Cellular therapies for the treatment of immune-mediated GI and liver disease

Abstract Introduction Immune-mediated liver and gastrointestinal diseases are chronic conditions that lack curative treatments. Despite advances in the understanding and treatment of these conditions, they frequently remain refractory to treatment and represent a significant unmet need. Cellular therapies are an emerging option and hold the potential to have a major impact. Data sources A literature review was carried out using Pubmed. Keywords used for search were ‘ATMP’, ‘immune mediated’, ‘autoimmune liver disease’ and ‘immune mediated gastrointestinal conditions’, ‘cell therapy’, ‘MSC’, ‘HSCT’, ‘Regulatory T cells’, ‘GVHD’, ‘Coeliac disease’ ‘IBD’, ‘PSC’, ‘AIH’, ‘PBC’. No new data were generated or analysed in support of this review. Areas of agreement There is substantial evidence from clinical trials to support the use of cell therapies as a treatment for immune-mediated liver and gastrointestinal conditions. Cellular therapy products have the ability to ‘reset’ the dysregulated immune system and this in turn can offer a longer term remission. There are ongoing clinical trials with mesenchymal stromal cells (MSCs) and other cells to evidence their efficacy profile and fill the gaps in current knowledge. Insights gained will inform future trial designs and subsequent therapeutic applications. Areas of controversy There remains some uncertainty around the extrapolation of results from animal studies to clinical trials. Longevity of the therapeutic effects seen after the use of cell therapy needs to be scrutinized further. Heterogeneity in the selection of cells, source, methods of productions and cell administration pose challenges to the interpretation of the data. Growing points MSCs are emerging as a key therapeutic cells in immune-mediated liver and gastrointestinal conditions. Ongoing trials with these cells will provide new insights and a better understanding thus informing future larger scale studies. Areas timely for developing research Larger scale clinical trials to build on the evidence from small studies regarding safety and efficacy of cellular therapy are still needed before cellular therapies can become off the shelf treatments. Alignment of academia and industry to standardize the processes involved in cell selection, manipulation and expansion and subsequent use in clinical trials is an important avenue to explore further.

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New trends in cellular therapy

Development ◽

10.1242/dev.192567 ◽

2020 ◽

Vol 147 (18) ◽

pp. dev192567 ◽

Cited By ~ 3

Author(s):

Hideyuki Okano ◽

Doug Sipp

Keyword(s):

Stem Cells ◽

Clinical Trials ◽

Cell Therapy ◽

Pluripotent Stem Cells ◽

Clinical Studies ◽

Cellular Therapy ◽

Current Status ◽

Cellular Therapies ◽

Safety Issues ◽

Regenerative Therapies

ABSTRACTRegenerative therapies, including both gene and cellular therapies, aim to induce regeneration of cells, tissues and organs and restore their functions. In this short Spotlight, we summarize the latest advances in cellular therapies using pluripotent stem cells (PSCs), highlighting the current status of clinical trials using induced (i)PSC-derived cells. We also discuss the different cellular products that might be used in clinical studies, and consider safety issues and other challenges in iPSC-based cell therapy.

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Melatonin in Cancer Treatment: Current Knowledge and Future Opportunities

Molecules ◽

10.3390/molecules26092506 ◽

2021 ◽

Vol 26 (9) ◽

pp. 2506

Author(s):

Wamidh H. Talib ◽

Ahmad Riyad Alsayed ◽

Alaa Abuawad ◽

Safa Daoud ◽

Asma Ismail Mahmod

Keyword(s):

Clinical Trials ◽

Current Knowledge ◽

Biological Activities ◽

Experimental Studies ◽

Therapeutic Effects ◽

Cell Proliferation Inhibition ◽

Different Types ◽

Solid Foundation

Melatonin is a pleotropic molecule with numerous biological activities. Epidemiological and experimental studies have documented that melatonin could inhibit different types of cancer in vitro and in vivo. Results showed the involvement of melatonin in different anticancer mechanisms including apoptosis induction, cell proliferation inhibition, reduction in tumor growth and metastases, reduction in the side effects associated with chemotherapy and radiotherapy, decreasing drug resistance in cancer therapy, and augmentation of the therapeutic effects of conventional anticancer therapies. Clinical trials revealed that melatonin is an effective adjuvant drug to all conventional therapies. This review summarized melatonin biosynthesis, availability from natural sources, metabolism, bioavailability, anticancer mechanisms of melatonin, its use in clinical trials, and pharmaceutical formulation. Studies discussed in this review will provide a solid foundation for researchers and physicians to design and develop new therapies to treat and prevent cancer using melatonin.

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946 Standardized transcriptional profiling for optimizing cellular therapies: a multi-center PICI-NanoString collaboration

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-sitc2021.946 ◽

2021 ◽

Vol 9 (Suppl 3) ◽

pp. A995-A995

Author(s):

Sarah Church ◽

Christina Bailey ◽

Sarah Warren ◽

Lisa Butterfield

Keyword(s):

Cell Therapy ◽

Cellular Therapy ◽

Expression Profiles ◽

Network Cell ◽

Cellular Therapies ◽

Cancer Data ◽

Individual Site ◽

Essential Components ◽

Study Gene Expression ◽

Car T

BackgroundThe field of cellular therapy remains one of the most promising areas for the development of new cancer treatments. To further these improvements, it is imperative to broadly understand cell therapy products at the molecular level and to identify factors that contribute to their efficacy. NanoString and the Parker Institute for Cancer Immunotherapy (PICI) have established a ground-breaking collaboration to characterize up to 1,000 apheresis and cellular therapy infusion products with the primary goal to dissect and study molecular pathways that correlate with optimal cellular therapies.MethodsUsing a large and diverse sample cohort collected from eight PICI network Cell Therapy Centers the team will aim to study gene expression profiles (GEP) that correlate with optimal apheresis and downstream cellular products, identifying biomarkers and signatures for clinical response or toxicity and further explore unique cancer-specific and shared characteristics that make an optimal and effective chimeric antigen receptor (CAR) T cell. As shown here, this first of its kind study will include samples that target dozens of different antigens covering both primary and metastatic hematological and solid tumors. Samples will be characterized using the standardized set of genes included in the nCounter CAR-T Characterization Panel and will measure essential components of CAR-T including: metabolic fitness, phenotype, TCR diversity, toxicity, activation, persistence, exhaustion and cell typing along with individual transgene expression.ResultsPresented here are initial questions that will be asked as part of this study. Meta-analysis will be performed as an aggregated set of data and individual site-specific analysis. Data will further be analyzed across individual cancer types, target types, outcome and manufacturing conditions as examples. We anticipate this information will prove useful across many aspects of the development, manufacturing and clinical applications for cellular therapies and further hypothesize that these findings will promote the understanding of pathways affecting safety and efficacy that may help optimize the therapy.ConclusionsThe project is anticipated to begin Fall of 2021 with work continuing in phases through 2022 with periodic data reports to be shared through scientific conferences. All data and findings will be made publicly available to the scientific community through PICI’s Cancer Data and Evidence Library analysis platform (CANDEL).

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Therapeutic effect and safety of stem cell therapy for chronic liver disease: a systematic review and meta-analysis of randomized controlled trials

Stem Cell Research & Therapy ◽

10.1186/s13287-020-01935-w ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Guang-Peng Zhou ◽

Yi-Zhou Jiang ◽

Li-Ying Sun ◽

Zhi-Jun Zhu

Keyword(s):

Stem Cell ◽

Liver Disease ◽

Adverse Events ◽

Cell Therapy ◽

Stem Cell Therapy ◽

Meta Analysis ◽

Chronic Liver ◽

Controlled Trials ◽

Therapeutic Effects ◽

Term Survival

Abstract Background Stem cell therapy is becoming an emerging therapeutic option for chronic liver disease (CLD). However, whether stem cell therapy is more effective than conventional treatment remains questionable. We performed a large-scale meta-analysis of randomized controlled trials (RCTs) to evaluate the therapeutic effects and safety of stem cell therapy for CLD. Methods We systematically searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov databases for the period from inception through March 16, 2020. Primary outcomes were all-cause mortality and adverse events related to stem cell therapy. Secondary outcomes included the model for end-stage liver disease score, total bilirubin, albumin, alanine aminotransferase, prothrombin activity, and international normalized ratio. The standardized mean difference (SMD) and odds ratio (OR) with 95% confidence interval (CI) were calculated using a random-effects model. Results Twenty-four RCTs were included and the majority of these studies showed a high risk of bias. The meta-analysis indicated that compared with conventional treatment, stem cell therapy was associated with improved survival and liver function including the model of end-stage liver disease score, total bilirubin, and albumin levels. However, it had no obvious beneficial effects on alanine aminotransferase level, prothrombin activity, and international normalized ratio. Subgroup analyses showed stem cell therapy conferred a short-term survival benefit for patients with acute-on-chronic liver failure (ACLF), a single injection was more effective than multiple injections, hepatic arterial infusion was more effective than intravenous infusion, and bone marrow-derived stem cells were more effective than those derived from the umbilical cord. Thirteen trials reported adverse events related to stem cell therapy, but no serious adverse events were reported. Conclusions Stem cell therapy is a safe and effective therapeutic option for CLD, while patients with ACLF benefit the most in terms of improved short-term survival. A single injection administration of bone marrow-derived stem cells via the hepatic artery has superior therapeutic effects.

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Regenerative Cardiovascular Therapies: Stem Cells and Beyond

International Journal of Molecular Sciences ◽

10.3390/ijms20061420 ◽

2019 ◽

Vol 20 (6) ◽

pp. 1420 ◽

Cited By ~ 17

Author(s):

Bernhard Wernly ◽

Moritz Mirna ◽

Richard Rezar ◽

Christine Prodinger ◽

Christian Jung ◽

...

Keyword(s):

Stem Cells ◽

Clinical Trials ◽

Stem Cell ◽

Cell Therapy ◽

Stem Cell Therapy ◽

Basic Science ◽

Left Ventricular ◽

Specific Cell ◽

Therapeutic Effects ◽

Cell Processing

Although reperfusion therapy has improved outcomes, acute myocardial infarction (AMI) is still associated with both significant mortality and morbidity. Once irreversible myocardial cell death due to ischemia and reperfusion sets in, scarring leads to reduction in left ventricular function and subsequent heart failure. Regenerative cardiovascular medicine experienced a boost in the early 2000s when regenerative effects of bone marrow stem cells in a murine model of AMI were described. Translation from an animal model to stem cell application in a clinical setting was rapid and the first large trials in humans suffering from AMI were conducted. However, high initial hopes were early shattered by inconsistent results of randomized clinical trials in patients suffering from AMI treated with stem cells. Hence, we provide an overview of both basic science and clinical trials carried out in regenerative cardiovascular therapies. Possible pitfalls in specific cell processing techniques and trial design are discussed as these factors influence both basic science and clinical outcomes. We address possible solutions. Alternative mechanisms and explanations for effects seen in both basic science and some clinical trials are discussed here, with special emphasis on paracrine mechanisms via growth factors, exosomes, and microRNAs. Based on these findings, we propose an outlook in which stem cell therapy, or therapeutic effects associated with stem cell therapy, such as paracrine mechanisms, might play an important role in the future. Optimizing stem cell processing and a better understanding of paracrine signaling as well as its effect on cardioprotection and remodeling after AMI might improve not only AMI research, but also our patients’ outcomes.

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Potential Effects of Coronaviruses on the Liver: An Update

Frontiers in Medicine ◽

10.3389/fmed.2021.651658 ◽

2021 ◽

Vol 8 ◽

Author(s):

Xinyi Wang ◽

Jianyong Lei ◽

Zhihui Li ◽

Lunan Yan

Keyword(s):

Clinical Trials ◽

Liver Disease ◽

Liver Injury ◽

Severe Acute Respiratory Syndrome ◽

Respiratory Tract ◽

Liver Diseases ◽

Direct Damage ◽

Animal Trials ◽

Immune Mediated ◽

Coronavirus Infection

The coronaviruses that cause notable diseases, namely, severe acute respiratory syndrome (SARS), middle east respiratory syndrome (MERS) and coronavirus disease 2019 (COVID-19), exhibit remarkable similarities in genomic components and pathogenetic mechanisms. Although coronaviruses have widely been studied as respiratory tract pathogens, their effects on the hepatobiliary system have seldom been reported. Overall, the manifestations of liver injury caused by coronaviruses typically involve decreased albumin and elevated aminotransferase and bilirubin levels. Several pathophysiological hypotheses have been proposed, including direct damage, immune-mediated injury, ischemia and hypoxia, thrombosis and drug hepatotoxicity. The interaction between pre-existing liver disease and coronavirus infection has been illustrated, whereby coronaviruses influence the occurrence, severity, prognosis and treatment of liver diseases. Drugs and vaccines used for treating and preventing coronavirus infection also have hepatotoxicity. Currently, the establishment of optimized therapy for coronavirus infection and liver disease comorbidity is of significance, warranting further safety tests, animal trials and clinical trials.

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Cell Therapy for Retinal Dystrophies: From Cell Suspension Formulation to Complex Retinal Tissue Bioengineering

Stem Cells International ◽

10.1155/2019/4568979 ◽

2019 ◽

Vol 2019 ◽

pp. 1-14 ◽

Cited By ~ 8

Author(s):

Karim Ben M’Barek ◽

Christelle Monville

Keyword(s):

Cell Therapy ◽

Current Knowledge ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Age Related Macular Degeneration ◽

Future Research ◽

Therapeutic Effects ◽

Primary Defect ◽

Retinal Tissue ◽

Age Related

Retinal degeneration is an irreversible phenomenon caused by various disease conditions including age-related macular degeneration (AMD) and retinitis pigmentosa (RP). During the course of these diseases, photoreceptors (PRs) are susceptible to degeneration due to their malfunctions or to a primary dysfunction of the retinal pigment epithelium (RPE). Once lost, these cells could not be endogenously regenerated in humans, and cell therapy to replace the lost cells is one of the promising strategies to recover vision. Depending on the nature of the primary defect and the stage of the disease, RPE cells, PRs, or both might be transplanted to achieve therapeutic effects. We describe in this review the current knowledge and recent progress to develop such approaches. The different cell sources proposed for cell therapy including human pluripotent stem cells are presented with their advantages and limits. Another critical aspect described herein is the pharmaceutical formulation of the end product to be delivered into the eye of patients. Finally, we also outline the future research directions in order to develop a complex multilayered retinal tissue for end-stage patients.

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Neuroimmune Interactions in the Gut and Their Significance for Intestinal Immunity

Cells ◽

10.3390/cells8070670 ◽

2019 ◽

Vol 8 (7) ◽

pp. 670 ◽

Cited By ~ 13

Author(s):

David J. Brinkman ◽

Anne S. ten Hove ◽

Margriet J. Vervoordeldonk ◽

Misha D. Luyer ◽

Wouter J. de Jonge

Keyword(s):

Clinical Trials ◽

Nervous System ◽

Immune System ◽

Current Knowledge ◽

Unmet Need ◽

Autonomic Nerves ◽

Intestinal Immunity ◽

Intestinal Immune System ◽

Bowel Diseases ◽

Inflammatory Processes

Inflammatory bowel diseases (IBD) have a complex, multifactorial pathophysiology with an unmet need for effective treatment. This calls for novel strategies to improve disease outcome and quality of life for patients. Increasing evidence suggests that autonomic nerves and neurotransmitters, as well as neuropeptides, modulate the intestinal immune system, and thereby regulate the intestinal inflammatory processes. Although the autonomic nervous system is classically divided in a sympathetic and parasympathetic branch, both play a pivotal role in the crosstalk with the immune system, with the enteric nervous system acting as a potential interface. Pilot clinical trials that employ vagus nerve stimulation to reduce inflammation are met with promising results. In this paper, we review current knowledge on the innervation of the gut, the potential of cholinergic and adrenergic systems to modulate intestinal immunity, and comment on ongoing developments in clinical trials.

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Cell Therapy for Liver Disease: From Promise to Reality

Seminars in Liver Disease ◽

10.1055/s-0040-1717096 ◽

2020 ◽

Vol 40 (04) ◽

pp. 411-426

Author(s):

Sheeba Khan ◽

Reenam S. Khan ◽

Philip N. Newsome

Keyword(s):

Liver Disease ◽

Cell Therapy ◽

Molecular Mechanisms ◽

Treatment Options ◽

Autologous Bone Marrow ◽

Cell Types ◽

Good Manufacturing Practice ◽

Cell Populations ◽

Therapeutic Effects ◽

Cell Therapies

AbstractOver the last decade, there has been a considerable progress in the development of cell therapy products for the treatment of liver diseases. The quest to generate well-defined homogenous cell populations with defined mechanism(s) of action has enabled the progression from use of autologous bone marrow stem cells comprising of heterogeneous cell populations to allogeneic cell types such as monocyte-derived macrophages, regulatory T cells, mesenchymal stromal cells, macrophages, etc. There is growing evidence regarding the multiple molecular mechanisms pivotal to various therapeutic effects and hence, careful selection of cell therapy product for the desired putative effects is crucial. In this review, we have presented an overview of the cell therapies that have been developed thus far, with preclinical and clinical evidence for their use in liver disease. Limitations associated with these therapies have also been discussed. Despite the advances made, there remain multiple challenges to overcome before cell therapies can be considered as viable treatment options, and these include larger scale clinical trials, scalable production of cells according to good manufacturing practice standards, pathways for delivery of cell therapy within hospital environments, and costs associated with the production.

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Hepatoprotective effects of resveratrol in non-alcoholic fatty live disease

Current Pharmaceutical Design ◽

10.2174/1381612826666200417165801 ◽

2020 ◽

Vol 26 ◽

Cited By ~ 4

Author(s):

Silvia Tejada ◽

Xavier Capó ◽

Catalina Mª Mascaró ◽

Margalida Monserrat-Mesquida ◽

Mª Magdalena Quetglas-Llabrés ◽

...

Keyword(s):

Clinical Trials ◽

Liver Disease ◽

Overweight And Obesity ◽

Lifestyle Changes ◽

Sirtuin 1 ◽

Therapeutic Effects ◽

Potential Candidate ◽

Alcoholic Fatty Liver ◽

Number Of Patients ◽

Accumulation Of Lipids

Background: Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease worldwide directly related to the progressive increase in overweight and obesity. The accumulation of lipids in patients with NAFLD contributes to the development of insulin resistance, inflammatory response and oxidative stress in hepatocytes and an alteration of the circulating lipid and glycaemic profile. However, to date there are no effective pharmacological treatments for patients with NAFLD. Lifestyle changes and dietary modifications aimed to weight loss are the best current alternatives, therefore, new approaches should be considered. Resveratrol, a natural polyphenol of the stilbene group, is a potential candidate to be aware of the management of NAFLD for its anti-inflammatory, antioxidant properties, and calorie restriction-like effects. Methods: In this review, the available information on the potential therapeutic effects of resveratrol on NAFLD developed mainly in animal models and in some clinical trials are summarize. Results: In vitro and animal model studies have shown beneficial effects of resveratrol treatment on NAFLD. Resveratrol reduces hepatic accumulation of lipids and improves lipid and glycaemic metabolism. Some of the mechanisms of action are the signalling pathways of AMP-activated protein kinase, sirtuin 1 and nuclear factor κB. However, the results obtained in clinical trials are inconclusive. Conclusion: Although preclinical trials have shown promising results of resveratrol against NALFD, the lack of clear results in clinical trials makes necessary more studies with a larger number of patients and for a longer time.

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