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Mesenchymal Stem Cell Therapy for Inflammatory Bowel Disease: A Systematic Review and Meta-analysis.Inflammatory Bowel Diseases Nov 2015Recent advances in inflammatory bowel disease (IBD) therapeutics include novel medical, surgical, and endoscopic treatments. Among these, stem cell therapy is still in... (Meta-Analysis)
Meta-Analysis Review
Recent advances in inflammatory bowel disease (IBD) therapeutics include novel medical, surgical, and endoscopic treatments. Among these, stem cell therapy is still in its infancy, although multiple studies suggest that the immunomodulatory effect of stem cell therapy may reduce inflammation and tissue injury in patients with IBD. This review discusses the novel avenue of stem cell therapy and its potential role in the management of ulcerative colitis and Crohn's disease. We conducted a comprehensive literature search to identify studies examining the role of stem cell therapy (without conditioning and immunomodulatory regimens) in IBD. Taken together, these studies suggest a promising role for stem cell therapy in IBD although the substantial challenges, such as cost and inadequate/incomplete characterization of effect, limit their current use in clinical practice.
Topics: Animals; Colitis, Ulcerative; Crohn Disease; Genetic Therapy; Humans; Mesenchymal Stem Cell Transplantation; Mice
PubMed: 26230863
DOI: 10.1097/MIB.0000000000000543 -
Journal For Immunotherapy of Cancer Jul 2021With rapid advances in our understanding of cancer, there is an expanding number of potential novel combination therapies, including novel-novel combinations.... (Review)
Review
With rapid advances in our understanding of cancer, there is an expanding number of potential novel combination therapies, including novel-novel combinations. Identifying which combinations are appropriate and in which subpopulations are among the most difficult questions in medical research. We conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-guided systematic review of trials of novel-novel combination therapies involving immunotherapies or molecular targeted therapies in advanced solid tumors. A MEDLINE search was conducted using a modified Cochrane Highly Sensitive Search Strategy for published clinical trials between July 1, 2017, and June 30, 2020, in the top-ranked medical and oncology journals. Trials were evaluated according to a criterion adapted from previously published Food and Drug Administration guidance and other key considerations in designing trials of combinations. This included the presence of a strong biological rationale, the use of a new established or emerging predictive biomarker prospectively incorporated into the clinical trial design, appropriate comparator arms of monotherapy or supportive external data sources and a primary endpoint demonstrating a clinically meaningful benefit. Of 32 identified trials, there were 11 (34%) trials of the novel-novel combination of anti-programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) and anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) therapy, and 10 (31%) trials of anti-PD-1/PD-L1 and anti-vascular endothelial growth factor (VEGF) combination therapy. 20 (62.5%) trials were phase II trials, while 12 (37.5%) were phase III trials. Most (72%) trials lacked significant preclinical evidence supporting the development of the combination in the given indication. A majority of trials (69%) were conducted in biomarker unselected populations or used pre-existing biomarkers within the given indication for patient selection. Most studies (66%) were considered to have appropriate comparator arms or had supportive external data sources such as prior studies of monotherapy. All studies were evaluated as selecting a clinically meaningful primary endpoint. In conclusion, designing trials to evaluate novel-novel combination therapies presents numerous challenges to demonstrate efficacy in a comprehensive manner. A greater understanding of biological rationale for combinations and incorporating predictive biomarkers may improve effective evaluation of combination therapies. Innovative statistical methods and increasing use of external data to support combination approaches are potential strategies that may improve the efficiency of trial design. Designing trials to evaluate novel-novel combination therapies presents numerous challenges to demonstrate efficacy in a comprehensive manner. A greater understanding of biological rationale for combinations and incorporating predictive biomarkers may improve effective evaluation of combination therapies. Innovative statistical methods and increasing use of external data to support combination approaches are potential strategies that may improve the efficiency of trial design.
Topics: Combined Modality Therapy; Humans; Immunotherapy; Neoplasms
PubMed: 34215688
DOI: 10.1136/jitc-2021-002459 -
BMC Pregnancy and Childbirth May 2019Preeclampsia remains a significant danger to both mother and child and current prevention and treatment management strategies are limited. The objective of this... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Preeclampsia remains a significant danger to both mother and child and current prevention and treatment management strategies are limited. The objective of this systematic review was to investigate the current literature on evidence for the use of the regenerative capacity of mesenchymal stem cell (MSC) therapy, the anticoagulant activity of antithrombin (AT), or the free radical scavenging activity of alpha-1-microglobulin (A1M) as potential novel treatments for severe preeclampsia and Hemolysis, Elevated Liver enzymes, Low Platelet count (HELLP).
METHOD
We conducted a systematic review of potential biological therapies for preeclampsia. We screened MEDLINE and Embase from inception through May 2017 for studies using AT, A1M or MSCs as potential treatments for preeclampsia and/or HELLP. A meta-analysis was performed to pool data from randomized control trials (RCTs) with homogenous outcomes using the inverse variance method. The Newcastle-Ottawa Scale, the Cochrane risk of bias tool for RCTs, and SYRCLE's risk of bias tool for animal studies were used to investigate potential bias of studies.
RESULTS
The literature search retrieved a total of 1015 articles, however, only 17 studies met the selection criteria: AT (n = 9, 8 human and 1 animal); A1M (n = 4, 3 animal and 1 ex-vivo); and, MSCs (n = 4, 3 animal and 1 ex-vivo). A meta-analysis of AT therapy versus placebo and a meta-analysis for AT therapy with heparin versus heparin alone did not show significant differences between study groups. Animal and ex-vivo studies demonstrated significant benefits in relevant outcomes for A1M and MSCs versus control treatments. Most RCT studies were rated as having a low risk of bias across categories with some studies showing an unclear risk of bias in some categories. The two cohort studies both received a total of four out of nine stars (a rating of "poor" quality). Most animal studies had an unclear risk of bias across most categories, with some studies having a low risk of bias in some categories.
CONCLUSIONS
The findings of this review are strengthened by rigorous systematic search and review of the literature. Results of our meta-analyses do not currently warrant further exploration of AT as a treatment of preeclampsia in human trials. Results of animal and ex-vivo studies of A1M and MSCs were encouraging and supportive of initiating human investigations.
Topics: Alpha-Globulins; Animals; Anticoagulants; Antithrombins; Biological Therapy; Female; Free Radical Scavengers; Humans; Mesenchymal Stem Cell Transplantation; Pre-Eclampsia; Pregnancy; Randomized Controlled Trials as Topic
PubMed: 31072315
DOI: 10.1186/s12884-019-2268-9 -
Frontiers in Immunology 2023We conducted a systematic review and meta-analysis to evaluate outcomes following chimeric antigen receptor T cell (CAR-T) therapy in relapsed/refractory acute myeloid... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
We conducted a systematic review and meta-analysis to evaluate outcomes following chimeric antigen receptor T cell (CAR-T) therapy in relapsed/refractory acute myeloid leukemia (RR-AML).
METHODS
We performed a literature search on PubMed, Cochrane Library, and Clinicaltrials.gov. After screening 677 manuscripts, 13 studies were included. Data was extracted following PRISMA guidelines. Pooled analysis was done using the meta-package by Schwarzer et al. Proportions with 95% confidence intervals (CI) were computed.
RESULTS
We analyzed 57 patients from 10 clinical trials and 3 case reports. The pooled complete and overall response rates were 49.5% (95% CI 0.18-0.81, I=65%) and 65.2% (95% CI 0.36-0.91, I=57%). The pooled incidence of cytokine release syndrome, immune-effector cell associated neurotoxicity syndrome, and graft-versus-host disease was estimated as 54.4% (95% CI 0.17-0.90, I=77%), 3.9% (95% CI 0.00-0.19, I=22%), and 1.6% (95%CI 0.00-0.21, I=33%), respectively.
CONCLUSION
CAR-T therapy has demonstrated modest efficacy in RR-AML. Major challenges include heterogeneous disease biology, lack of a unique targetable antigen, and immune exhaustion.
Topics: Humans; Receptors, Chimeric Antigen; Antigens, CD19; Immunotherapy, Adoptive; Leukemia, Myeloid, Acute; Cell- and Tissue-Based Therapy
PubMed: 37168849
DOI: 10.3389/fimmu.2023.1152457 -
Stem Cell Research & Therapy Nov 2021Lymphedema, the accumulation of interstitial fluid caused by poor lymphatic drainage, is a progressive and permanent disease with no curative treatment. Several studies... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Lymphedema, the accumulation of interstitial fluid caused by poor lymphatic drainage, is a progressive and permanent disease with no curative treatment. Several studies have evaluated cell-based therapies in secondary lymphedema, but no meta-analysis has been performed to assess their efficacy.
METHODS
We conducted a systematic review and meta-analysis of all available preclinical and clinical studies, with assessment of their quality and risk of bias.
RESULTS
A total of 20 articles using diverse cell types were selected for analysis, including six clinical trials and 14 pre-clinical studies in three species. The meta-analysis showed a positive effect of cell-based therapies on relevant disease outcomes (quantification of edema, density of lymphatic capillaries, evaluation of the lymphatic flow, and tissue fibrosis). No significant publication bias was observed.
CONCLUSION
Cell-based therapies have the potential to improve secondary lymphedema. The underlying mechanisms remain unclear. Due to relevant heterogeneity between studies, further randomized controlled and blinded studies are required to substantiate the use of these novel therapies in clinical practice.
Topics: Cell- and Tissue-Based Therapy; Humans; Lymphedema
PubMed: 34801084
DOI: 10.1186/s13287-021-02632-y -
Frontiers in Immunology 2023Cytokines are pivotal mediators of cell communication in the tumor microenvironment. Multiple cytokines are involved in the host antitumor response, but the production... (Review)
Review
Cytokines are pivotal mediators of cell communication in the tumor microenvironment. Multiple cytokines are involved in the host antitumor response, but the production and function of these cytokines are usually dysregulated during malignant tumor progression. Considering their clinical potential and the early successful use of cytokines in cancer immunotherapy, such as interferon alpha-2b (IFNα-2b; IntronA) and IL-2 (Proleukin), cytokine-based therapeutics have been extensively evaluated in many follow-up clinical trials. Following these initial breakthroughs, however, clinical translation of these natural messenger molecules has been greatly limited owing to their high-degree pleiotropic features and complex biological properties in many cell types. These characteristics, coupled with poor pharmacokinetics (a short half-life), have hampered the delivery of cytokines via systemic administration, particularly because of severe dose-limiting toxicities. New engineering approaches have been developed to widen the therapeutic window, prolong pharmacokinetic effects, enhance tumor targeting and reduce adverse effects, thereby improving therapeutic efficacy. In this review, we focus on the recent progress and competitive landscape in cytokine engineering strategies and preclinical/clinical therapeutics for cancer. In addition, aiming to promote engineered cytokine-based cancer immunotherapy, we present a profound discussion about the feasibility of recently developed methods in clinical medicine translation.
Topics: Humans; Cytokines; Neoplasms; Immunotherapy; Tumor Microenvironment
PubMed: 37483629
DOI: 10.3389/fimmu.2023.1218082 -
Italian Journal of Pediatrics Jul 2023Robust routine immunization schedules for pertussis-containing vaccines have been applied for years, but pertussis outbreaks remain a worldwide problem. This study aimed... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Robust routine immunization schedules for pertussis-containing vaccines have been applied for years, but pertussis outbreaks remain a worldwide problem. This study aimed to investigate the association between vaccine hesitancy and pertussis in infants and children.
METHODS
We searched PubMed, Cochrane, Web of Science, Embase, and China National Knowledge Internet for studies published between January 2012 and June 2022. This study included case-control and cohort studies that assessed the association between childhood/maternal vaccine hesitancy and odds ratios (ORs), risk ratios (RRs), and vaccine effectiveness (VE) related to pertussis in infants and children [Formula: see text] 9 years old. ORs/VEs with a 95% confidence interval (CI) were calculated. Random-effects meta-analysis models were used for appropriate pooled estimates, and heterogeneity was assessed using [Formula: see text]. Cumulative meta-analysis and subgroup analyses stratified by study characteristics were performed.
RESULTS
Twenty-two studies were included, with a mean quality score of 7.0 (range 6.0-9.0). Infants and children with pertussis were associated with higher vaccine hesitancy to all doses (OR = 4.12 [95% CI: 3.09-5.50]). The highest OR was between children who were unvaccinated over four doses and children who were fully vaccinated (OR = 14.26 [95%CI: 7.62-26.70]); childhood vaccine delay was not statistically significantly associated with pertussis risk (OR = 1.18 [95% CI: 0.74-1.89]). Maternal vaccine hesitancy was associated with significantly higher pertussis risk in infants aged 2 and 3 months old, with higher pertussis ORs in infants [Formula: see text] 2 months old (OR = 6.02 [95%CI: 4.31-8.50], OR = 5.14 [95%CI: 1.95-13.52] for infants [Formula: see text] 2 and [Formula: see text] 3 months old, respectively). Maternal and childhood VEs were high in reducing pertussis infection in infants and children. The administration time of maternal vaccination had little effect on VE.
CONCLUSION
Vaccine hesitancy increased pertussis risks in infants and children. Ensuring that children receive up-to-date pertussis vaccines is essential; short delays in receiving childhood vaccinations may be unimportant. Maternal vaccinations for pertussis should be encouraged.
Topics: Child; Infant; Humans; Whooping Cough; Vaccination Hesitancy; Vaccination; Immunization Schedule; Vaccines
PubMed: 37443026
DOI: 10.1186/s13052-023-01495-8 -
Nature Communications Dec 2020Cell and gene therapies offer opportunities for treating disease with potential to restore function, and cure disease. However, they are not without risk and pose...
Cell and gene therapies offer opportunities for treating disease with potential to restore function, and cure disease. However, they are not without risk and pose complex logistical, economic, ethical and social challenges for health systems. Here we report our systematic review of the current evidence on patient and public knowledge and perspectives of cell and gene therapies, to inform future research, education and awareness raising activities. We screened 10,735 titles and abstracts, and evaluated the full texts of 151 publications. The final selection was 35 publications. Four themes were generated from the narrative synthesis of the study findings namely: (1) Knowledge and understanding of cell and gene therapies, (2) Acceptance of cell and gene therapies (3) Understanding of risk and benefits of therapy, and (4) Information needs and current sources of information. As potential funders or future recipients, it is important that the public and patients are aware of these therapies, understand the issues involved, and can contribute to the debate. This review highlights the need for appropriate patient and public education on the various aspects of cell and gene therapies. High quality studies exploring patient and public opinions and experiences of cell and gene therapy are required. Patient and public perceptions of these therapies, alongside evidence of clinical and cost-effectiveness, will be central to their uptake and use.
Topics: Cell Transplantation; Cost-Benefit Analysis; Delivery of Health Care; Genetic Therapy; Health Education; Humans; Patient Education as Topic; Public Opinion; Qualitative Research
PubMed: 33293538
DOI: 10.1038/s41467-020-20096-1 -
Medicine Mar 2016To establish the comparative effectiveness of all available biologic therapy regimens for ankylosing spondylitis, we performed a systematic review and a Bayesian network... (Comparative Study)
Comparative Study Meta-Analysis Review
To establish the comparative effectiveness of all available biologic therapy regimens for ankylosing spondylitis, we performed a systematic review and a Bayesian network meta-analysis of randomized controlled trials. PubMed, Medline, Embase, Cochrane library, and ClinicalTrials.gov were searched from the inception of each database to June 2015. Systematic review and network meta-analysis was reported according to the Preferred Reporting Items of Systematic Reviews and Meta-Analyses Extension Statement for Reporting of Systematic Reviews Incorporating Network Meta-analyses. The primary outcome was 20% improvement of Assessments in SpondyloArthritis International Society Response Criteria (ASAS20) at Week 12 or 14; secondary outcomes were ASAS40, ASAS5/6, ASAS partial remission and 50% improvement in baseline Bath ankylosing spondylitis (AS) disease activity index. We reported relative risks and 95% confidence intervals from direct meta-analysis and 95% credible intervals from Bayesian network meta-analysis, and ranked the treatment for outcomes. We also used Grading of Recommendations Assessment, Development and Evaluation criteria to appraise quality of evidence. Fourteen RCTs comprising 2672 active AS patients were included in the network meta-analysis. Most biologic therapy regimens were more effective than placebo regarding all the outcomes assessed, except for secukinumab and tocilizumab. No differences between biologic therapies in the treatment of AS could be found, except for the finding that infliximab 5 mg was superior to tocilizumab. Infliximab 5 mg/kg had the highest probability of being ranked the best for achieving ASAS20, whereas notably, secukinumab had the highest probability of being ranked the second best. Our study suggests that no differences between biologic therapies in the treatment of AS could be found except that infliximab 5 mg was superior to tocilizumab. Infliximab 5 mg/kg seems to be the better biologic therapy regimen for AS. Secukinumab appears promising, though additional data is warranted. Nevertheless, these interpretations should be accepted very cautiously.
Topics: Biological Therapy; Humans; Spondylitis, Ankylosing; Treatment Outcome
PubMed: 26986130
DOI: 10.1097/MD.0000000000003060 -
Gene Therapy Sep 2022Spinal muscular atrophy (SMA) is a severe childhood neuromuscular disease for which two genetic therapies, Nusinersen (Spinraza, an antisense oligonucleotide), and... (Meta-Analysis)
Meta-Analysis
Spinal muscular atrophy (SMA) is a severe childhood neuromuscular disease for which two genetic therapies, Nusinersen (Spinraza, an antisense oligonucleotide), and AVXS-101 (Zolgensma, an adeno-associated viral vector of serotype 9 AAV9), have recently been approved. We investigated the pre-clinical development of SMA genetic therapies in rodent models and whether this can predict clinical efficacy. We have performed a systematic review of relevant publications and extracted median survival and details of experimental design. A random effects meta-analysis was used to estimate and compare efficacy. We stratified by experimental design (type of genetic therapy, mouse model, route and time of administration) and sought any evidence of publication bias. 51 publications were identified containing 155 individual comparisons, comprising 2573 animals in total. Genetic therapies prolonged survival in SMA mouse models by 3.23-fold (95% CI 2.75-3.79) compared to controls. Study design characteristics accounted for significant heterogeneity between studies and greatly affected observed median survival ratios. Some evidence of publication bias was found. These data are consistent with the extended average lifespan of Spinraza- and Zolgensma-treated children in the clinic. Together, these results support that SMA has been particularly amenable to genetic therapy approaches and highlight SMA as a trailblazer for therapeutic development.
Topics: Animals; Disease Models, Animal; Genetic Therapy; Mice; Muscular Atrophy, Spinal; Oligonucleotides, Antisense; Rodentia; Treatment Outcome
PubMed: 34611322
DOI: 10.1038/s41434-021-00292-4