Low-dose ATG (55% and 103%) and teplizumab (48% and 63%) ranked highest in C-peptide preservation at 1 and 2 years, respectively. Low-dose ATG and teplizumab show the greatest impact on C-peptide preservation among recent new-onset T1D studies; these should be further explored as core immunotherapies in the T1D prevention setting.
Topics: Abatacept; Alefacept; Antibodies, Monoclonal, Humanized; Antilymphocyte Serum; C-Peptide; Clinical Trials as Topic; Diabetes Mellitus, Type 1; Granulocyte Colony-Stimulating Factor; Humans; Immunotherapy; Insulin; Insulin-Secreting Cells; Rituximab
PubMed: 32833543
DOI: 10.1089/dia.2020.0305 -
Frontiers in Immunology 2020The glycoprotein CD2 is a costimulatory receptor expressed mainly on T and NK cells that binds to LFA3, a cell surface protein expressed on e.g., antigen-presenting... (Review)
Review
The glycoprotein CD2 is a costimulatory receptor expressed mainly on T and NK cells that binds to LFA3, a cell surface protein expressed on e.g., antigen-presenting cells. CD2 has an important role in the formation and organization of the immunological synapse that is formed between T cells and antigen-presenting cells upon cell-cell conjugation and associated intracellular signaling. CD2 expression is upregulated on memory T cells as well as activated T cells and plays an important role in activation of memory T cells despite the coexistence of several other costimulatory pathways. Anti-CD2 monoclonal antibodies have been shown to induce immune modulatory effects and clinical studies have proven the safety and efficacy of CD2-targeting biologics. Investigators have highlighted that the lack of attention to the CD2/LFA3 costimulatory pathway is a . Overall, CD2 is an attractive target for monoclonal antibodies intended for treatment of pathologies characterized by undesired T cell activation and offers an avenue to more selectively target memory T cells while favoring immune regulation.
Topics: Animals; CD2 Antigens; Humans; Immunological Synapses; Lymphocyte Activation; T-Lymphocytes
PubMed: 32582179
DOI: 10.3389/fimmu.2020.01090 -
The AAPS Journal Mar 2020Despite decades of efforts to develop a pharmacotherapy for cocaine abuse treatment, there is still no FDA-approved treatment of diseases associated with this commonly...
Despite decades of efforts to develop a pharmacotherapy for cocaine abuse treatment, there is still no FDA-approved treatment of diseases associated with this commonly abused drug. Our previously designed highly efficient cocaine hydrolases (CocHs) and the corresponding Fc-fusion proteins (e.g., CocH3-Fc) are recognized as potentially promising therapeutic enzyme candidates for cocaine abuse treatment, but all with limited biological half-lives. In order to prolong the biological half-life and, thus, decrease the required frequency of the enzyme administration for cocaine abuse treatment, we have modeled the Fc-fusion CocH binding with neonatal Fc receptor (FcRn) in the present study. This approach led to the design and testing of CocH3-Fc(M6), a CocH3-Fc mutant with nearly 100-fold increased binding affinity: from K = ~ 4 μM to K = 43 nM. As a result, CocH3-Fc(M6) indeed revealed a markedly prolonged biological half-life (t = 206 ± 7 h or ~ 9 days) in rats, longer than other known Fc-fusion protein drugs such as abatacept and alefacept (for other therapeutic purposes) in the same species (rats). It has been demonstrated that a single dose of 3 mg/kg CocH3-Fc(M6) effectively blocked 20 mg/kg cocaine-induced hyperactivity on day 18 after CocH3-Fc(M6) administration. This is the first attempt to rationally design long-acting Fc-fusion enzyme mutant based on combined computational modeling and experimental measurement of the Fc-fusion CocH binding with FcRn. The similar structure-based design strategy may be used to prolong the biological half-lives of other Fc-fusion protein drugs.
Topics: Animals; Carboxylic Ester Hydrolases; Cocaine-Related Disorders; Drug Design; Drug Evaluation, Preclinical; Half-Life; Histocompatibility Antigens Class I; Male; Models, Molecular; Rats; Rats, Sprague-Dawley; Receptors, Fc; Recombinant Fusion Proteins; Recombinant Proteins
PubMed: 32189158
DOI: 10.1208/s12248-020-00442-3 -
Expert Review of Clinical Pharmacology Mar 2020: Primary endpoints and inclusion/exclusion criteria of biologics and small oral molecules for psoriasis treatment have been evolving due to a better understanding of... (Review)
Review
: Primary endpoints and inclusion/exclusion criteria of biologics and small oral molecules for psoriasis treatment have been evolving due to a better understanding of the pathogenesis and potential risks.: We analyzed the designs of key phase 3 pivotal trials of all biologics and small oral molecules approved for moderate to severe plaque psoriasis from published data on the ClinicalTrials.gov website and literature in the PubMed database. Alefacept, efalizumab, anti-tumor necrosis factors, anti-interleukin (IL)-12/IL-23, anti-IL-17 and anti-IL-23 inhibitors were discussed chronologically. Small oral molecules including tofacitinib and apremilast were also reviewed.: The primary endpoints of trials of biologics have been raised progressively and psoriasis area and severity index (PASI) 100 can now be readily achievable by the recent biologics. For safety, 5-year observation periods have become a gold standard after the report of progressive multifocal leukoencephalopathy after efalizumab. Also, the need for tuberculosis (TB) prophylaxis has also been relaxed in one trial of risankizumab. Small oral molecules are the future of affordable effective treatment for psoriasis, but the safety concerns must be overcome as reflected by their more stringent exclusion criteria. More biologic switch data and inclusion of patients previously excluded, e.g. viral hepatitis, are still needed.
Topics: Biological Products; Clinical Trials, Phase III as Topic; Dermatologic Agents; Endpoint Determination; Humans; Patient Selection; Psoriasis; Research Design; Severity of Illness Index
PubMed: 32167790
DOI: 10.1080/17512433.2020.1743175 -
Frontiers in Immunology 2018Elimination of the latent HIV reservoir remains the biggest hurdle to achieve HIV cure. In order to specifically eliminate HIV infected cells they must be...
Elimination of the latent HIV reservoir remains the biggest hurdle to achieve HIV cure. In order to specifically eliminate HIV infected cells they must be distinguishable from uninfected cells. CD2 was recently identified as a potential marker enriched in the HIV-1 reservoir on CD4+ T cells, the largest, longest-lived and best-characterized constituent of the HIV reservoir. We previously proposed to repurpose FDA-approved alefacept, a humanized α-CD2 fusion protein, to reduce the HIV reservoir in CD2hi CD4+ memory T cells. Here, we show the first evidence that alefacept can specifically target and reduce CD2hi HIV infected cells . We explore a variety of natural killer (NK) cells as mediators of antibody-dependent cell-mediated cytotoxicity (ADCC) including primary NK cells, expanded NK cells as well as the CD16 transduced NK-92 cell line which is currently under study in clinical trials as a treatment for cancer. We demonstrate that CD16.NK-92 has a natural preference to kill CD2hi CD45RA- memory T cells, specifically CD45RA- CD27+ central memory/transitional memory (T) subset in both healthy and HIV patient samples as well as to reduce HIV DNA from HIV samples from donors well controlled on antiretroviral therapy. Lastly, alefacept can combine with CD16.NK-92 to decrease HIV DNA in some patient samples and thus may yield value as part of a strategy toward sustained HIV remission.
Topics: Adoptive Transfer; Alefacept; Anti-HIV Agents; Antibody-Dependent Cell Cytotoxicity; Biomarkers; CD2 Antigens; CD4-Positive T-Lymphocytes; Cell Line; DNA, Viral; Drug Therapy, Combination; GPI-Linked Proteins; HIV Infections; HIV-1; Humans; Immunologic Memory; Jurkat Cells; Killer Cells, Natural; Leukocyte Common Antigens; Receptors, IgG; Tumor Necrosis Factor Receptor Superfamily, Member 7; Virus Latency
PubMed: 30455699
DOI: 10.3389/fimmu.2018.02552 -
The Australasian Journal of Dermatology Feb 2019A range of systemic treatments are used for alopecia areata with variable evidence supporting efficacy. In this systematic review, we evaluated the evidence surrounding...
A range of systemic treatments are used for alopecia areata with variable evidence supporting efficacy. In this systematic review, we evaluated the evidence surrounding systemic treatments for alopecia areata, alopecia totalis and alopecia universalis. A systematic search was conducted of the peer-reviewed literature published between 1946 and March 2018 via Medline, Embase, Amed, the Cochrane Central Register of Controlled Trials, PsychINFO and Lilacs. All randomised controlled trials (RCTs) that evaluated the effectiveness of systemic treatments for individuals with alopecia areata, totalis or universalis were included. Sixteen studies were included with a total of 768 participants. We found eight placebo-controlled RCTs, three RCTs comparing two systemic treatments and five RCTs comparing three treatments. A total of 15 different systemic therapies were investigated. The most frequently investigated therapy was oral prednisolone pulse therapy and oral inosiplex. There was significant variability in the definition of treatment success. No study evaluated the impact of pharmacotherapy on quality of life using complete quantitative quality of life instruments. Adverse events were reported in 13 studies and were corticosteroid related or otherwise well tolerated. Relapse rates were considerable in the four studies that reported this outcome. There is currently no specific systemic therapy that is supported by robust body of evidence from RCTs. The current evidence suggests efficacy of oral prednisolone pulse therapy and oral inosiplex. Evidence does not support the use of oral zinc sulphate, alefacept and efalizumab. Future RCTs should be adequately powered and employ clearly defined clinical response endpoints to allow future meta-analyses.
Topics: Adjuvants, Immunologic; Administration, Intravenous; Administration, Oral; Alopecia; Alopecia Areata; Antidepressive Agents; Biological Products; Complementary Therapies; Glucocorticoids; Humans; Inosine Pranobex; Prednisolone; Randomized Controlled Trials as Topic
PubMed: 30191561
DOI: 10.1111/ajd.12913