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Treating diseases such as Muscular dystrophy (MD) and HIV/AIDS pose several challenges to the rapidly evolving field of regenerative medicine. Previously, stem cell therapy has been said to affect the clinical courses of HIV/AIDS and MD, but, in practice, eradication or control of these diseases was not achievable. The introduction of gene editing into stem cell therapy has stimulated HIV/AIDS and MD cell therapy research studies substantially. Here, we review current methods of treating HIV/AIDS and MD using stem cell therapy. This review also details the use of different types of cells and methods in cell therapy and the modeling of new cell-based therapies to treat Duchenne muscular dystrophy. We speculate that the effective use of stem cell therapy in conjunction with other treatment therapies , such as steroids and rehabilitation , could improve livelihood.

Background: Phase I/II clinical trials using fetal retinal pigment epithelium (fRPE), human embryonic stem cell (hESC)-derived RPE, or human induced pluripotent stem cell (hiPSC)-derived RPE as potential sources of materials for cell-based therapy to treat degenerative retinal diseases have been carried out during the past decade. Challenges for successful translational cell-based therapy include cell manufacture, cell quality, cell storage, and cell behavior in vivo. In this study, we investigated the culture-induced changes in passaged fetal RPE, hESC-RPE and hiPSC-RPE cells in vitro and explored the differentiation and maturation effect of all-trans retinoic acid (ATRA) on those RPE cells. Methods: A total of 9 fetal RPE cell lines, hESC-RPE and hiPSC-RPE cell lines were set up using previously described methods. The culture-induced changes in subsequent passages caused by manipulating plating density, dissociation method and repeated passaging were studied by microscope, real-time quantitative PCR, western blot and immunofluorescent assays. Gene and protein expression and functional characteristics of fRPE, hESC-RPE and hiPSC-RPE incubated with ATRA at different concentration were also evaluated.Results: Compared with fRPE, hESC-RPE and hiPSC-RPE showed decreased gene and protein expression of RPE markers. Passage 3 RPE of all three types seeded at a density of 6×105 and 9x105 cells/mL in basal medium maintained pigmented polygonal, cobblestone-like morphology. RPE cells underwent mesenchymal changes showing increased expression of mesenchymal markers including a-SMA, N-cadherin, fibronectin and decreased expression of RPE markers including RPE65, E-cadherin and ZO-1, as a subsequence of low plating density, inappropriate dissociated method, and repeated passaging. fRPE, hESC-RPE and iPSC-RPE treated by ATRA at different concentrations showed increased expression of RPE markers such as RPE65, bestrophin (BEST) and CRALBP, and increased expression of negative complement regulatory proteins (CRP) including complement factor H (CFH), CD46, CD55 and CD59, and increased transepithelial resistance (TER) as well.Conclusion: Although hESC and hiPSC-derived RPE are morphologically similar to fRPE, and also have the tendency to undergo epithelial-to-mesenchymal transition (EMT) changes during the culturing and passaging process in vitro, differences in protein and gene expression among three RPE types exist. Moreover, ATRA can increase RPE markers expression, as well as to increase the expression levels of CRPs gene and protein in fRPE and stem cell-derived RPE.

Although cross-correction was discovered more than 50 years ago, and held the promise of drastically improving disease management, still no cure exists for lysosomal storage diseases (LSDs). Cell therapies have the potential to halt disease progression: either a subset of autologous cells can be ex vivo/ in vivo transfected with the functional gene or allogenic wild type stem cells can be transplanted. However, the majority of cell-based attempts have been ineffective, due to the difficulties in reversing neuronal symptomatology, in finding appropriate gene transfection approaches, in inducing immune tolerance, reducing the risk of graft versus host disease (GVHD) when allogenic cells are used and that of immune response when engineered viruses are administered, coupled with a limited secretion and uptake of some enzymes. In the last decade, due to advances in our understanding of lysosomal biology and mechanisms of cross-correction, coupled with progresses in gene therapy, ongoing pre-clinical and clinical investigations have remarkably increased. Even gene editing approaches are currently under clinical experimentation. This review proposes to critically discuss and compare trends and advances in cell-based and gene therapy for LSDs. Systemic gene delivery and transplantation of allogenic stem cells will be initially discussed, whereas proposed brain targeting methods will be then critically outlined.

Background aims The novelty of cell and gene therapies (CGTs) has introduced unique supply chain challenges and considerations not seen by chemically synthesized (small-molecule) drugs. These complexities increase during the clinical phases, where drug safety and efficacy milestones are still underdeveloped. For example, for autologous therapies such as chimeric antigen receptor T-cell therapies, in which the treatment is developed from the patient's own cells, supply chain management plays an integral role in chemistry, manufacturing and control processes. Supply chain management requires proactive planning because of the strict cold chain requirements and time sensitivity of CGTs. This research examines strategies and responses to challenges experienced by industry stakeholders (e.g., sponsors and manufacturers) during the implementation phases of clinical supply chain management. This research further evaluates the adequacy of the current regulatory framework for distribution and supply chain management of CGTs in the US. Methods A survey methodology was used to query subject matter experts from the biopharmaceutical industry who were familiar with the clinical supply management of CGTs in the US. The survey instrument was developed using an implementation framework and disseminated electronically to mid- and senior-level subject matter experts who had experience with clinical trials, supply chain management and CGTs. Results A total of 128 respondents accessed the survey, and 105 respondents answered at least one question. Seventy-five respondents completed the survey. Results showed that a lack of harmonization in regulations across the supply chain, limited resources, challenges with vendor management, high costs and complexities in the supply chain due to product specificity and customization proved to be impediments for the industry. In addition, the coronavirus disease 2019 pandemic had a significant impact on supply chain implementation. The results revealed that less than half of the respondents had business continuity plans in place. These challenges increased for smaller and mid-size organizations. Thirty percent of small and mid-size organizations were less prepared to scale up than larger companies. Conclusions Suggestions from industry stakeholders were to adopt and enforce Good Distribution Practices in the US (81%), pre-plan distribution strategies with internal and external stakeholders along the supply chain and develop agile systems and robust processes end to end. Hurdles in scaling up and scaling out from the clinical to commercial phases for time- and temperature-sensitive CGT products make it difficult to predict the supply chain's long-term feasibility. Although there are initiatives to improve these impediments, such as improving industry partnerships and creating global CGT transportation standards, there are still regulatory knowledge gaps present for CGTs. Therefore, it is essential to establish a baseline and foundation for CGT supply chains extending beyond the loading dock.

Immune effector cell (IEC) therapies have revolutionized our approach to relapsed B-cell malignancies, and interest in the investigational use of IECs is rapidly expanding into other diseases. Current challenges in the analysis of IEC therapies include small sample sizes, limited access to clinical trials and a paucity of predictive biomarkers of efficacy and toxicity associated with IEC therapies. Retrospective and prospective multi-center cell therapy trials can assist in overcoming these barriers through harmonization of clinical endpoints and correlative assays for immune monitoring, allowing additional cross-trial analysis to identify biomarkers of failure and success. The Consortium for Pediatric Cellular Immunotherapy (CPCI) offers a unique platform to address the aforementioned challenges by delivering cutting-edge cell and gene therapies for children through multi-center clinical trials. Here the authors discuss some of the important pre-analytic variables, such as biospecimen collection and initial processing procedures, that affect biomarker assays commonly used in IEC trials across participating CPCI sites. The authors review the recent literature and provide data to support recommendations for alignment and standardization of practices that can affect flow cytometry assays measuring immune effector function as well as interpretation of cytokine/chemokine data. The authors also identify critical gaps that often make parallel comparisons between trials difficult or impossible.

Adoptive T cell therapy (ACT) with tumor-reactive lymphocytes can overcome the immune desert of poorly immunogenic tumors and instruct tumor eradication. Several hurdles limit the efficacy of this strategy against solid tumor including, but not limited to, sub optimal T cell engraftment, tumor infiltration, poor tumor antigenicity/immunogenicity, and immunosuppressive or resistance mechanisms. Recent advances indicate that concomitant treatments can be set in place to offset such barriers. In this review, we highlight the beneficial effects of combining ACT with conventional chemo and/or radiotherapy. While originally classified as immunosuppressive, these methodologies can also promote the engraftment of ACT products, immunogenic cell death, and the reprogramming of more favorable microenvironments. Data indicates that systemic and local chemo/radiotherapy regimens promote intratumoral cytokine and chemokine upregulation, tumor antigen presentation and cross presentation, infiltration and in situ T cells reactivation. Here we review the most recent contributions supporting these notions and discuss further developments.

Organ transplantation is a modern medical success story. However, since its inception it has been limited by the need for pharmacological immunosuppression. Regulatory cellular therapies offer an attractive solution to these challenges by controlling transplant alloresponses through multiple parallel suppressive mechanisms. A number of cell types have seen an accelerated development into human trials and are now on the threshold of a long-awaited breakthrough in personalized transplant therapeutics. Here we assess recent developments with a focus on the most likely candidates, some of which have already facilitated successful immunosuppression withdrawal in early clinical trials. We propose that this may constitute a promising approach in clinical transplantation but also evaluate outstanding issues in the field, providing cause for cautious optimism.

Parkinson’s disease (PD) is the second most common neurodegenerative disease and a prime target of cell therapies. In fact, aborted fetal tissue has been used as donor material for such therapies since the 1980s. These cell therapies, however, suffer from several problems, such as a short supply of donor materials, quality instability of the tissues, and ethical restrictions. The advancement of stem cell technologies has enabled the production of donor cells from pluripotent stem cells with unlimited scale, stable quality, and less ethical problems. Several research groups have established protocols to induce dopamine neural progenitors from pluripotent stem cells in a clinically compatible manner and confirmed efficacy and safety in non-clinical studies. Based on the results from these non-clinical studies, several clinical trials of pluripotent stem cell-based therapies for PD have begun. In the context of immune rejection, there are several modes of stem cell-based therapies: autologous transplantation, allogeneic transplantation without human leukocyte antigen-matching, and allogeneic transplantation with matching. In this mini-review, several practical points of stem cell-based therapies for PD are discussed.

Background aims Cell and gene therapy products (CGTPs) are anticipated to bring many benefits for the treatment of conditions with limited or no satisfactory treatment options. However, they are associated with concerns of potential safety risks because of their high complexity. The National Pharmaceutical Regulatory Agency (NPRA) of Malaysia took the first step toward the regulation of CGTPs by publishing the Malaysian Guidance Document and Guidelines for CGTPs in 2016. As mandatory registration and enforcement of CGTPs were scheduled to begin January 1, 2021, the aim of this study was to ascertain the industry's readiness for the regulation of CGTPs in terms of awareness of the guidelines, challenges and acceptance of the regulatory requirements. Methods The authors invited 48 CGTP companies to participate in the survey between October 2019 and June 2020, and 30 companies responded. Results The majority of respondents were aware of the mandatory CGTP regulatory control and the availability of the guidelines. Many CGTPs were in the early development phase, and the most difficult registration barriers were dossier preparation and compliance with the pre-clinical and clinical requirements. Conclusions These findings represent the current CGTP landscape in Malaysia from the industry's viewpoint, enabling the NPRA to implement initiatives to facilitate registration and enforcement.

Immunotherapy has greatly improved outcomes for subgroups of patients with cancer. As indications keep expanding, there is an unmet need to gain a better understanding of the effect of these therapies on pregnancy and fertility. During pregnancy, substantial adaptations occur in the maternal immune system to maintain protection against pathogens while avoiding detrimental reactions to the semi-allogeneic fetus. The pathways involved in the establishment of this fetomaternal tolerance can be hijacked by cancers. Immunotherapies that target these inhibitory pathways, or that directly interact with the regulatory immune cells involved in tolerance mechanisms, might therefore result in complications during pregnancy. Similarly, by activating the patient's immune system with immunotherapy, a broad range of immune-related adverse events can occur that could negatively affect the fetus or impede a future desired pregnancy. This Review summarises preclinical and clinical data related to the use of immunotherapy during pregnancy, including all approved immune checkpoint inhibitors, recombinant cytokines, cell therapies, vaccines, and immunomodulatory drugs.

Advanced therapy medicinal products (ATMPs) are innovative therapies that mainly target orphan diseases and high unmet medical needs. The uncertainty about the product's benefit-risk balance at the time of approval, the limitations of nonclinical development, and the complex quality aspects of those highly individualized advanced therapies are playing a key role in the clinical development, approval, and post-marketing setting for these therapies. This article reviews the current landscape of clinical development of advanced therapies, its challenges, and some of the efforts several stakeholders are conducting to move forward within this field. Progressive iteration of the science, methodologically sound clinical developments, establishing new standards for ATMPs development with the aim to ensure consistency in clinical development, and the reproducibility of knowledge is required, not only to increase the evidence generation for approval but to set principles to achieve translational success in this field., Graphical abstract, Most authorized ATMPs are based on small, open-label, uncontrolled, and single-arm pivotal trials using single and intermediate variables to evaluate outcomes. Health authorities are demanding methodologically sound clinical development to guide higher-quality evidence generation and decision-making. New standards for ATMP development are required to ensure consistency in clinical development.

Chimeric antigen receptor T-cell (CAR-T) therapy is a paradigm-shifting immunotherapy modality in oncology; however, unique toxicities such as cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome limit its ability to be implemented more widely in the outpatient setting or at smaller-volume centers. Three operational challenges with CAR-T therapy include the following: (1) the logistics of toxicity monitoring, ie, with frequent vital sign checks and neurologic assessments; (2) the specialized knowledge required for toxicity management, particularly with regard to CRS and immune effector cell–associated neurotoxicity syndrome; and (3) the need for high-quality symptomatic and supportive care during this intensive period. In this review, we explore potential niches for digital innovations that can improve the implementation of CAR-T therapy in each of these domains. These tools include patient-facing technologies and provider-facing platforms: for example, wearable devices and mobile health apps to screen for fevers and encephalopathy, electronic patient-reported outcome assessments–based workflows to assist with symptom management, machine learning algorithms to predict emerging CRS in real time, clinical decision support systems to assist with toxicity management, and digital coaching to help maintain wellness. Televisits, which have grown in prominence since the novel coronavirus pandemic, will continue to play a key role in the monitoring and management of CAR-T–related toxicities as well. Limitations of these strategies include the need to ensure care equity and stakeholder buy-in, both operationally and financially. Nevertheless, once developed and validated, the next-generation implementation of CAR-T therapy using these digital tools may improve both its safety and accessibility.

Intracerebral cell therapy (CT) is emerging as a new therapeutic paradigm for stroke. However, the impact of physical therapy (PT) on implanted cells and their ability to promote recovery remains poorly understood. To address this translational issue, a clinical-grade neural stem cell (NSC) line was implanted into peri-infarct tissue using MRI-defined injection sites, two weeks after stroke. PT in the form of aerobic exercise (AE) was administered 5 × per week post-implantation using a paradigm commonly applied in patients with stroke. A combined AE and CT exerted sub-additive therapeutic effects on sensory neglect, whereas AE suppressed CT effects on motor integration and grip strength. Behavioral testing emerged as a potentially major component for task integration. It is expected that this study will guide and inform the incorporation of PT in the design of clinical trials evaluating intraparenchymal NSCs implantation for stroke.

Tissue engineering is biomedical engineering that uses suitable biochemical and physicochemical factors to assemble functional constructs that restore or improve damaged tissues. Recently, cell therapies as a subset of tissue engineering have been very promising in the treatment of ocular diseases. One of the most important biophysical factors to make this happen is noninvasive electrical stimulation (ES) to target ocular cells that may preserve vision in multiple retinal and optic nerve diseases. The science of cellular and biophysical interactions is very exciting in regenerative medicine now. Although the exact effect of ES on cells is unknown, multiple mechanisms are considered to underlie the effects of ES, including increased production of neurotrophic agents, improved cell migration, and inhibition of proinflammatory cytokines and cellular apoptosis. In this review, we highlighted the effects of ES on ocular cells, especially on the corneal, retinal, and optic nerve cells. Initially, we summarized the current literature on the in vitro and in vivo effects of ES on ocular cells and then we provided the clinical studies describing the effect of ES on ocular complications. For each area, we used some of the most impactful articles to show the important concepts and results that advanced the state of these interactions. We conclude with reflections on emerging new areas and perspectives for future development in this field.

Standard of care (SOC) chimeric antigen receptor (CAR) T-cell therapies such as axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) are associated with multisystem toxicities. There is limited information available about cardiovascular (CV) events associated with SOC axi-cel or tisa-cel. Patients with CV comorbidities, organ dysfunction, or lower performance status were often excluded in the clinical trials leading to their Food and Drug Adminsitration approval. An improved understanding of CV toxicities in the real-world setting will better inform therapy selection and management of patients receiving these cellular therapies. Here, we retrospectively reviewed the characteristics and outcomes of adult patients with relapsed/refractory large B-cell lymphoma treated with SOC axi-cel or tisa-cel. Among the 165 patients evaluated, 27 (16%) developed at least one 30-day (30-d) major adverse CV event (MACE). Cumulatively, these patients experienced 21 arrhythmias, four exacerbations of heart failure/cardiomyopathy, four cerebrovascular accidents, three myocardial infarctions, and one patient died due to myocardial infaction. Factors significantly associated with an increased risk of 30-d MACE included age ≥60 years, an earlier start of cytokine release syndrome (CRS), CRS ≥ grade 3, long duration of CRS, and use of tocilizumab. After a median follow-up time of 16.2 months (range, 14.3-19.1), the occurrence of 30-d MACE was not significantly associated with progression-free survival or with overall survival. Our results suggest that the occurrence of 30-d MACE is more frequent among patients who are elderly, with early, severe, and prolonged CRS. However, with limited follow-up, larger prospective studies are needed, and multidisciplinary management of these patients is recommended.

Adoptive T cell therapies have shown impressive signals of activity, but their clinical impact could be enhanced by technologies to increase T cell potency and diminish the cost and labor involved in manufacturing these products. Gene editing platforms are under study in this arena to (1) enhance immune cell potency by knocking out molecules that inhibit immune responses; (2) deliver genetic payloads into precise genomic locations and thereby enhance safety and/or improve the gene expression profile by leveraging physiologic promoters, enhancers, and repressors; and (3) enable off-the-shelf therapies by preventing alloreactivity and immune rejection. This review discusses gene editing approaches that have been the best studied in the context of human T cells and adoptive T cell therapies, summarizing their current status and near-term potential for translation.

Objective This study was designed to assess the demographic characteristics of patients with Crohn's perianal fistula (CPF) who were treated at a tertiary referral institution. Surgical outcomes were compared in groups of patients who underwent seton placement, fistulotomy, and stem cell therapy. Methods Patients who underwent surgery for CPF between 2015 and 2017 at Asan Medical Center, Seoul, Korea, were retrospectively evaluated. Patients were divided into groups who underwent seton placement, fistulotomy, and stem cell therapy. Their clinical variables and closure rates were compared. Results This study included 156 patients who underwent a total of 209 operations. More than half of the operations consisted of seton placement (67%), followed by stem cell therapy (18%) and fistulotomy (15%) patients. Of the 209 fistulas, 153 (73%) were complex, with an overall closure rate of 38% during a median follow-up of 29 months. Closure rates following fistulotomy, stem cell therapy, and seton placement were 90%, 70%, and 18%. Seton placement was more significantly frequently used than the other procedures in patients with complex fistula and those with abscesses. Of the 79 fistulas that achieved complete closure, 11 (14%) recurred. The recurrence rates did not differ among the various techniques. Conclusion Surgical treatment of CPF is dependent on lesion type. Seton placement was the primary draining procedure for complex fistulas and abscesses, resulting in low closure rates. Fistulotomy was the definite procedure for low type and simple fistula. Stem cell therapy showed high closure rates as definitive treatment, even for complex fistulas.

Ischemic stroke (IS) is the leading cause of disability and contributes to a significant socio-economic cost in the western world. Brain repair strategies investigated in the pre-clinical models include the delivery of drug or cell-based therapeutics; which is hindered by the complex anatomy and functional organization of the brain. Biomaterials can be instrumental in alleviating some of these challenges by providing a structural support, localization, immunomodulation and/or modulating cellular cross-talk in the brain. This review addresses the significance of and challenges associated with cell therapy in an ischemic brain. This is followed by a detailed insight into the biomaterial-based delivery systems which have been designed to provide sustained trophic factor delivery for endogenous repair and to support transplanted cell survival and integration. A biomaterial intervention uses a multifaceted approach in enhancing the survival and engraftment of cells during transplantation and this has driven them as potential candidates for the treatment of IS. The biological processes that are activated as a response to the biomaterials and how to modulate them is one of the key factors contributing to the success of the biomaterial-based therapeutic approach. Future perspectives highlight the need of a combinative approach of merging the material design with disease biology to fabricate effective biomaterial-based intervention of stroke.

Brain degeneration and damage is difficult to cure due to the limited endogenous repair capability of the central nervous system. Furthermore, drug development for treatment of diseases of the central nervous system remains a major challenge. However, it now appears that using human pluripotent stem cell-derived neural cells to replace degenerating cells provides a promising cell-based medicine for rejuvenation of brain function. Accordingly, a large number of studies have carried out preclinical assessments, which have involved different neural cell types in several neurological diseases. Recent advances in animal models identify the transplantation of neural derivatives from pluripotent stem cells as a promising path toward the clinical application of cell therapies [Stem Cells Transl Med 2019;8:681-693; Drug Discov Today 2019;24:992-999; Nat Med 2019;25:1045-1053]. Some groups are moving toward clinical testing in humans. However, the difficulty in selection of valuable critical quality criteria for cell products and the lack of functional assays that could indicate suitability for clinical effect continue to hinder neural cell-based medicine development [Biologicals 2019;59:68-71]. In this review, we summarize the current status of preclinical studies progress in this area and outline the biological characteristics of neural cells that have been used in new developing clinical studies. We also discuss the requirements for translation of stem cell-derived neural cells in examples of stem cell-based clinical therapy.

[Voir la version anglaise de l’article ici: www.cmaj.ca/lookup/doi/10.1503/cmaj.202907][1] Points cles L’immunotherapie cellulaire est un traitement novateur qui fait appel aux proprietes anticancereuses des cellules immunitaires du corps. L’une des techniques les plus prometteuses est

PURPOSEPatients with relapsed or refractory T-cell acute lymphoblastic leukemia (r/r T-ALL) have few options and poor prognosis. The aim was to assess donor-derived anti-CD7 chimeric antigen receptor (CAR) T-cell safety and efficacy in patients with r/r T-ALL.METHODSIn this single-center, phase I trial, we administered anti-CD7 CAR T cells, manufactured from either previous stem-cell transplantation donors or new donors, to patients with r/r T-ALL, in single infusions at doses of 5 × 105or 1 × 106(±30%) cells per kilogram of body weight. The primary end point was safety with efficacy secondary.RESULTSTwenty participants received infusions. Adverse events including cytokine release syndrome grade 1-2 occurred in 90% (n = 18) and grade 3-4 in 10% (n = 2), cytopenia grade 3-4 in 100% (n = 20), neurotoxicity grade 1-2 in 15% (n = 3), graft-versus-host disease grade 1-2 in 60% (n = 12), and viral activation grade 1-2 in 20% (n = 4). All adverse events were reversible, except in one patient who died through pulmonary hemorrhage related to fungal pneumonia, which occurred at 5.5 months, postinfusion. Ninety percent (n = 18) achieved complete remission with seven patients proceeding to stem-cell transplantation. At a median follow-up of 6.3 months (range, 4.0-9.2), 15 remained in remission. CAR T cells were still detectable in five of five patients assessed in month 6, postinfusion. Although patients' CD7-positive normal T cells were depleted, CD7-negative T cells expanded and likely alleviated treatment-related T-cell immunodeficiency.CONCLUSIONAmong 20 patients with r/r T-ALL enrolled in this trial, donor-derived CD7 CAR T cells exhibited efficient expansion and achieved a high complete remission rate with manageable safety profile. A multicenter, phase II trial of donor-derived CD7 CAR T cells is in progress ( NCT04689659 ).

Glioblastoma (GBM) are the most common and aggressive primary brain tumors in adults. Current mainstay treatments include surgery, chemotherapy, and radiation; however, these are ineffective. As a result, immunotherapy treatment strategies are being developed to harness the body's natural defense mechanisms against gliomas. Adoptive cell therapy with chimeric antigen receptor (CAR) T cells uses patients' own T cells that are genetically modified to target tumor-associated antigens. These cells are harvested from patients, engineered to target specific proteins expressed by the tumor and re-injected into the patient with the goal of destroying tumor cells. In this mini review, we outline the history of CAR T cell therapy, describe current antigen targets, and review challenges this treatment faces specifically in targeting GBM.

It has been nearly 15 years since the discovery of human-induced pluripotent stem cells (iPSCs). During this time, differentiation methods to targeted cells have dramatically improved, and many types of cells in the human body can be currently generated at high efficiency. In the cardiovascular field, the ability to generate human cardiomyocytes in vitro with the same genetic background as patients has provided a great opportunity to investigate human cardiovascular diseases at the cellular level to clarify the molecular mechanisms underlying the diseases and discover potential therapeutics. Additionally, iPSC-derived cardiomyocytes have provided a powerful platform to study drug-induced cardiotoxicity and identify patients at high risk for the cardiotoxicity; thus, accelerating personalized precision medicine. Moreover, iPSC-derived cardiomyocytes can be sources for cardiac cell therapy. Here, we review these achievements and discuss potential improvements for the future application of iPSC technology in cardiovascular diseases.

Cell therapy involves transplantation of human cells to promote repair of diseased or injured tissues and/or cells. Only a limited number of mostly small‐scale trials have studied cell therapy in nonischemic cardiomyopathy (NICM). We performed a meta‐analysis of randomized clinical trials (RCTs) to assess the safety and efficacy of cell therapy in NICM. Electronic databases were searched for relevant RCTs from inception until August 2020. Outcomes assessed were left ventricular ejection fraction (LVEF), left ventricular end‐diastolic diameter or volume (LVEDD), quality of life (QoL) indices, and major adverse cardiac events (MACEs). Weighted mean differences (MDs) and standardized mean differences (SMDs) were calculated using random‐effects methods. Eleven RCTs with 574 participants were included in the analysis. There was a significant increase in mean LVEF (MD, 4.17%; 95% confidence interval [CI] = 1.66‐6.69) and modest decrease in LVEDD (SMD, −0.50; 95% CI = −0.95 to −0.06) in patients treated with cell therapy compared with controls. Cell therapy was also associated with improvement in functional capacity, as assessed by the 6‐minute walking distance (MD, 72.49 m; 95% CI = 3.44‐141.53). No significant differences were seen in MACEs and QoL indices between treated and control groups. This meta‐analysis suggests that cell therapy may improve LV systolic function and may be associated with improvement in LVEDD and functional capacity compared with maximal medical therapy. Cell therapy was safe, with no significant difference in MACEs between treatment and control groups. However, given the limitations of current studies, larger well‐designed RCTs are needed to evaluate the efficacy of cell therapy in patients with NICM., Among 11 studies included in our systematic review, meta‐analysis of nine studies that reported mean change in left ventricular systolic function from baseline to the end of follow‐up after cell therapy in comparison to control group showed significant increase in left ventricular systolic function over time.

Cell and gene therapy is a promising and disruptive new field of medicine for diseases lacking effective treatments. Collaboration among stakeholders has become critically important as investigators, health care providers, manufacturers, couriers, data registries, regulators and payers all become more invested in the success of this field. Many organizations have collaborated with each other to increase clarity, advocate for improvements and share lessons learned. These efforts appear to be making an impact, although the potential for duplicative efforts could slow progress. The second Regenerative Medicine InterCHANGE, hosted by the Foundation for the Accreditation of Cellular Therapy, took place at the Phacilitate Leaders World/World Stem Cell Summit conference in Miami, Florida, on January 24, 2020. Participants from several organizations outlined needs to advance cell and gene therapies. Efforts to address these include standardization, workforce development and advocacy. This article summarizes the major challenges and opportunities discussed during the InterCHANGE.

Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has led to unprecedented results to date in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), yet its clinical application in elderly patients with R/R DLBCL remains somewhat limited. In this study, a total of 31 R/R DLBCL patients older than 65 years of age were enrolled and received humanized anti-CD19 CAR T-cell therapy. Patients were stratified into a fit, unfit, or frail group according to the comprehensive geriatric assessment (CGA). The fit group had a higher objective response (OR) rate (ORR) and complete response (CR) rate than that of the unfit/frail group, but there was no difference in the part response (PR) rate between the groups. The unfit/frail group was more likely to experience AEs than the fit group. The peak proportion of anti-CD19 CAR T-cells in the fit group was significantly higher than that of the unfit/frail group. The CGA can be used to effectively predict the treatment response, adverse events, and long-term survival.

Background: Chimeric antigen receptor (CAR) T cells directed against CD19 (CART19) are effective in B-cell malignancies, but little is known about the molecular factors predicting clinical outcome of CART19 therapy. The increasingly recognized relevance of epigenetic changes in cancer immunology prompted us to determine the impact of the DNA methylation profiles of CART19 cells on the clinical course. Methods: We recruited 114 patients with B-cell malignancies, comprising 77 patients with acute lymphoblastic leukemia and 37 patients with non-Hodgkin lymphoma who were treated with CART19 cells. Using a comprehensive DNA methylation microarray, we determined the epigenomic changes that occur in the patient T cells upon transduction of the CAR vector. The effects of the identified DNA methylation sites on clinical response, cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, event-free survival, and overall survival were assessed. All statistical tests were 2-sided. Results: We identified 984 genomic sites with differential DNA methylation between CAR-untransduced and CAR-transduced T cells before infusion into the patient. Eighteen of these distinct epigenetic loci were associated with complete response (CR), adjusting by multiple testing. Using the sites linked to CR, an epigenetic signature, referred to hereafter as the EPICART signature, was established in the initial discovery cohort (n = 79), which was associated with CR (Fisher exact test, P < .001) and enhanced event-free survival (hazard ratio [HR] = 0.36; 95% confidence interval [CI] = 0.19 to 0.70; P = .002; log-rank P = .003) and overall survival (HR = 0.45; 95% CI = 0.20 to 0.99; P = .047; log-rank P = .04;). Most important, the EPICART profile maintained its clinical course predictive value in the validation cohort (n = 35), where it was associated with CR (Fisher exact test, P < .001) and enhanced overall survival (HR = 0.31; 95% CI = 0.11 to 0.84; P = .02; log-rank P = .02). Conclusions: We show that the DNA methylation landscape of patient CART19 cells influences the efficacy of the cellular immunotherapy treatment in patients with B-cell malignancy., Supported by CERCA Programme/Generalitat de Catalunya, Health Department PERIS #SLT/002/16/00374, AGAUR-project #2017SGR1080; MCI/AEI/ERDF project #RTI2018-094049-B-I00; ERC EPIPHARM; Cellex Foundation; “la Caixa” Foundation (LCF/PR/GN18/51140001 and LCF/PR/GN18/50310007), RF-2016–02364388, Accelerator Award—Cancer Research UK/AIRC—INCAR Associazione Italiana Ricerca per la Ricerca sul Cancro (AIRC) Project 5 × 1000 no. 9962, AIRC IG 2018 id. 21724, AIRC MFAG id. 21769 and id. 20450; MIUR (Grant PRIN 2017); and RCR-2019–23669115.

Follicular lymphoma (FL) accounts for approximately 35% of all non-Hodgkin lymphomas and can progress to diffuse large B cell lymphoma (DLBCL) at a rate of 2% per year. Here, we present a 56-year-old female patient who was diagnosed with grade 3a FL. Further pathological investigation revealed that the lymphoma had transformed into DLBCL following six courses of R-CHOP regimen, and further disease progression was observed after two courses of R2-GemOx. We ultimately failed to collect hematopoietic stem cells after two courses of R2-ICE. CD-22 CAR-T cell therapy salvaged the patient; however, a new soft tissue mass of 4.8 × 4.1 cm rapidly emerged in the patient's right lung. Following the observation of strong tissue staining of PD-L1 (90%), the patient was administered PD-1 inhibitor and 26 Gy of radiotherapy and has maintained progression-free survival at more than 15 months of follow-up. Transformed FL with strong PD-L1 expression showed a poor response to standard immunochemotherapy. Our findings support the potential benefit of PD-1 inhibitor and combination therapies in this type of transformed FL.

Assess the safety and efficacy of upcoming stem cell treatments and analyze their effects on the cognitive and behavioral impairments in patients diagnosed with autism. We included controlled and noncontrolled, randomized and non-randomized trials evaluating stem cell therapy as a treatment in patients with autism spectrum disorder compared to placebo or without comparator. Data Sources: Scopus, Web of Science, MEDLINE and EMBASE. Risk of bias was assessed using Cochrane’s Risk of Bias tool and the NIH’s Quality Assessment Tool for Studies With No Control Group. Eleven trials including 461 patients proved eligible. ABC scale meta-analysis showed a mean raw of -11.97 in the intervention groups (95 % CI -91.45 to 67.52, p

Graphical Abstract In 2006, the induced pluripotent stem cell (iPSC) was presented to the world, paving the way for the development of a magnitude of novel therapeutic alternatives, addressing a diverse range of diseases. However, despite the immense cell therapy potential, relatively few clinical trials evaluating iPSC-technology have actually translated into interventional, clinically applied treatment regimens. Herein, our aim was to determine trends in globally conducted clinical trials involving iPSCs. Data were derived both from well-known registries recording clinical trials from across the globe, and databases from individual countries. Comparisons were firstly drawn between observational and interventional studies before the latter was further analyzed in terms of therapeutic and nontherapeutic trials. Our main observations included global distribution, purpose, target size, and types of disorder relevant to evaluated trials. In terms of nontherapeutic trials, the USA conducted the majority, a large average number of participants—187—was included in the trials, and studies on circulatory system disorders comprised a slightly higher proportion of total studies. Conversely, Japan was the frontrunner in terms of conducting therapeutic trials, and the average number of participants was much lower, at roughly 29. Disorders of the circulatory, as well as nervous and visual systems, were all studied in equal measure. This review highlights the impact that iPSC-based cell therapies can have, should development thereof gain more traction. We lastly considered a few companies that are actively utilizing iPSCs in the development of therapies for various diseases, for whom the global trends in clinical trials could become increasingly important. Supplementary Information The online version contains supplementary material available at 10.1007/s12015-021-10262-3.

Hematopoietic stem cell transplantation (HCT) is a potentially curative treatment for many hematologic conditions. Despite advances in conditioning and supportive measures, however, there remain significant comorbidities that threaten survivorship. Adverse effects of stress-related biobehavioral processes—defined here as the interactions of behavioral, psychological, and socioenvironmental factors with biology—impact immune recovery and function and are particularly salient in the HCT context, given the importance of immune reconstitution for improved survivorship. However, biobehavioral processes have been underinvestigated in this vulnerable group compared with other cancer populations. Here the Biobehavioral Research Special Interest Group (SIG) of the American Society for Transplantation and Cellular Therapy provides an expert review to inform research directions explicating the biological correlates of behavioral symptoms and evaluate the impact of these on HCT outcomes. The goal of this expert review is to provide a foundation for advancing science that effectively integrates behavioral and biological processes to optimize quality of life and improve clinical outcomes for HCT recipients.

The successful commercialization of cell therapies requires thorough planning and consideration of product quality, cost and scale of the manufacturing process. The implementation of automation can be central to a robust and reproducible manufacturing process at industrialized scales. There have been a number of wash-and-concentrate devices developed for cell manufacturing. These technologies have arisen from transfusion medicine, hematopoietic stem cell and biologics manufacturing where operating mechanisms are distinct from manual centrifugation. This review describes the historical origin and fundamental technologies underlying each currently available wash-and-concentrate device as well as their relative advantages and disadvantages in cell therapy applications. Understanding the specific attributes and limitations of these technologies is essential to optimizing cell therapy manufacturing.

Osteoarthritis (OA) is a degenerative disease of cartilage and bones, which results in severely compromised quality of life in the aged population. However, currently, no ideal treatment strategies have been developed to prevent OA progression. Cell therapies, such as chondrocyte and MSC transplantation, have been extensively tested and evaluated in clinical trials. Yet, to day, the clinical efficacy of articular injection of stem cells in OA has not been convincingly demonstrated. Recent studies have indicated that exosomes, one type of Extracellular Vesicles (EVs) play an important regulatory role in the pathogenesis of OA, suggesting the prospective therapeutic application of exosomes in OA treatment. In this review, we systematically summarized the paracrine effects of exosomes derived from MSCs and chondrocytes on cartilage regeneration, the use of exosomes as a delivery vehicle for OA treatment, the effectiveness of such treatments in OA animal models, and the future perspective of exosome-mediated drug delivery as a cell- free therapy of OA.

Biological treatments are one of the medical breakthroughs in the twenty-first century. The initial enthusiasm pushed the field towards indiscriminatory use of cell therapy regardless of the pathophysiological particularities of underlying conditions. In the reparative and regenerative cardiovascular field, the results of the over two decades of research in cell-based therapies, although promising still could not be translated into clinical scenario. Now, when we identified possible deficiencies and try to rebuild its foundations rigorously on scientific evidence, development of potency assays for the potential therapeutic product is one of the steps which will bring our goal of clinical translation closer. Although, highly challenging, the potency tests for cell products are considered as a priority by the regulatory agencies. In this paper we describe the main characteristics and challenges for a cell therapy potency test focusing on the cardiovascular field. Moreover, we discuss different steps and types of assays that should be taken into consideration for an eventual potency test development by tying together two fundamental concepts: target disease and expected mechanism of action. Graphical Abstract Development of potency assays for cell-based products consists in understanding the pathophysiology of the disease, identifying potential mechanisms of action (MoA) to counteract it and finding the most suitable cell-based product that exhibits these MoA. When applied, the potency assay needs to correlate bioactivity of the product, via a measurement related to the MoA, with treatment efficacy. However, in the cardiovascular field, the process faces several challenges and high requirements.

Cell therapy has emerged as an attractive therapeutic option in organ transplantation. During the last decade, the therapeutic potency of Treg immunotherapy has been shown in various preclinical animal models and safety was demonstrated in first clinical trials. However, there are still critical open questions regarding specificity, survival, and migration to the target tissue so the best Treg population for infusion into patients is still under debate. Recent advances in CAR technology hold the promise for Treg-functional superiority. Another exciting strategy is the generation of B-cell antibody receptor (BAR) Treg/cytotoxic T cells to specifically regulate or deplete alloreactive memory B cells. Finally, B cells are also capable of immune regulation, making them promising candidates for immunomodulatory therapeutic strategies. This article summarizes available literature on cell-based innovative therapeutic approaches aiming at modulating alloimmune response for transplantation. Crucial areas of investigation that need a joined effort of the transplant community for moving the field toward successful achievement of tolerance are highlighted.

Regenerative medicine, using cells as therapeutic agents for the repair or regeneration of tissues and organs, offers great hope for the future of medicine. Cell therapy for treating defects in articular cartilage has been an exemplar of translating this technology to the clinic, but it is not without its challenges. These include applying regulations, which were designed for pharmaceutical agents, to living cells. In addition, using autologous cells as the therapeutic agent brings additional costs and logistical challenges compared with using allogeneic cells. The main cell types used in treating chondral or osteochondral defects in joints to date are chondrocytes and mesenchymal stromal cells derived from various sources such as bone marrow, adipose tissue or umbilical cord. This review discusses some of their biology and pre-clinical studies before describing the most pertinent clinical trials in this area.

Severe acute respiratory syndrome-associated coronavirus 2 (SARS-CoV-2) is an extremely pathogenic virus belonging to the family of Coronaviridae. First identified in Wuhan, China in December 2019 after an epidemiological investigation of an emerging cluster of pneumonia of unknown etiology, SARS-CoV-2 was declared the cause of a pandemic on March 11 by the World Health Organization (WHO), pointing to the over 118000 cases of Coronavirus disease 2019 (COVID-19) in over 110 countries. Despite the promising results of drug repositioning studies in the treatment of COVID-19, the evidence of their safety and efficacy remains inconclusive. Cell based therapy has been proven safe and possibly effective in treating multiple lung injuries and diseases, but its potential use in the treatment of COVID-19 has not been yet elucidated. Our aim in this review is to provide an overview of the immunomodulatory effect and the regenerative capacity of stem cells and their secretome in the treatment of many diseases including lung injuries. Those findings may contribute to a better understanding of the potential of stem cell therapy in SARS-CoV-2 infection and its potential use in order to find a solution for this healthcare crisis.

PURPOSE OF REVIEW Current immunosuppressive regimens used in kidney transplantation are sometimes ineffective and carry significant risks of morbidity and mortality. Cellular therapies are a promising alternative to prolong graft survival while minimizing treatment toxicity. We review the recently published breakthrough studies using cell therapies in kidney transplantation. RECENT FINDINGS The reviewed phase I and II trials showed that cell therapies are feasible and safe in kidney transplantation, sometimes associated with less infectious complications than traditional regimens. Regulatory T cells and macrophages were added to the induction regimen, allowing for lower immunosuppressive drug doses without higher rejection risk. Regulatory T cells are also a treatment for subclinical rejection on the 6 months biopsy. Other strategies, like bone marrow-derived mesenchymal cells, genetically modified regulatory T cells, and chimerism-based tolerance are also really promising. In addition, to improve graft tolerance, cell therapy could be used to prevent or treat viral infection after transplantation. SUMMARY Emerging data underline that cell therapy is a feasible and safe treatment in kidney transplantation. Although the evidence points to a benefit for transplant recipients, studies with standardized protocols, representative control groups, and longer follow-up are needed to answer the question definitively and guide future research.

BACKGROUND Recent advances made in cell and gene therapies for cancer suggest that they represent plausible strategies to cure HIV. However, the health risks and constraints associated with these therapies require a deeper understanding of the expectations of such treatments among people living with HIV (PLWH). METHODS We conducted 15 semistructured in-depth interviews among patients from 2 HIV units in Switzerland. After a conversation about their perceptions of research on HIV therapies, participants were provided with a trial description using a gene-modified cell therapy as a potentially curative approach. They were invited to discuss how they might consider participation in the trial. Content analysis was performed to identify core themes. RESULTS Participants perceived the trial as burdensome and uncertain. Most were aware that cure was not guaranteed, and 6 of the 15 considered that they would participate. Two main concerns were expressed about potential participation: (1) the impact on the professional life and fear to be stigmatized because of this and (2) the fact that stopping antiretroviral treatment would challenge the balance currently achieved in their lives. The decision to participate would depend on their understanding of the trial, the availability of sufficient information, and the relationship with health care professionals. CONCLUSION Involving PLWH in early stages of research would be crucial to improve their understanding of gene-modified cell therapies. It could also help adapt trials to address key factors, including the anticipation of stigma, which may discourage PLWH from participating in treatment research.

BACKGROUND Scarring is an unfortunate result of acne because it causes the psychological and cosmetic problems for the patients. Unfortunately, no single treatment is suitable, and using multiple methods may have a better result. The autologous fat and stromal vascular fraction (SVF) cells and their secretory factors can enhance the angiogenesis, collagen synthesis, and migration of fibroblasts, therefore regenerate hurt tissues. Moreover, other treatments for acne scarring, such as platelet-rich plasma (PRP), induce the increase in scare. AIMS This study aimed to verify the effectiveness of transplantation of autologous fat, SVF cells, and PRP as cell therapy techniques on atrophic acne scars. PATIENTS/METHODS This study included 9 adult patients with atrophic acne scars on face. All patients received the transplantation of autologous fat, stromal vascular fraction (SVF) cells, and PRP. The treatment outcome was measured by biometric assessment (VisioFace 1000 D, Colorimeter, multi-probe adapter Cutometer, Tewameter, Mexameter, and skin ultrasound imaging system), and also, the satisfaction of patients was evaluated. The patients were followed 6 months after the treatment. RESULTS There was a significant improvement in the skin pores, spots, skin lightness and melanin content of skin, skin elasticity, and TEWL (transepidermal water loss) after 6 months of the treatment. Furthermore, denser skin layers were observed both in the epidermis and in the dermis. Moreover, 66.6% of patients showed good satisfaction after the treatment. CONCLUSION In brief, the transplantation of autologous fat, SVF cells, and PRP is an effective cell therapy for atrophic acne scars.

The prognosis of Ewing sarcoma caused by EWS/FLI1 fusion is poor, especially after metastasis. Although therapy with CTLs targeted against altered EWS/FLI1 sequences at the gene break/fusion site may be effective, CTLs generated from peripheral blood are often exhausted because of continuous exposure to tumor antigens. We addressed this by generating induced pluripotent stem cell (iPSC)–derived functionally rejuvenated CTLs (rejT) directed against the neoantigen encoded by the EWS/FLI1 fusion gene. In this study, we examined the antitumor effects of EWS/FLI1-rejTs against Ewing sarcoma. The altered amino acid sequence at the break/fusion point of EWS/FLI1, when presented as a neoantigen, evokes an immune response that targets EWS/FLI1+ sarcoma. Although the frequency of generated EWS/FLI1-specific CTLs was only 0.003%, we successfully established CTL clones from a healthy donor. We established iPSCs from a EWS/FLI1-specific CTL clone and redifferentiated them into EWS/FLI1-specific rejTs. To evaluate cytotoxicity, we cocultured EWS/FLI1-rejTs with Ewing sarcoma cell lines. EWS/FLI1-rejTs rapidly and continuously suppressed the proliferation of Ewing sarcoma for >40 hours. Using a Ewing sarcoma xenograft mouse model, we verified the antitumor effect of EWS/FLI1-rejTs via imaging, and EWS/FLI1-rejTs conferred a statistically significant survival advantage. “Off-the-shelf” therapy is less destructive and disruptive than chemotherapy, and radiation is always desirable, particularly in adolescents, whom Ewing sarcoma most often affects. Thus, EWS/FLI1-rejTs targeting a Ewing sarcoma neoantigen could be a promising new therapeutic tool.

Chimeric antigen receptor (CAR) T-cells have emerged as an efficacious modality in patients with non-Hodgkin lymphoma (NHL) and multiple myeloma (MM). Clonal hematopoiesis of indeterminate potential (CHIP), a state in which mutations in hematopoietic cells give rise to a clonal population of cells, is more common in patients exposed to cytotoxic therapies, has been shown to influence inflammatory immune programs, and is associated with an adverse prognosis in patients with NHL and MM receiving autologous transplantation. We therefore hypothesized that CHIP could influence clinical outcomes in patients receiving CAR T-cell therapy. In a cohort of 154 patients with NHL or MM receiving CAR T-cells, we found that CHIP was present in 48% of patients and associated with increased rates of complete response and cytokine release syndrome severity, but only in patients younger than age 60 years. Despite these differences, CHIP was not associated with a difference in progression-free or overall survival, regardless of age. Our data suggest that CHIP can influence CAR T-cell biology and clinical outcomes, but, in contrast to autologous transplantation, CHIP was not associated with worse survival and should not be a reason to exclude individuals from receiving this potentially life-prolonging treatment.

Wound healing has been greatly challenging in different acute and chronic skin injuries. Among them, nonrevascularizable critical limb ischemic ulcers, venous leg ulcers, and diabetic lower limb or extremity ulcers are well-known refractory skin injuries that are difficult to treat. Partly differentiated, progenitor cell-based graft transplantation or direct injection of autologous stem cells might promote the wound healing process. Studies aiming to comprehensively analyze the effects of cell therapy on skin wound healing could provide clinical evidence for skin injury treatment. Different databases were searched for full-text publications on the comparison between cell therapy and regular therapy. Heterogeneity was detected by the I2 method, and a fixed effect model was applied for data pooling if heterogeneity was absent. Publication bias was analyzed using a funnel plot, and 10 studies were finally included in this study. After a long-term follow-up, fewer patients underwent major amputation in the cell therapy group, compared with the standard therapy group, and those in the cell therapy group were characterized by a smaller ulcer area. Moreover, there was a significant difference in the wound healing rate between the intervention and control groups. However, pain caused by skin wounds was hardly mitigated by cell therapy in patients with critical limb ischemia. In this study, cell therapy proved effective in decreasing the size of ulcers and improving the wound closure rate. Additionally, the major amputation rate was decreased in the cell therapy group. However, the symptoms of pain were hardly alleviated by cell therapy in patients with cutaneous ulcers caused by peripheral artery disease-related critical limb ischemia.

Summary Regenerative medicine has great potential. The pace of scientific advance is exciting and the medical opportunities for regeneration and repair may be transformative. However, concerns continue to grow, relating to problems caused both by unscrupulous private clinics offering unregulated therapies based on little or no evidence and by premature regulatory approval on the basis of insufficient scientific rationale and clinical evidence. An initiative by the InterAcademy Partnership convened experts worldwide to identify opportunities and challenges, with a focus on stem cells. This was designed to be inclusive and consensus outputs reflected the diversity of the global research population. Among issues addressed for supporting research and innovation while protecting patients were ethical assessment; pre-clinical and clinical research; regulatory authorization and medicines access; and engagement with patients, policy makers, and the public. The InterAcademy Partnership (IAP) identified options for action for sharing good practice and building collaboration within the scientific community and with other stakeholders worldwide., Highlights • An inclusive IAP study examined global stem cell opportunities and challenges • Great potential leads to concerns for evidence base in unregulated clinics • Also concerns for premature regulatory approval without sufficient evidence • Recommendations for responsible research and innovation and collaborations, In this article, Fears and colleagues describe an inclusive global initiative by the InterAcademy Partnership examining stem cell opportunities and challenges. Great therapeutic potential brings concerns about the inadequate evidence base used by unregulated clinics. Concerns are also expressed about premature regulatory approval without sufficient evidence. Recommendations cover ethical assessment; pre-clinical and clinical research; regulatory authorization and medicines access; and engagement with patients, policy makers, and the public.

Introduction Geographic access to novel oncology therapies, and the extent to which it may vary by potential sites of care, regions, and population characteristics, is poorly understood. We examined how expanding access to chimeric antigen receptor (CAR) T cell therapy administration sites impacts patient travel distances and time. Methods We used geographic information system techniques to calculate shortest travel distance and time between patients with relapsed/refractory diffuse large B cell lymphoma (DLBCL) and the nearest CAR T cell therapy administration site in three scenarios: academic hospitals; academic and community multispecialty hospitals; and academic and community multispecialty hospitals plus nonacademic specialty oncology network centers. Main outcome measures were differences in travel distance and time among the scenarios and the relationship between travel time and socioeconomic status, race, rural–urban areas, and non-Hodgkin lymphoma clusters. Non-Hodgkin lymphoma incidence, socioeconomic status, and administration centers were derived from governmental/publicly available data sources. Results Of 3922 patients eligible for CAR T cell therapy, more than 37% had to travel more than 1 h to the nearest academic hospital. Average travel time and distance were significantly reduced by 23% and 30% (P

Сytokine release syndrome is the common complication of CAR-T therapy. We report a case of patient with B-cell acute lymphoblastic leukemia developing сytokine release syndrome with shock and multiple organ failure and requiring cytokine removal and hemodiafiltration. Remission of the disease was achieved after CAR-T therapy.Распространенным осложнением терапии T-клетками с химерным антигенным рецептором (CAR-T-терапии) является синдром высвобождения цитокинов (СВЦ). Представлено клиническое наблюдение за больным В-острым лимфобластным лейкозом, у которого после CAR-T-терапии развился СВЦ, протекавший с шоком и полиорганной недостаточностью, что потребовало применения сорбции цитокинов в сочетании с гемодиафильтрацией и позволило вывести больного из шока и привести к разрешению СВЦ. В результате CAR-T-терапии достигнута ремиссия лейкоза.

Duchenne muscular dystrophy (DMD) is a progressive and lethal disease, caused by X‐linked mutations of the dystrophin encoding gene. The lack of dystrophin leads to muscle weakness, degeneration, fibrosis, and progressive loss of skeletal, cardiac, and respiratory muscle function resulting in premature death due to the cardiac and respiratory failure. There is no cure for DMD and current therapies neither cure nor arrest disease progression. Thus, there is an urgent need to develop new approaches and safer therapies for DMD patients. We have previously reported functional improvements which correlated with increased dystrophin expression following transplantation of dystrophin expressing chimeric (DEC) cells of myoblast origin to the mdx mouse models of DMD. In this study, we demonstrated that systemic‐intraosseous transplantation of DEC human cells derived from myoblasts of normal and DMD‐affected donors, increased dystrophin expression in cardiac, respiratory, and skeletal muscles of the mdx/scid mouse model of DMD. DEC transplant correlated with preservation of ejection fraction and fractional shortening on echocardiography, improved respiratory function on plethysmography, and improved strength and function of the limb skeletal muscles. Enhanced function was associated with improved muscle histopathology, revealing reduced mdx pathology, fibrosis, decreased inflammation, and preserved muscle morphology and architecture. Our findings confirm that DECs generate a systemic protective effect in DMD‐affected target organs. Therefore, DECs represents a novel therapeutic approach with the potential to preserve or enhance multiorgan function of the skeletal, cardiac, and respiratory muscles critical for the well‐being of DMD patients., Systemic‐intraosseous transplantation of human dystrophin expressing chimeric (DEC) cells (0.5 × 106 and 1 × 106) results in significant increase in dystrophin expression in heart, diaphragm, and gastrocnemius muscle (GM) which correlates with the reduction of centrally nucleated fibers in diaphragm and GM indicating reduced muscle pathology and further confirming beneficial effect of DEC therapy at 90 days after systemic transplant to mdx/scid mouse model of DMD.

Significance: Heart failure is among the leading causes of morbidity worldwide with a 5-year mortality rate of ∼50%. Therefore, major efforts are invested to reduce heart damage upon injury or main...