Stem Cell Clinical Trials Research Articles

Alzheimer's Disease: From Pathogenesis to Mesenchymal Stem Cell Therapy - Bridging the Missing Link.

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease worldwide. With the increasing trend of population aging, the estimated number of AD continues to climb, causing enormous medical, social and economic burden to the society. Currently, no drug is available to cure the disease or slow down its progression. There is an urgent need to improve our understanding on the pathogenesis of AD and develop novel therapy to combat it. Despite the two well-known pathological hallmarks (extracellular amyloid plaques and intracellular Neurofibrillary Tangles), the exact mechanisms for selective degeneration and loss of neurons and synapses in AD remain to be elucidated. Cumulative studies have shown neuroinflammation plays a central role in pathogenesis of AD. Neuroinflammation is actively involved both in the onset and the subsequent progression of AD. Microglia are the central player in AD neuroinflammation. In this review, we first introduced the different theories proposed for the pathogenesis of AD, focusing on neuroinflammation, especially on microglia, systemic inflammation, and peripheral and central immune system crosstalk. We explored the possible mechanisms of action of stem cell therapy, which is the only treatment modality so far that has pleiotropic effects and can target multiple mechanisms in AD. Mesenchymal stem cells are currently the most widely used stem cell type in AD clinical trials. We summarized the ongoing major mesenchymal stem cell clinical trials in AD and showed how translational stem cell therapy is bridging the gap between basic science and clinical intervention in this devastating disorder.

Education can improve clinician confidence in information sharing and willingness to refer to stem cell clinical trials for cerebral palsy

To progress stem cell therapies for cerebral palsy, clinicians need to openly engage with patients about emerging evidence and be willing to refer to relevant clinical trials, if and when...

Anticipated impact of stem cell and other cellular medicine clinical trials for COVID-19.

Aim: There is a critical need for safe and effective treatments for COVID-19. One possible type of treatment is cellular medicine such as stem cell therapy, but its potential is unclear. Here, our aim was to assess the potential impact of the many cellular medicine trials for COVID-19. Materials & methods: We collected and analyzed data for defined criteria from trial registries. Results: Our data suggest that relatively few of these COVID-19 trials will produce high-level evidence, but that on average they may be somewhat more rigorous than typical cell therapy trials unrelated to COVID-19. Conclusion: Most COVID-19 cellular medicine trials have relatively low potential for rapid, concrete impact. We discuss the findings in the context of the cellular medicine field overall.

Pluripotent and Multipotent Stem Cells and Current Therapeutic Applications: Review.

There is numerous evidence for the presence of stem cells, which is important for the treatment of a wide variety of disease conditions. Stem cells have a great therapeutic effect on different degenerative diseases through the development of specialized cells. Embryonic stem (ES) cells are derived from preimplantation embryos, which have a natural karyotype. This cell has the capacity of proliferation indefinitely and undifferentiated. Stem cells are very crucial for the treatment of different chronic and degenerative diseases. For instance, stem cell clinical trials have been done for ischemic heart disease. Also, the olfactory cells for spinal cord lesions and human fetal pancreatic cells for diabetes mellitus are the other clinical importance of stem cell therapy. Extracellular matrix (ECM) and other environmental factors influence the fate and activity of stem cells.

Types of Stem Cells Used in US-Based Clinical Trials between 1999 and 2014

This study looks at the number of clinical trials involving specific stem cell types. To our knowledge, this has never been done before. Stem cell clinical trials that were conducted at locations in the US and registered on the National Institutes of Health database at ‘clinicaltrials.gov’ were categorized according to the type of stem cell used (adult, cancer, embryonic, perinatal, or induced pluripotent) and the year that the trial was registered. From 1999 to 2014, there were 2,357 US stem cell clinical trials registered on ‘clinicaltrials.gov,’ and 89 percent were from adult stem cells and only 0.12 percent were from embryonic stem cells. This study concludes that embryonic stem cells should no longer be used for clinical study because of their irrelevance, moral questions, and induced pluripotent stem cells.

Mesenchymal stem cells secretome: The cornerstone of cell-free regenerative medicine.

Mesenchymal stem cells (MSCs) are the most frequently used stem cells in clinical trials due to their easy isolation from various adult tissues, their ability of homing to injury sites and their potential to differentiate into multiple cell types. However, the realization that the beneficial effect of MSCs relies mainly on their paracrine action, rather than on their engraftment in the recipient tissue and subsequent differentiation, has opened the way to cell-free therapeutic strategies in regenerative medicine. All the soluble factors and vesicles secreted by MSCs are commonly known as secretome. MSCs secretome has a key role in cell-to-cell communication and has been proven to be an active mediator of immune-modulation and regeneration both in vitro and in vivo. Moreover, the use of secretome has key advantages over cell-based therapies, such as a lower immunogenicity and easy production, handling and storage. Importantly, MSCs can be modulated to alter their secretome composition to better suit specific therapeutic goals, thus, opening a large number of possibilities. Altogether these advantages now place MSCs secretome at the center of an important number of investigations in different clinical contexts, enabling rapid scientific progress in this field.

Improving Stem Cell Clinical Trial Design and Conduct: Development of a Quality Assessment Tool for Stem Cell Clinical Trials.

Background Clinical trials are at the cornerstone of evidence-based stem cell therapies, but the quality assessment for designing and conduct these sometimes-complex studies are scarce of evidence. This study is aimed at developing a handy quality assessment tool for stem cell clinical trials, enhancing capacity of the self-regulate overall quality, and participating protection. Methods The framework of quality assessment tool was based on the PQRS (progress-quality-regulation-scientific) quality assessment tool, and detailed quality indicators were developed by leader group discussion, expert consulting, and literature review. Stem cell clinical trials were retrieved from the International Clinical Trials Registry Platform, and corresponding quality indicators were assessed and extracted. The validity and feasibility of conceptual quality assessment tool were further evaluated by using structural equation modeling. Results The quality assessment tool for stem cell clinical trials contains four critical quality attributes, including participant protection, scientific value, quality control, and stem cell products, and 9 observed quality indicators. From 11 primary clinical trial registries in the International Clinical Trials Registry Platform, 9410 stem cell trial registrations were identified, and 1036 studies were eligible for publications and protocols screening. After reviewed full text, 37 studies were included in the validity and feasibility evaluation: 32 studies were completed, and 3 studies terminated early. Most of the studies (83.79%) were in the early phase, and 63.16% of the studies were investigator-initiated trial. To further tested for validity, the critical quality attributes and quality indicators (QIs) between expertise further validated by the SEM method, which showed a good fit for the model (chi − square = 26.008; P = 0.353; TLI = 0.967; CFI = 0.978; RMSEA = 0.048). Compared with exploratory trials, evaluating using the quality assessment tool, confirmatory trials performed similarly in participant protection, scientific value, and quality control, but lower in stem cell products. Conclusions The results of critical quality attributes and quality indicators between expertise and confirmatory validation analysis are basically consistent, indicating the feasibility and validity of applying this quality assessment tool for overall quality evaluation of stem cell trials.

Mesenchymal stem cells in the treatment of COVID-19-progress and challenges

At present, SARS-CoV-2 is raging, and novel coronavirus pneumonia (COVID-19) has caused more than 35 million confirmed patients and more than 500 000 cases death, which seriously endanger human health, socioeconomic development, as well as global medical and public health systems. COVID-19 is highly contagious, has a long incubation period, and causes many death cases due to lack of effective specific treatment. Mesenchymal stem cells have powerful anti-inflammatory and immunoregulatory functions, and can effectively reduce the cytokine storm caused by coronavirus in patients, and improve the pulmonary fibrosis of patients, promote the repair of damaged lung tissue, and reduce the mortality. Currently, a number of related clinical trials of mesenchymal stem cell treatment of COVID-19 have been conducted, and have confirmed the safety and efficacy, suggesting a good clinical application prospect. While progress has been made in mesenchymal stem cell therapy for COVID-19, we should also catch sight of the problems and challenges faced by mesenchymal stem cell clinical trials under severe epidemic situation, including clinical trials design, stem cell quality management, and ethics in treatment. Only by paying attention to these can we guarantee the safe and effective development of mesenchymal stem cell clinical trials in the treatment of COVID-19.

Disparities in Racial and Ethnic Representation in Stem Cell Clinical Trials.

ClinicalTrials.gov (CTG) provides integrated access to structured records of thousands of randomized clinical trials (RCT). CTG functionality allows download of the entire dataset in XML format for further knowledge discovery and analytics. This study represents an instructive use case of utilizing this functionality for identifying patient representation disparities in stem cell RCTs. The goal of this study was to determine the racial and ethnic composition of stem cell clinical trials and to identify potential disparities in minority representation. The clinical trial registration portal ClinicalTrials.gov was queried to identify stem cell trials and to compare their racial and ethnic composition to the US population data. Based on our analysis of 248 available trials, we have concluded that not all races and ethnicities are adequately represented in US stem cell trials; thus, concerted efforts are warranted for more inclusive representation of minorities in future stem cell trials.

“I Want to Do It, But I Want to Make Sure That I Do It Right.” Views of Patients with Parkinson’s Disease Regarding Early Stem Cell Clinical Trial Participation

Background: First-in-human clinical trials with stem cells for Parkinson’s disease (PD) are on the horizon. Their epistemic success depends on ensuring the participation of a sufficient number and appropriately diverse group of patients with PD. Their ethical soundness requires that the research community ensures that subjects’ decisions about whether to participate or not are consistent with participants’ values, motivations, and goals. We sought to identify PD patients’ knowledge, concerns, and expectations regarding early-phase stem cell research in PD. Methods: We conducted five semi-structured focus groups with patients with PD. Group discussions were recorded, transcribed, and coded to identify participants’ knowledge, concerns, and expectations regarding participation in early stem cell clinical research in PD. Results: Four themes were generated from our data analysis: (1) participants’ skepticism about the potential benefits of these trials; (2) their desire to obtain information about various aspects related to this research; (3) a recognition that accessing available knowledge was often difficult; and (4) the relevance of trusting relationships with various stakeholders. Conclusions: Participants expressed skepticism about the immediate impact of stem cell research. Nonetheless, such skepticism often reflected an appropriate consideration of the risks and potential benefits of participating in high-risk clinical trials. Despite their skepticism, participants were eager to learn more about stem cell research and clinical trials processes. They identified consistently trusted avenues of knowledge on these topics, but they often found it difficult to access relevant information or to determine its value.

Stem Cell Clinical Trials in Spinal Cord Injury: A Brief Review of Studies in the United States

Background: Although many therapeutic approaches have been attempted to treat spinal cord injury, cellular transplantation offers the greatest promise in reconstituting the architecture of the damaged cord. Methods: A literature review was conducted to search for clinical trials investigating stem cells as treatment for spinal cord injury in the United States. Results: Overall, eight studies met inclusion criteria. Of the included studies, four were identified as being terminated, suspended, or not yet recruiting. Two studies were identified as currently recruiting, including one phase one trial evaluating stereotactic injections of human spinal cord-derived neural stem cells in patients with chronic spinal cord injuries, and one trial of transplantation of autologous bone marrow derived stem cells via paraspinal injections, intravenous injections, and intranasal placement. One study was identified as an active study, a phase one trial of intrathecal injection of 100 million autologous, ex-vivo expanded, adipose-derived mesenchymal stem cells. One trial that was listed as completed is a phase 1/2a, dose escalation study, investigating stereotactic injection of human embryonic stem cell derived oligodendrocyte progenitor cells. Conclusions: Although few significant publications have emerged to this point, current trial results are promising.

Strategies to improve Adipose Mesenchymal Stromal Cell Therapeutic Effect: Application to pelvic radiotherapy side effects

Background & Aim Healthy tissues surrounding pelvic tumours may be impaired during radiotherapy (RT) and could lead to chronic gastrointestinal complications with substantial mortality. Injection of Adipose-derived Mesenchymal Stromal Cells (Ad-MSC) represents a promising therapeutic strategy. However, many stem cell clinical trials do not confer expected beneficial effect, suggesting a real need to accelerate research towards the successful clinical application. We hypothesized that heparan sulfate (HS)-mimetic injections that restore the extracellular matrix network and enhance the biological activity of growth factors, associated with local injection of MSC protected in a hydrogel that improves cell engraftment and cell survival, could improve the therapeutic benefit of MSC treatment. Methods, Results & Conclusion We used an experimental model of radiation proctitis developed in rats that reproduces severe colonic mucosal damages and fibrosis similar to those observed in patients treated by radiotherapy. We tested injections of HS-m, local injection through endoscopy of Ad-MSC embedded in Si-HPMC hydrogel as well as combinations of these various treatments. The therapeutic benefit was evaluated by endoscopy, histology and functional parameters as epithelial barrier were also tested. We demonstrated that hydrogel loaded-Ad-MSCs were viable, able to secrete trophic factors and responsive to the inflammatory environment. In animal model, Ad-MSC+Si-HPMC improve colonic epithelial structure and hyperpermeability. This therapeutic benefit is associated with greater engraftment of Si-HPMC-embedded Ad-MSCs in the irradiated colonic mucosa. We demonstrated that combination of HS-m to hydrogel-embedded MSC treatment enhances the therapeutic benefit of MSC therapy alone. We also demonstrated that the combined treatment favored the epithelial regenerative process. Finally, using an animal model of colonic surgery after irradiation, we demonstrated that the combined treatment improved rat survival, healing of the anastomosis and scar quality assessed by collagen deposit. In this study, we identified a new way, clinically applicable, to optimize stem-cell therapy and could be proposed to patients suffering from severe colonic defect after RT.

Application of protection motivation theory to clinical trial enrolment for pediatric chronic conditions

BackgroundParents of children living with chronic but manageable conditions hope for improved therapies or cures, including Advanced Therapy Medicinal Products (ATMPs). Multiple pediatric clinical trials for ATMPs are underway, but the risk profile of ATMPs for chronic conditions is largely unknown and likely different than for terminal pediatric illnesses. Applying Protection Motivation Theory modified to the context of pediatric ATMP clinical trial enrollment, our study analyses information needs of parents of children living with chronic manageable conditions: Type 1 Diabetes (T1D) or Inherited Retinal Diseases (IRD).MethodsWe conducted semi-structured interviews with 15 parents of children living with T1D and 14 parents of children living with an IRD about: a) family background and the diagnostic experience; b) awareness of gene and stem cell therapy research and clinical trials for T1D and IRD; c) information sources on trials and responses to that information; d) attitudes to trial participation, including internationally; e) understanding of trial purpose and process; and f) any experiences with trial participation. We then discussed a pediatric ATMP clinical trial information sheet, which we developed with experts. We applied directed qualitative content analysis, based on PMT, to examine the information preferences of parents in deciding whether to enrol their children in stem cell or gene therapy clinical trials.ResultsParents balanced trial risks against their child’s ability to cope with the chronic condition. The better the child’s ability to cope with vision impairment or insulin management, the less likely parents were to assume trial risks. Conversely, if the child struggled with his/her vision loss, parents were more likely to be interested in trial participation, but only if the risks were low and likelihood for potential benefit was high.ConclusionsFear of adverse events as part of threat appraisal was the predominant consideration for parents in considering whether to enroll their child living with a manageable, chronic condition in a pediatric clinical trial of an ATMP. This consideration outweighed potential benefits and severity of their child’s condition. Parents called for available safety data and fulsome communication processes that would enable them to make informed decisions about clinical trial enrolment on behalf of their children.

Characteristics and Trends of Adult Acute Lymphoblastic Leukemia in a Large, Public Safety-Net Hospital

BackgroundManagement of acute lymphoblastic leukemia (ALL) in a socioeconomically vulnerable population without ready access to a hematopoietic stem cell transplant (HCT) center and clinical trials is challenging. Data regarding the outcomes of such patients are sparse. Patients and MethodsThis retrospective analysis included 90 consecutive patients with ALL who presented to Harbor-UCLA between 2003 and 2018. The primary objective was overall survival (OS), whereas secondary objectives included leukemia-free survival, toxicities of therapy, and referral for HCT and incidence of successful HCT. ResultsMost patients were male (56.7%) and Hispanic (72.2%). The median age of diagnosis was 36 years (range, 18-63 years). The median OS was 26.8 months (95% confidence interval [CI], 17.4-59.0 months). In patients who achieved complete remission with therapy, the median leukemia-free survival was 16.4 months. Fifty percent of patients experienced at least 1 episode of bacteremia, and nearly 25% of patients developed an invasive fungal infection. Thirty-six percent (n = 32) of patients were referred for HCT. The referral rate increased over time, which led to improved OS in patients who underwent evaluation at a tertiary cancer center (hazard ratio, 0.44; 95% CI, 0.21-0.89; P = .02). Patients who underwent HCT had significantly better OS compared with those who did not (OS not reached vs. 21.9 months; hazard ratio, 0.16; 95% CI, 0.04-0.68; P = .01). ConclusionRisk stratification and evidence-based treatment approaches are important for patients with ALL treated in a resource-limited setting. Most patients can be induced successfully and achieve complete remission with therapy. Partnership with a cancer center with early referral for HCT can facilitate curative HCT to be performed.

Embryonic Stem Cells in Clinical Trials: Current Overview of Developments and Challenges.

The first isolation of human embryonic stem cells (hESC) reported in the late 90s opened a new window to promising possibilities in the fields of human developmental biology and regenerative medicine. Subsequently, the differentiation of hESC lines into different precursor cells showed their potential in treating different incurable diseases. However, this promising field has consistently had remarkable ethical and experimental limitations. This paper is a review of clinical trial studies dealing with hESC and their advantages, limitations, and other specific concerns. Some of the hESC limitations have been solved, and several clinical trial studies are ongoing so that recent clinical trials have strived to improve the clinical applications of hESC, especially in macular degeneration and neurodegenerative diseases. However, regarding hESC-based therapy, several important issues need more research and discussion. Despite considerable studies to Date, hESC-based therapy is not available for conventional clinical applications, and more studies and data are needed to overcome current clinical and ethical limitations. When all the limitations of Embryonic stem cells (ESC) are wholly resolved, perhaps hESC can become superior to the existing stem cell sources. This overview will be beneficial for understanding the standard and promising applications of cell and tissue-based therapeutic approaches and for developing novel therapeutic applications of hESC.

Mononuclear cell evaluation: A correlation study between manual and analyzer-based estimation

Background: Bone marrow transplantation (BMT) is being routinely done at the Army Hospital for the past 15 years. Our experience with Stem Cell Transplantation and clinical trial on stem cell efficacy, our Centre had brought out the issue of trial deviates ( 20,000 showing significant difference. Conclusion: The good correlation of 5-part hematology analyzer with manual gold standard method of MNC count is indicating equivalent performance. MNC can be performed by 5-part with nonsignificant difference and can be used as good as manual count.

Trends in mesenchymal stem cell clinical trials 2004-2018: Is efficacy optimal in a narrow dose range?

The number of clinical trials using mesenchymal stem cells (MSCs) has increased since 2008, but this trend slowed in the past several years and dropped precipitously in 2018. Previous reports have analyzed MSC clinical trials by disease, phase, cell source, country of origin, and trial initiation date, all of which can be downloaded directly from http://clinicaltrials.gov. We have extended analyses to a larger group of 914 MSC trials reported through 2018. To search for potential factors that may influence the design of new trials, we extracted data on routes of administration and dosing from individual http://clinicaltrials.gov records as this information cannot be downloaded directly from the database. Intravenous (IV) injection is the most common, least invasive and most reproducible method, accounting for 43% of all trials. The median dose for IV delivery is 100 million MSCs/patient/dose. Analysis of all trials using IV injection that reported positive outcomes indicated minimal effective doses (MEDs) ranging from 70 to 190 million MSCs/patient/dose in 14/16 trials with the other two trials administering much higher doses of at least 900 million cells. Dose‐response data showing differential efficacy for improved outcomes were reported in only four trials, which indicated a narrower MED range of 100‐150 million MSCs/patient with lower and higher IV doses being less effective. The results suggest that it may be critical to determine MEDs in early trials before proceeding with large clinical trials.

Minorities Do Not Have Worse Outcomes for Diffuse Large B Cell Lymphoma (DLBCL) If Optimally Managed

BACKGROUND: DLBCL is the most common and a potentially curable non-Hodgkin lymphoma. Multiple previous studies have shown that minority populations have worse outcomes compared to Caucasians (Tao L, Blood 2014; Griffiths R, BMC Cancer 2010; Koroukian et al, Cancer, 2010, Shenoy PJ Cancer 2010). Moreover, it has been reported that uninsured and Medicaid insured patients with DLBCL have inferior survival compared to privately insured patients (Han X, Cancer 2014; Koroukian et al, Cancer 2010;). It has also been well established that minorities are underrepresented in clinical trials (Gerrero S, Sci Rep 2018; Kwiatkowski K, Cancer 2013). We present the baseline characteristics, treatment paradigms and outcomes of Caucasian (C) and non-Caucasian (NC) patients with de novo DLBCL treated at a single academic hybrid cancer center. METHODS: We collected demographic, disease, insurance coverage, treatment characteristics, and treatment outcomes for patients with de novo DLBCL who presented between January 2016 and January 2019 at Levine Cancer Institute, Charlotte, North Carolina. Patient race, C or NC were self-reported. Insurance was categorized as Government (Medicaid or Medicare), Private, or Uninsured. We used the Revised International Prognostic Index (R-IPI) to risk stratify patients. Double-hit lymphomas (DHL) were defined as having the MYC translocation with either BCL2 or BCL6 translocation on fluorescent in situ hybridization. Treatments included standard chemoimmunotherapies, stem cell transplantation and clinical trials including chimeric antigen receptor therapies (CART). Outcomes of overall survival (OS) and progression free survival (PFS) were calculated using the Kaplan Meier method and compared with log rank test. Demographic data was compared using Fisher's Exact tests. RESULTS: One hundred and ninety-six consecutive patients with de novo DLBCL were included in the analysis [155 (79%) = C, 41 (21%) = NC] (Table). The NC group was predominantly African American (71%) followed by Hispanic (15%). Prognostic scores (R-IPI) and the incidence of DHL were similar between C and NC. The median age at diagnosis in the NC group was lower than in C. There were significant differences in insurance coverage between the 2 groups (p=0.012). The C group did not have any uninsured patients and had more patients with private insurance (33%) compared to the NC group (7% uninsured and 27% with private insurance). The most common frontline treatment was RCHOP (C=66%, NC=70%) followed by dose adjusted REPOCH (C=12%, NC=15%). Median follow up was 31.6 months. There was no difference in OS and PFS between the 2 groups (Figure 1). OS at 2 years from date of diagnosis was 81% for C and 84% for NC, p=0.852. Two-year PFS from time of diagnosis were similar for both groups: 61% for C and 63% for NC, p=0.999. Similar numbers of patients in both groups developed relapsed or refractory (R/R) disease after frontline therapy. Median number of treatments was 2 for both groups, p=0.582. For patients who developed R/R DLBCL, the 2-year OS was 60% for C and 63% for NC, p=0.590. Similar proportions underwent stem cell transplantation: 11% for C and 20% for NC, p= 0.186. Clinical trial enrollment was comparable: 11% for C and 12% for NC, p=0.785. CONCLUSION: Unlike previous population-based studies that have shown racial disparities with superior outcomes for Caucasians and for patients with private insurance, our single center experience demonstrates similar survival outcomes between Caucasians and non-Caucasians diagnosed with de novo DLBCL, despite differences in insurance coverage favoring Caucasians. In the R/R setting, similar proportions of both groups underwent stem cell transplantation and enrolled on clinical trials. The likely explanation is that our safety net cancer center, with extensive nurse navigator support and access to standard treatments, stem cell transplants and cutting-edge clinical trials may abrogate the inferior outcomes in minority populations that have been previously reported. Disclosures Symanowski: Immatics: Consultancy; Eli Lilly: Consultancy; Carsgen Therapeutics: Consultancy; Boston Biomedical: Consultancy. Park:Rafael Pharma: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Research Funding; Gilead: Speakers Bureau; Teva: Consultancy, Research Funding; G1 Therapeutics: Consultancy; Seattle Genetics: Research Funding, Speakers Bureau. Avalos:Juno: Membership on an entity's Board of Directors or advisory committees; Best Practice-Br Med J: Patents & Royalties: receives royalties from a coauthored article on evaluation of neutropenia. Jacobs:Genentech: Speakers Bureau; AstraZeneca: Speakers Bureau; TG Therapeutics: Honoraria, Research Funding; AbbVie: Consultancy, Speakers Bureau; JUNO: Consultancy; Gilead: Consultancy; Pharmacyclics LLC, an AbbVie Company: Research Funding, Speakers Bureau. Ghosh:TG Therapeutics: Consultancy, Honoraria, Research Funding; SGN: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding; Genentech: Research Funding; AstraZeneca: Honoraria, Speakers Bureau; Forty Seven Inc: Research Funding.

Analysis of d-dimer as stem cell treatment marker and cytokines as prognostic marker in intravenous transplantation of umbilical cord-derived mesenchymal stem cells for acute stroke

Stem cell clinical trials for stroke patients have been increasingly investigated, but their results have controversy. We recently performed the human umbilical cord-derived mesenchymal stem cells (Cordstem-ST) intravenous transplantation in acute cerebral infarction and found that Cordstem-ST had effects on functional improvement in stroke. In this study, we evaluated the possibility of therapeutic marker through the D-dimer and cytokine analysis in treatment of Cordstem-ST for stroke. In total 19 patients, we investigated the differences of D-dimer between placebo (4 patients) and stem cell groups (15 patients). And then, we analyzed differences of interval changes of various cytokines level between groups. Also, we investigated association between interval change of various cytokines and prognosis (good and poor) among stem cell group. D-dimer on following day after administration of Cordstem-ST was markedly increased in stem cell group than placebo group with significance on day 1. In interval change of D-dimer, there were significant differences on 1, 3, and 7 days. Although d-dimer was increased, but suspicious inflammatory symptoms and signs such as fever and leukocytosis was not accompanied. IL-1 alpha and IL-21 was markedly decreased in stem cell group than placebo group. Good prognosis group had higher level of BDNF, CCL2, CXCL10, PDGF-BB, and PLGF than poor prognosis group. It was suggested that D-dimer was a marker of stem cell treatment. And we found that Cordstem-ST increased cytokines related to anti-inflammation, neuronal regeneration and neovascularization.

Cell-Based Therapies for Stroke: Are We There Yet?

Stroke is the second leading cause of death and physical disability, with a global lifetime incidence rate of 1 in 6. Currently, the only FDA approved treatment for ischemic stroke is the administration of tissue plasminogen activator (tPA). Stem cell clinical trials for stroke have been underway for close to two decades, with data suggesting that cell therapies are safe, feasible, and potentially efficacious. However, clinical trials for stroke account for <1% of all stem cell trials. Nevertheless, the resources devoted to clinical research to identify new treatments for stroke is still significant (53–64 million US$, Phase 1–4). Notably, a quarter of cell therapy clinical trials for stroke have been withdrawn (15.2%) or terminated (6.8%) to date. This review discusses the bottlenecks in delivering a successful cell therapy for stroke, and the cost-to-benefit ratio necessary to justify these expensive trials. Further, this review will critically assess the currently available data from completed stroke trials, the importance of standardization in outcome reporting, and the role of industry-led research in the development of cell therapies for stroke.