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Heart failure with preserved ejection fraction (HFpEF) is defined by increased left ventricular (LV) stiffness, impaired vascular compliance, and fibrosis. Although systemic inflammation, driven by comorbidities, has been proposed to play a key role, the precise pathogenesis remains elusive. To test the hypothesis that inflammation drives endothelial dysfunction in HFpEF, we used cardiosphere-derived cells (CDCs), which reduce inflammation and fibrosis, improving function, structure, and survival in HFpEF rats. Dahl salt-sensitive rats fed a high-salt diet developed HFpEF, as manifested by diastolic dysfunction, systemic inflammation, and accelerated mortality. Rats were randomly allocated to receive intracoronary infusion of CDCs or vehicle. Two weeks later, inflammation, oxidative stress, and endothelial function were analyzed. Single-cell RNA sequencing of heart tissue was used to assay transcriptomic changes. CDCs improved endothelial-dependent vasodilation while reducing oxidative stress and restoring endothelial nitric oxide synthase (eNOS) expression. RNA sequencing revealed CDC-induced attenuation of pathways underlying endothelial cell leukocyte binding and innate immunity. Exposure of endothelial cells to CDC-secreted extracellular vesicles in vitro reduced VCAM-1 protein expression and attenuated monocyte adhesion and transmigration. Cell therapy with CDCs corrects diastolic dysfunction, reduces oxidative stress, and restores vascular reactivity. These findings lend credence to the hypothesis that inflammatory changes of the vascular endothelium are important, if not central, to HFpEF pathogenesis.

In a three-way blinded, randomized design, we determined whether allogeneic CDCs administered at reperfusion improved myocardial function and whether intravenous cyclosporine enhanced their efficacy. In contrast to prior studies using oral cyclosporine, CDCs with or without intravenous cyclosporine had no effect on function or infarct size. This indicates that CDCs may be most efficacious for treating chronic LV dysfunction where cyclosporine can be initiated at least 72 h before cell therapy.

Chimeric antigen receptor (CAR) T-cell is potentially curative therapy for patients with hematologic malignancies but can cause life-threatening toxicities. Data on perceptions of prognosis and psychological distress are lacking.The authors conducted a cross-sectional study of patients receiving CAR-T. Before hospitalization for CAR-T, patients completed assessments of quality of life (QOL) (Functional Assessment of Cancer Therapy-General), anxiety and depression symptoms (Hospital Anxiety and Depression Scale) and post-traumatic stress disorder symptoms (Post-Traumatic Stress Checklist). Patients also completed the Prognostic Awareness Impact Scale (PAIS), which measures three domains: cognitive understanding of prognosis, emotional coping with prognosis, and adaptive response.A total of 71.8% (102 of 142) of eligible patients were enrolled. A total of 34% of patients reported that their oncologist said their cancer is curable and 64% reported there was50% chance of cure. Overall, 26%, 30%, and 21% of patients reported clinically significant depression, anxiety, and posttraumatic stress disorder (PTSD) symptoms, respectively. We found no association between patients' cognitive understanding of prognosis and QOL or mood. Higher emotional coping with prognosis was associated with better QOL (Β = 0.72; SE = 0.10; p =.001) and lower depression (Β = -0.17; SE = 0.02; p =.001), anxiety (Β = -0.21; SE = 0.02; p =.001), and PTSD (Β = -0.43; SE = 0.06; p =.001) symptoms. Higher adaptive response was associated with better QOL (Β = 0.19; SE = 0.09; p = .028) and lower depression (Β = -0.05; SE = 0.02; p = .023), anxiety (Β = -0.09; SE = 0.02; p =.001), and PTSD (Β = -0.19; SE = 0.05; p =.001) symptoms.Patients undergoing CAR-T report overly optimistic perception of their prognosis and have high rates of psychological distress. Higher emotional coping with prognosis and adaptive response were associated with better QOL and less psychological distress, underscoring the need to develop interventions to promote coping with this treatment.Patients undergoing chimeric antigen receptor T-cell therapy experience report overly optimistic perceptions of their prognosis and have high rates of psychological distress. Notably, higher emotional coping with prognosis and adaptive response were associated with better quality of life and less psychological distress.

Chimeric antigen receptor (CAR) T-cells are now a well-established treatment for hematologic malignancies. Their use in clinical practice has expanded quite rapidly and hospitals have developed CAR T-cell protocols to evaluate patients for associated toxicities, and particularly for neurotoxicity. There are many variables that influence the risk for developing this complication, many of which are not fully understood. The severity can be related to a particular product. Clinical vigilance is critical to facilitate early recognition of neurotoxicity, hence the importance of pre-CAR T-cell neurological evaluation of each patient. While details of such an evaluation may slightly differ between institutions, generally a comprehensive neurological evaluation including assessment of cognitive abilities along with magnetic resonance imaging (MRI) of the brain is a gold standard. Management of neurotoxicity requires a well-orchestrated team approach with specialists from oncology, neurology, oftentimes neurosurgery and neuro-intensive care. Diagnostic work-up frequently includes detailed neurologic evaluation with comparison to the baseline assessment, imaging of the brain, electroencephalogram, and lumbar puncture. While steroids are uniformly used for treatment, many patients also receive tocilizumab for an underlying and frequently concomitant cytokine release syndrome (CRS) in addition to symptom-driven supportive care. Novel CAR T-cell constructs and other agents allowing for potentially lower risk of toxicity are being explored. While neurotoxicity is predominantly an early, and reversible, event, a growing body of literature suggests that late neurotoxicity with variable clinical presentation can also occur.

Chimeric antigen receptor (CAR) T-cell therapy is an example of gene engineering-based cellular therapy, which combines immunotherapy, gene therapy, and cellular therapy. Historically, the second clinical trial of gene therapy for patients with haemophilia B was conducted by Chinese scientists in 1991, and China became the first country to approve a commercial gene therapy product in 2003. However, China almost lost its lead in this field, partly due to an early scarcity of clear and cohesive policies regarding cellular therapy. Cellular therapy is not only a novel medical practice but also a medicinal product. The increasing commercialisation of globally approved cell therapy products made the Chinese Government issue a series of relevant policies to promote the canonical development of cell therapy and its standardisation in China. Encouraged by flexible regulatory frameworks that have facilitated the development of cellular therapy since 2017, remarkable progress has been achieved, thereby putting China back at the forefront of the field worldwide. Some policies on cellular therapy launched by the Chinese government in 2019 have contributed to the growth of cellular therapy in China; however, the regulation, governance, and management of commercialised products remain challenging. This Series paper aims to provide an overview of the current regulatory reforms on clinical cellular therapy in China with a historical perspective. We also highlight several important contributors that could promote innovation and industrialisation of cellular therapy in China. Further efforts are needed to establish a legislative system with clear and cohesive policies for the increasing use of cellular therapy in China, enabling a more prescriptive, diligent, and informed process.

Chimeric antigen receptor (CAR) T-cell therapies have achieved remarkable success in the treatment of haematological malignancies. Over the past 9 years, the use of CAR T-cell therapies has expanded throughout China, from the first clinical trials of CAR T cells conducted in 2013, to the world's largest number of CAR T-cell-related clinical trials in 2017, to a cumulative US$2·37 billion in funding for cell therapy companies in 2021, and a significant growth in the number of CAR T-cell-related clinical trials and basic research. This strong increase in activity is the result of a culmination of factors in China: strong government support, capital inflow, large patient demand, a unique health-care system, and the efforts of Chinese physicians and scientists. This Series paper provides an overview of the scope of CAR T-cell clinical trials in China (especially in the field of haematological malignancies), analyses the relevant policies, summarises the characteristics of corporate and capital support, and explores the achievements and challenges of CAR T-cell therapy in China to provide a better understanding for further promoting the development of cellular therapy and its clinical application.

The purpose of our paper is to describe the all-encompassing supportive care for patients with relapsed or refractory lymphoma undergoing cellular therapy, with a focus on the advanced practice provider's (APPs) perspective.Chimeric antigen receptor-T (CAR-T) cell therapy has become more available for treating relapsed or refractory B-cell hematologic malignancies, requiring proficient and adequate treatment of side effects, complications, and infections that may occur during therapy. APPs often meet these patients during the initial referral and help to support them through the CAR-T cell therapy process. As APPs acquire a complete understanding and comprehensive knowledge of how to treat, support, and guide patients with B-cell malignancies through CAR-T cell therapy, they play a pivotal role in these patients throughout their treatment. Standardization of supportive care is paramount.

Modular automation is a flexible and reliable option to build the foundation of a new or evolving process or to introduce automation to a process that is already established. Herein the authors demonstrate that modular automation provides both high-quality and high-yield T-cell products.Cells from three individual donors collected on an automated continuous flow centrifugation system were successfully expanded in a functionally closed, automated, perfusion-based hollow fiber bioreactor. These cells were then prepared for cryopreservation in an automated closed-system device that maintains temperature and aliquots a mixed cell product and cryoprotectant into product bags. Cell product bags were thawed and expanded in flasks. Samples taken throughout this manufacturing process were analyzed for cell phenotype, exhaustion markers and functionality. The proportion of CD4+ and CD8+ T cells was maintained through each step, from pre-expansion and post-expansion to immediately after thaw and 24 h after thaw.Interestingly, phenotypic markers such as CD45RO, CD45RA and CCR7 evolved throughout the process and stem-like memory T cells emerged as the predominant phenotype in the clinically relevant 24-h post-thaw sample.Modular automation supported the generation of stem-like memory T cells that were not terminally exhausted and were able to produce effector cytokines upon restimulation.

Cytokine release syndrome (CRS) is a potentially lethal toxicity associated with chimeric antigen receptor T cell therapy for pediatric acute lymphoblastic leukemia (ALL). Outcomes after critical illness due to severe CRS are poorly described. Our aim was to characterize critical illness outcomes across a multicenter cohort of PICU patients with ALL and CRS.Multicenter retrospective cohort study.Twenty-one PICUs contributing data to Virtual Pediatric Systems, LLC (January 2020-December 2021).PICU patients with ALL or unclassified leukemia and CRS.None.We identified 55 patients; 34 (62%) were 12 years or older, 48 (87%) were admitted from a hospital inpatient ward, and 23 (42%) received advanced organ failure support or monitoring. Fifty-one survived to PICU discharge (93%) including 19 of 23 (83%) who received advanced organ failure support or monitoring defined as receipt of noninvasive or invasive ventilation, cardiopulmonary resuscitation, extracorporeal membrane oxygenation, continuous renal replacement therapy, or placement of a tracheostomy, arterial catheter, hemodialysis catheter, or intracranial catheter. Twelve patients (22%) received invasive ventilation, nine of whom survived to PICU discharge. Two of four patients who received continuous renal replacement therapy and one of three patients who required cardiopulmonary resuscitation survived to PICU discharge. Lengths of PICU stay were median 3.0 days (interquartile range, 1.4-7.8 d) among PICU survivors, 7.8 (5.4-11.1) among those receiving advanced organ failure support or monitoring, and 7.2 days (interquartile range, 2.9-14.7 d) among nonsurvivors. Of the 51 patients who survived to PICU discharge, 48 (94%) survived the hospitalization.PICU patients with CRS frequently received a high level of support, and the majority survived their PICU stay and hospitalization. Additional multicenter investigations of severe CRS are necessary to inform evidence-based practice.

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.

The effect of the gut microbiota on patients' outcomes after allogeneic haematopoietic cell transplantation (HCT) is now well established. In particular, gut microbiota dysbiosis has been associated with acute graft-versus-host disease (GVHD). Furthermore, increasing data also suggest an effect of the gut microbiota on outcome after autologous HCT and CAR T cells. In fact, the bacterial gut microbiota interplays with the immune system and contributes to immunological complication and antitumour response to treatment. Therefore, faecal microbiota transplantation has been evaluated in patients with haematological malignancies for various indications, including Clostridioides difficile infection, eradication of multidrug-resistant bacteria, and steroid refractory acute GVHD. In addition, use of prophylactic faecal microbiota transplantation to restore the gut microbiota and improve patients' outcomes is being developed in the setting of allogeneic HCT, but also probably very soon in patients receiving autologous HCT or CAR T cells.

Budding off from the broader developmental biology and stem cell research fields, cellular reprogramming is now established as a prominent discipline in its own right. Direct cell reprogramming is defined as the cell fate conversion of a somatic cell toward another identity without a pluripotent intermediate state. In addition to the opportunity for mechanistic dissection of lineage commitment in human cells, the field offer the promise of diverse applications such as for disease modeling, cell replacement therapy, regenerative medicine, and immunotherapy that have recently spurred innovation and out of the box thinking to unleash the potential of cellular plasticity.

Mesenchymal stem cell (MSC) products are promising therapeutic candidates to treat a wide range of pathologies. The successful commercialization of these cell therapies will, however, depend on the development of reproducible cell production processes. For this, using microcarriers as growth supports within controlled conditions may be a viable process option. Although increasing microcarrier concentration may be associated with greater productivity due to the increased available culture surface, additional friction or shocks between microcarriers are likely to lead to undesired cell death. However, data detailing the impact of microcarrier collisions on MSC growth remains scarce. The following work demonstrates that MSC growth on microcarriers is greatly influenced by particle concentration even when little impact is observed on the apparent growth rate. It is suggested that the apparent growth rate may result in an equilibrium between growth and death kinetics which are independently affected by particle concentration and that certain MSC quality attributes may be progressively degraded in parallel. In addition, the theoretical reduction of the MSC growth rate was modeled according to the ratio between the average interparticle distance and the Kolmogorov scale. This study is an original contribution toward understanding the hydrodynamic effects in microcarrier-based stem cell cultures.

Over the last decades, the success of advanced cell therapies and the increasing production volumes of vaccines, proteins, or viral vectors have raised the need of robust cell-based manufacturing processes for ensuring product quality and satisfying good manufacturing practice requirements. The cultivation process of cells needs to be highly controlled for improved productivity, reduced variability, and optimized bioprocesses. Cell cultures can be easily monitored using different technologies, which could deliver direct or indirect assessment of the cells' viability. Among these techniques, nuclear magnetic resonance (NMR) spectroscopy is a powerful technology that permits the evaluation and the identification of key endogenous metabolites. NMR can provide information on the cell metabolic pathways, on the bioprocesses, and is also capable to quickly test for impurities. In this study, NMR was successfully used as a technology for monitoring cell viability and expansion in different supports for cell growth (including bioreactors), to predict the bioprocess output and for the early identification of key metabolites linked to cell starvation. This investigation will allow the timely control of culture conditions and favor the optimization of the bioprocesses.

Hematological malignancies represent defying clinical conditions, with high levels of morbidity and mortality, particularly considering patients who manifest multiple refractory diseases. Recently, chimeric antigen receptor (CAR)-T cell therapy has emerged as a potential treatment option for relapsed/refractory B cell malignancies, which have motivated the Food and Drug Administration approval of a series of products based on this technique. The objective of this systematic review was to assess the efficacy and safety of CAR-T cell therapy for patients with hematological malignancies. A comprehensive literature search was conducted in the electronic databases (CENTRAL, Embase, LILACS, and MEDLINE), clinical trials register platforms (Clinicaltrials.gov and WHO-ICTRP), and grey literature (OpenGrey). The Cochrane Handbook for Reviews of Interventions was used for developing the review and the PRISMA Statement for manuscript reporting. The protocol was prospectively published in PROSPERO database (CRD42020181047). After the selection process, seven RCTs were included, three of which with available outcome results. The available results are from studies assessing axicabtagene, lisocabtagene, and tisagenlecleucel for patients with B cell lymphoma, and the certainty of evidence ranged from very low to low for survival and progression-related outcome and for safety outcomes. Additionally, four randomized controlled trials comparing CAR-T cell therapy to the standard treatment for various types of relapsed/refractory B cell non-Hodgkin lymphomas and multiple myeloma included in this systematic review still did not have available outcome data. The results of this review may be used to guide clinical practice but evidence concerning the safety and efficacy of CAR-T Cell therapy for hematological malignancies is still immature to recommend its application outside of clinical trials or compassionate use context for advanced and terminal cases. It is expected the results of the referred comparative studies will provide further elements to subsidize the broader application of this immunotherapy.

This white paper was developed to provide leukapheresis guidance for the collection of mononuclear cells from adult and pediatric patients who are destined for immune effector cell (IEC) therapies for commercial and research applications. Currently, there is considerable variability in leukapheresis processes and limited published information regarding best practices relevant to new cellular therapies, especially IECs. Herein the authors address critical leukapheresis questions in five domains to help guide consistent collection processes and ensure high-quality products. The first four domains are onboarding, pre-collection, collection and post-collection, with protocol feasibility, preparation, care and follow-up of the patient/donor at each step, respectively, and technical considerations during collection. The fifth domain of quality assurance focuses on ensuring product potency, purity, safety and auditing.The American Society for Apheresis (ASFA) Clinical Applications Committee (IEC Therapy Subcommittee) was charged by the society's board of directors with working collaboratively with other ASFA committees and organizations, including the Foundation for the Accreditation of Cellular Therapy, Association for the Advancement of Blood and Biotherapies, American Society for Transplantation and Cellular Therapy, National Marrow Donor Program and International Society for CellGene Therapy, to develop guidelines regarding leukapheresis collection of cells destined for the manufacture of IEC therapies. After a review of the literature and discussion with members of the involved committees and various institutions, a draft guidance was created and circulated for comment and revision.Critical aspects of apheresis that could affect the quality and quantity of the leukapheresis product were identified. These areas were then discussed and reviewed. After consensus, the best practice guidelines were proposed and accepted.In the current era of rapid growth of IEC therapies, it is important to address critical leukapheresis steps to provide high-quality products and more consistent practices and to eliminate redundant efforts.

Cell therapy, gene therapy, and tissue engineering have the potential to revolutionize the field of regenerative medicine. In particular, gene therapy is understood as the therapeutical correction of mutated genes by addition of a correct copy of the gene or site-specific gene modifications. Gene correction of somatic stem cells sustaining renewing tissues is critical to ensure long-term clinical success of ex vivo gene therapy. To date, remarkable clinical outcomes arose from combined ex vivo cell and gene therapy of different genetic diseases, such as immunodeficiencies and genodermatoses. Despite the efforts of researchers around the world, only a few of these advanced approaches have yet made it to routine therapy. In fact, gene therapy poses one of the greatest technical challenges in modern medicine, spanning safety and efficacy issues, regulatory constraints, registration and market access, all of which need to be addressed to make the therapy available to patients with rare disease. In this review, we survey some of the main challenges in the development of combined cell and gene therapy of genetic skin diseases.

The purpose of this review is to primarily discuss the unwarranted decline in the use of umbilical cord blood (UCB) as a source of donor hematopoietic stem cells (HSC) for hematopoietic cell transplantation (HCT) and the resulting important implications in addressing healthcare inequities, and secondly to highlight the incredible potential of UCB and related birthing tissues for the development of a broad range of therapies to treat human disease including but not limited to oncology, neurologic, cardiac, orthopedic and immunologic conditions.When current best practices are followed, unrelated donor umbilical cord blood transplant (CBT) can provide superior quality of life-related survival compared to other allogeneic HSC donor sources (sibling, matched or mismatched unrelated, and haploidentical) through decreased risks of relapse and chronic graft vs. host disease. Current best practices include improved UCB donor selection criteria with consideration of higher resolution human leukocyte antigen (HLA) typing and CD34+ cell dose, availability of newer myeloablative but reduced toxicity conditioning regimens, and rigorous supportive care in the early posttransplant period with monitoring for known complications, especially related to viral and other infections that may require intervention. Emerging best practice may include the use of ex vivo expanded single-unit CBT rather than double-unit CBT (dCBT) or 'haplo-cord' transplant, and the incorporation of posttransplant cyclophosphamide as with haploidentical transplant and/or incorporation of novel posttransplant therapies to reduce the risk of relapse, such as NK cell adoptive transfer. Novel, non-HCT uses of UCB and birthing tissue include the production of UCB-derived immune effector cell therapies such as unmodified NK cells, chimeric antigen receptor-natural killer cells and immune T-cell populations, the isolation of mesenchymal stem cells for immune modulatory treatments and derivation of induced pluripotent stem cells haplobanks for regenerative medicine development and population studies to facilitate exploration of drug development through functional genomics.The potential of allogeneic UCB for HCT and novel cell-based therapies is undervalued and underutilized. The inventory of high-quality UCB units available from public cord blood banks (CBB) should be expanding rather than contracting in order to address ongoing healthcare inequities and to maintain a valuable source of cellular starting material for cell and gene therapies and regenerative medicine approaches. The expertise in Good Manufacturing Practice-grade manufacturing provided by CBB should be supported to effectively partner with groups developing UCB for novel cell-based therapies.

Chimeric antigen receptor T cell (CAR-T) therapy has breakthrough potential for relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL). However, because of the risk for neurotoxicity, trials usually exclude patients with central nervous system leukemia (CNSL) or active neurological comorbidities (NC). Here, we evaluated the efficacy and neurotoxicity of humanized CD19-directed CAR-T therapy for R/R ALL with CNSL or NC. Of 12 enrolled patients, 4 had CNSL with bone marrow (BM) or testicular recurrence, 3 had BM relapses with NC, and 5 had BM relapse without NC. Bridging chemotherapy was performed for high tumor burden before CAR-T therapy. Patients with CNSL or BM relapse with NC or without NC experienced 100% complete remission. Tumor burden reduction did not occur in 1 patient with NC, who developed grade 5 neurotoxicity before BM assessment, and one patient with CNSL developed leukoencephalopathy. Severe cytokine release syndrome and neurotoxicity developed in 0% with CNSL, 33.3% with BM relapse and NC, and 0% without NC. CAR-T cells expanded in the cerebrospinal fluid (CSF) of all patients with no difference among CNSL, BM with NC, or no NC (respective median percentages among lymphocyte: 33.7%, 48.2% and 34.5%, P =0.899; respective median concentrations: 0.82, 2.21, and 0.46/μL, P =0.719). Median CSF CAR-T cell duration was 5.5 (3-9) months with CNSL and 3 (2-3) months without CNSL ( P =0.031). CAR-T can be given safely and effectively to pediatric patients with R/R ALL with CNSL or NC who have near-normal neurological status. High tumor burden may confer increased risk for severe neurotoxicity.

Mesenchymal stromal cells (MSC) are a promising platform for regenerative medicine applications because of their multilineage differentiation abilities and ease of collection, isolation, and growth ex vivo. To meet the demand for clinical applications, large-scale manufacturing will be required using three-dimensional culture platforms in vessels such as stirred suspension bioreactors. As MSCs are an adherent cell type, microcarriers are added to the culture to increase the available surface area for attachment and growth. Although extensive research has been performed on efficiently culturing MSCs using microcarriers, challenges persist in downstream processing, including harvesting, filtration, and volume reduction, which all play a critical role in the translation of cell therapies to the clinic. The objective of this review is to assess the current state of downstream technologies available for microcarrier-based MSC cultures. This includes a review of current research within the three stages: harvesting, filtration, and volume reduction. Using this information, a downstream process for MSCs is proposed, which can be applied to a wide range of applications.

There are several successive and overlapping phases in wound healing as a complex process. By the disruption of each of these phases, chronic non-healing wounds are resultant. Despite the present soothing surgeries, standard wound dressings and topical gels, the wound is often not completely closed. Today, stem cells have attracted a huge deal of attention therapeutically and pharmaceutically considering their unique features. However, they have some restrictions. Moreover, it is hoped to eliminate the limitations of cellular therapies based on their derivatives known as exosomes. Exosomes are extracellular vesicles secreted from cells. They have a diameter of almost 30-150 nm and miRNAs, mRNAs, and proteins that are possibly different from the source cell are included in exosomal contents. Such nanovesicles have a key role in the intercellular communication of pathological and physiological procedures. Exosome-based therapy is a new significant method for wound healing. By exosomes effects, wound management may be improved and a new therapeutic model may be highlighted for cell-free therapies with reduced side effects for the wound repair.

Breast cancer (BC) is a highly prevalent solid cancer with a high-rise infiltration of immune cells, turning it into a significant candidate for tumor-specific immunotherapies. Chimeric antigen receptor (CAR)-T cells are emerging as immunotherapeutic tools with genetically engineered receptors to efficiently recognize and attack tumor cells that express specific target antigens. Technological advancements in CAR design have provided five generations of CAR-T cells applicable to a wide range of cancer patients while boosting CAR-T cell therapy safety. However, CAR-T cell therapy is ineffective against breast cancer because of the loss of specified antigens, the immunosuppressive nature of the tumor and CAR-T cell-induced toxicities. Next-generation CAR-T cells actively pass through the tumor vascular barriers, persist for extended periods and disrupt the tumor microenvironment (TME) to block immune escape.CAR-T cell therapy embodies advanced immunotherapy for BC, but further pre-clinical and clinical assessments are recommended to achieve maximized efficiency and safety.

Efficient and large-scale expansion of mesenchymal stem/stromal cells (MSCs) has always been a formidable challenge to researchers in cell-based therapies and regenerative medicine. To reconcile major drawbacks of 2D planar culturing system, we innovatively developed an automated closed industrial scale cell production (ACISCP) platform based on GMP-grade microcarrier for culture of umbilical cord-mesenchymal stem/stromal cells (UCMSCs), in accordance with the criteria of stem cell bank. ACISCP system is a fully closed system, which employs different models of vivaSPIN bioreactors (CytoNiche Biotech, China) for scale-up cell culture and vivaPREP (CytoNiche Biotech, China) for automated cell harvesting and cell dosage preparation. To realize industrial scale expansion of UCMSCs, a three-stage expansion was conducted with 1 L, 5 and 15 L vivaSPIN bioreactors. Using 3D TableTrixsup®/supand ACISCP system, we inoculated 1.5 × 10sup7/supof UCMSCs into 1 L vivaSPIN bioreactor and finally scaled to two 15 L bioreactor. A final yield of 2.09 × 10sup10/supcells with an overall expansion factor of 1975 within 13 days. The cells were harvested, concentrated, washed and prepared automatically with vivaPREP. The entire process was realized with ACISCP platform and was totally enclosed. Critical quality attributes (CQA) assessments and release tests of MSCs, including sterility, safety, purity, viability, identity, stability and potency were performed accordingly. The quality of cells harvested from 3D culture on the ACISCP and conventional 2D planar culture counterpart has no significant difference. This study provides a bioprocess engineering platform, harnessing GMP-grade 3D TableTrixsup®/supmicrocarriers and ACISCP to achieve industrial-scale manufacturing of clinical-grade hMSCs.

Hematopoietic stem cell transplantation (HSCT) represents an example of a highly complex and costly medical procedure with major applications in hematology and oncology. It is associated with life-threatening complications and, consequently, increased demands on healthcare resources. Although improving quality is an integral component of healthcare strategic planning, drivers of quality may be variable, and there is logical debate as to what drives quality in HSCT. Moreover, HSCT programs differ in structure and availability of resources, which drive the type of transplantations provided and determine what is affordable and/or economically feasible. The complexity of HSCT procedures with involvement of different stakeholders necessitates not only regulatory frameworks, but also robust quality systems to ensure consistent standards, demonstrate transparency for regulators, and define what quality means within the HSCT program. In an era of escalating healthcare complexity and heightened fiscal responsibility, transparency and accountability, accreditation contributes to ensuring that care meets the highest standards and can serve as a risk mitigation strategy. Quality management has become an indispensable tool for the management of a complex medical intervention such as HSCT. It allows the transplantation team to monitor its activities and identify areas for continuous improvement. The Worldwide Network for Blood and Marrow Transplantation invited a group of international experts in HSCT and quality management to work on providing a summary document about the key elements in quality and accreditation in HSCT and highlight the foremost challenges of implementing them, with a special focus on low- and middle-income economies.

Cancer vaccines and T-cell receptor (TCR) engineered T cells (Tg-T cell) represent two different therapeutic strategies that can target the same tumour epitopes. The first approach requires the induction of a specific immune response in patients, while the second relies on the efficacy of adoptively transferred T cells. Because the ratio of antigen-specific T cells to tumour cells engaged by these strategies may influence the clinical outcome, we evaluated the efficacy of these two therapeutic approaches in solid tumours according to the tumour burden.We performed a meta-analysis restricted to the therapeutic vaccine and Tg-T cell trials, presenting annotated individual clinical data. We adapted a previously published mathematical model for tumour immune dynamics to estimate the clinical impact of the number of specific T cells in regard to the tumour burden.A focused analysis of Tg-T cell studies revealed that clinical responses were mostly observed with the highest doses of infused T cells, suggesting that exceeding a threshold of effector T cells may be required for clinical efficacy. In silico modelling of cancer vaccine and Tg-T cell therapies starting at different tumour burdens showed that therapeutic vaccines control low or moderate tumour burdens, whereas increasing the amount of infused Tg-T cells succeeds in controlling high tumour masses.We propose that therapeutic vaccines should be considered in the context of low or moderate tumour burden, whereas Tg-T cell strategies may be more adapted for the treatment of advanced metastatic diseases.

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.

Since B7-H3 is overexpressed or amplified in many types of solid tumors with a restricted expression in the normal tissues, it has been an emerging immunotherapeutic target for solid tumors. This review will focus on the structural designs of developing chimeric antigen receptors (CARs) targeting B7-H3. The expression, receptor, and function of the B7-H3, as well as a short overview of B7-H3-targeted monoclonal antibody therapy, are discussed. Finally, a detailed summary of B7-H3 redirected CAR-T and CAR-NK cell approaches utilized in preclinical models and currently ongoing or completed clinical trials are presented. It has been demonstrated that B7-H3-targeted CAR-based cell therapies were safe in initial trials, but their efficacy was limited. Employing the local delivery routes, the introduction of novel modifications promoting CAR-T persistence, and combined treatment with other standard therapies could improve the efficacy of B7-H3-targeted CAR-T cell therapy against solid tumors.Cancers develop by avoiding being discovered and destructed by the immune system. Cancer immunotherapy is characterized as an approach to assist the immune system to recognize and fight cancer by using uses some substances. Chimeric antigen receptor (CAR) is a protein designed to recognize a target of interest on tumor cells, immune cells armed with which are able to treat human cancers. B7-H3 is a type I transmembrane protein overexpressed in various solid tumors but scarcely detected in normal tissues. Moreover, it is associated with a poor prognosis for many cancer patients. Therefore, we discussed the role of B7-H3 in solid tumors, and concluded it as a promising therapeutic target for CAR-based immunotherapy. A number of B7-H3 CARs have been developed and tested in recent years, but which CAR construct targeting B7-H3 works best remains uncertain. Up till now, the design of B7-H3 CARs is still controversial and challenging. Hence, we summarized and compared the designs and efficacies of B7-H3 CARs utilized in preclinical models and currently ongoing or completed clinical trials in this review, and aimed to provide a better reference for future B7-H3 CAR design.

PURPOSE OF REVIEW: The purpose of this review is to summarize the status and utilization of chimeric antigen receptor T-cell (CAR-T) therapy based on the most recent clinical trials in patients with leukemia and lymphoma. Additionally, this review will highlight limitations in current strategies, discuss efforts in toxicity mitigation, and outline future directions for investigation. RECENT FINDINGS: CD19 targeted CAR-T-cell therapy (CD19-CAR) is highly effective in patients with relapsed/refractory (r/r) B-cell hematologic malignancies. However, multiple challenges have arisen, particularly life-threatening adverse events such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. Despite these challenges, recent CD19-CAR trials, including two randomized studies, have demonstrated both impressive initial results along with durable responses. Combined with results emerging from “real-world” experience, the efficacy of CAR-T-cells is high, propelling CAR-T-cells studies targeting alternate B-cell antigens (e.g., CD20, CD22 and CD269 (BCMA)) and other targets for hematologic malignancies, along with solid and CNS tumors. SUMMARY: Given the benefit for CD19-CAR, determining the appropriate place in utilization for both an individual patient’s treatment course and more broadly in the generalized treatment paradigm is critically needed. We discuss the most recent trials exploring this topic and future directions in the field.

Chimeric antigen receptor (CAR) T cell therapy is changing the paradigm in hematologic malignancies, but disparities in access exist in the real-world setting. Efforts to address and eliminate these disparities will ensure availability of this life-saving therapy. This study aimed to determine patterns of racial/ethnic distribution, socioeconomic strata, insurance coverage, and travel time of CAR T cell recipients. We used the Vizient Clinical Database (CDB) to capture and analyze elective encounters for CAR T administration as well as encounters for any reason other than CAR T administration (non-CAR T) in patients with lymphoma, myeloma, and acute lymphoblastic leukemia. Travel time and median household income were calculated based on ZIP code of residence. We found that African Americans (AA) were less likely than other racial/ethnic groups to receive CAR T cell therapy. In addition, AA and Hispanic participants were underrepresented in clinical trials. Among the patients with myeloma, all of whom received CAR T cell therapy on a clinical trial, only 1% were African American and 5.4% were Hispanic, and only 7.3% of CAR T cell therapy-related admissions were of patients from neighborhoods with a mean income$40,000. Almost one-third of the CAR T cell recipients lived2 hours away from the center in which they were treated; the majority of these patients were from the higher socioeconomic stratum (P.001). There were fewer patients with Medicare and uninsured patients in the CAR T cell group. Our data indicate that socioeconomic stratum and insurance coverage are important underlying determinants of the identified disparities. Low clinical trial enrollment of minorities also feeds the inequity. Strategies to improve access need to be framed around addressing the causes for the observed disparities.

Corneal epithelial stem cells (CEpSCs) mostly reside at the limbal area and are responsible for tissue homeostasis throughout life. Once complete CEpSC deficiency occurs, regenerative medicine cell-based therapy using CEpSCs or their alternatives can provide successful clinical outcomes. Due to an improved understanding of CEpSCs and mucosal epithelial stem cells, major advancements have been made over the past few decades in in vivo and ex vivo cell-based ocular surface reconstruction therapies for the treatment of severe ocular surface diseases. New therapeutic concepts and clinical strategies are emerging for the treatment of corneal endothelial dysfunction. For example, unlike corneal epithelial cells, in vivo corneal endothelial cells (CECs) stop proliferating and are arrested in the G1 phase of the cell cycle due to cell-to-cell contact inhibition and exposure to a high concentration of transforming growth factor-beta in the aqueous humor. Thus, the production of CECs with good functionality in culture has consistently been difficult. To solve this problem, Rho-associated protein kinase inhibition has taken center stage, as it not only makes the production of human CECs in culture closely mimic the functional characteristics of in vivo healthy CECs possible but also helps sustain those biological properties. Thus, cultured human CEC injection therapy is now moving to the forefront for the treatment of corneal endothelial failure. Herein, we summarize key historical discoveries in corneal cell-based regenerative medicine and illustrate the concept of corneal cell therapy for the treatment of refractory corneal epithelial and endothelial diseases.

Most clinically evaluated chimeric antigen receptor (CAR)-based cell therapies are generated from autologous immune cells. However, there are several limitations to autologous cell therapy, including low availability, poor quality of starting cellular material and limited expansion capability. Recently, induced pluripotent stem cell (iPSC)-derived allogeneic cell therapy platforms have gained popularity, as they seek to overcome many of the challenges inherent to current autologous cell therapies. However, teratoma risk associated with residual undifferentiated cells (i.e., iPSCs) in the drug product may restrict potential clinical applications if left unaddressed. To ensure the safety of the final cell therapy product, there is a need to develop quality control assays to detect residual iPSCs. Combining microRNA (miRNA) sequencing data with publicly archived miRNA microarray datasets, we demonstrated that miRNAs belonging to the 300 family (miR-302a-5p, miR-302c-3p and miR-302d-5p) and 500 family (miR-518f-5p and miR-519-3p) were highly expressed in iPSCs (both periperal blood mononuclear cell- and T cell-derived iPSCs) compared with a number of differentiated cell types. We developed and validated a sensitive digital droplet polymerase chain reaction (ddPCR) assay targeting these miRNAs to detect low levels of residual iPSCs in differentiated cell samples. The miRNA ddPCR-based method with primers for miR-302a-5p, miR-302c-3p and miR-302d-5p detected as few as 5, 3 and 10 undifferentiated iPSCs, respectively, in the background of 10

Adoptive cellular therapies are making major strides in the treatment of cancer, both for hematologic and solid tumors. These cellular products include chimeric antigen receptor T cells and T-cell receptor-modified T cells, tumor-infiltrating lymphocytes, marrow-infiltrating T cells, natural killer cells as well as macrophage-based therapeutics. Advancement in genomics, computational biology, immunology, and cell therapy manufacturing has facilitated advancement of adoptive T cell therapies into the clinic, whereas clinical efficacy has driven Food and Drug Administration approvals. The growth of adoptive cellular therapy has, in turn, led to innovation in the preclinical models available, from ex vivo cell-based models to in vivo xenograft models of treatment. This review focuses on the development and application of in vitro models and in vivo models (cell line xenograft, humanized mice, and patient-derived xenograft models) that directly evaluate these human cellular products.

Over the last decade, cancer immunotherapy has progressed from an academically interesting field to one of the most promising forms of new treatments in which not the cancer but the immune system is treated. In particular, genetic modification for purposeful redirection of autologous T cells is providing hope to many treatment-resistant patients. This personalized form of medicine is radically different from more traditional oncologic drugs. With these evolving medical advancements and more cellular therapies becoming available, some regulatory agencies have created new regulatory requirements to manage the production of these types of products. The regulations are specifically suited for the manufacture of gene and cell therapy products, as they use a risk-based approach towards product development and manufacturing, when there is limited characterization available. The correct interpretation of how and when requirements apply is crucial, since theoretical approaches to implementing GMP can easily lead to disproportionate and unwarranted restrictions that may not address the specific risks that regulators were intending to control. This is especially relevant for cell collection and biopreservation preceding the manufacturing process for products manufactured from autologous T cells. Both the fresh and cryopreserved apheresis materials can be filed as minimally manipulated starting materials to the authorities. The preservation of such cellular material can then routinely be managed using the available regulations for tissues and cells, allowing for a more fit-for-purpose approach to the control measures implemented.

This cohort study examines the cumulative incidence of rehospitalizations and emergency department visits during the first 12 months after hospitalization for chimeric antigen receptor T-cell infusion among commercially insured patients.

Pivotal clinical trials of B-cell maturation antigen-targeted chimeric antigen receptor T (CART)-cell therapy in patients with relapsed/refractory multiple myeloma (MM) resulted in remarkable initial responses, which led to a recent US Food and Drug Administration approval. Despite the success of this therapy, durable remissions continue to be low, and the predominant mechanism of resistance is loss of CART cells and inhibition by the tumor microenvironment (TME). MM is characterized by an immunosuppressive TME with an abundance of cancer-associated fibroblasts (CAFs). Using MM models, we studied the impact of CAFs on CART-cell efficacy and developed strategies to overcome CART-cell inhibition. We showed that CAFs inhibit CART-cell antitumor activity and promote MM progression. CAFs express molecules such as fibroblast activation protein and signaling lymphocyte activation molecule family-7, which are attractive immunotherapy targets. To overcome CAF-induced CART-cell inhibition, CART cells were generated targeting both MM cells and CAFs. This dual-targeting CART-cell strategy significantly improved the effector functions of CART cells. We show for the first time that dual targeting of both malignant plasma cells and the CAFs within the TME is a novel strategy to overcome resistance to CART-cell therapy in MM.

Cost-effectiveness data on chimeric antigen receptor (CAR) T cell therapies for relapsed/refractory large B cell lymphoma (R/R LBCL), accounting for inpatient/outpatient site of care (site), are sparse.This payer model compares lifetime costs/benefits for CAR T cell-treated (axicabtagene ciloleucel [axi-cel], lisocabtagene maraleucel [liso-cel], tisagenlecleucel [tisa-cel]) patients with R/R LBCL in the USA. Three-month post-infusion costs were derived from unit costs and real-world all-payer (RW) site-specific utilization data for 1175 patients with diffuse R/R LBCL (CAR T cell therapy October 2017-September 2020). Therapy- and site-specific grade 3+ cytokine release syndrome (CRS) and neurologic event (NE) incidences were imputed from published trials. Lifetime quality-adjusted life-years (QALYs) and long-term costs were calculated from therapy-specific overall and progression-free survival data, adjusted for differences in trial populations. The base case used 17% outpatient site (RW) for all therapies. ZUMA-1 trial cohorts 1/2 informed other axi-cel base case inputs; ZUMA-1 cohorts 4/6 data (updated safety management) supported scenario analyses.Base case total costs for axi-cel exceeded liso-cel ($637 K versus $621 K) and tisa-cel ($631 K versus $577 K) costs. Three-month post-infusion costs were $57 K to $59 K across all therapies. Total QALYs for axi-cel also exceeded those for liso-cel (7.7 versus 5.9) and tisa-cel (7.2 versus 5.0) with incremental costs per QALY gained of $9 K versus liso-cel and $25 K versus tisa-cel. Base case incremental net monetary benefit was $255 K (95% confidence interval (CI) $181-326 K) for axi-cel versus liso-cel, and $280 K (95% CI $200-353 K) versus tisa-cel. Longer survival with axi-cel conferred higher lifetime costs. In all scenarios (e.g., varied outpatient proportions, CRS/NE incidence), axi-cel was cost-effective versus both comparators at a maximum willingness-to-pay of under $26 K/QALY as a result of axi-cel's higher incremental survival gains and quality-of-life.Axi-cel is a cost-effective CAR T cell therapy for patients with R/R LBCL compared to tisa-cel and liso-cel. Site of care does not impact the cost-effectiveness of CAR T cell therapy.

Many academic researchers are familiar with the technical challenges inherent in creating patient-specific, tissue-engineered therapeutics for clinical applications. However, for the potential of these products to mature into clinical practice and the profound possibilities to be realized, developers must apply not only technical expertise but also a comprehensive translational strategy─making a product marketable, scalable, manufacturable, and approvable by regulators, while providing genuine advantages to patients. Here, we provide a brief overview of three crucial steps for successful translation: adoption of a "translational mindset," consideration of three categories of core challenges (economic, regulatory, and manufacturing), and detailed planning at the earliest stages of development.

The number of clinical trials using human pluripotent stem cells (hPSC)—both embryonic and induced pluripotent stem cells (hESC/iPSC)—has expanded in the last several years beyond expectations. By the end of 2021, a total of 90 trials had been registered in 13 countries with more than 3000 participants. However, only US, Japan, China, and the UK are conducting both hESC- and hiPSC-based trials. Together US, Japan, and China have registered 78% (70 out of 90) of all trials worldwide. More than half of all trials (51%) are focused on the treatment of degenerative eye diseases and malignancies, enrolling nearly 2/3 of all participants in hPSC-based trials. Although no serious adverse events resulting in death or morbidity due to hPSC-based cellular therapy received have been reported, information about safety and clinical efficacy are still very limited. With the availability of novel technologies for precise genome editing, a new trend in the development of hPSC-based cellular therapies seems to be emerging. Engineering universal donor hPSC lines has become a holy grail in the field. Indeed, because of its effectiveness and simplicity nanomedicine and in vivo delivery of gene therapy could become more advantageous than cellular therapies for the treatment of multiple diseases. In the future, for the best outcome, hPSC-based cellular therapy might be combined with other technological advancements, such as biomimetic epidural electrical stimulation that can restore trunk and leg motor functions after complete spinal injury.

Cell viability is an important release criterion in the manufacturing of cell therapy products. Low cell viability can have significant impact on product quality and manufacturing efficiency. Counterflow centrifugation technology has been applied to the manufacturing of cell therapy products, to enable cell separation based on size and density. This study evaluated the utility of counterflow centrifugation technology for dead cell removal to improve cell viability of the final product.Jurkat cell cultures with low and high dead cell burden were subjected to counterflow centrifugal elutriation to determine the correlation between process parameters (e.g., flow rate, centrifugal force) and processing outcomes (i.e., cell recovery and viability). Subsequently, the optimized parameters were applied to dead cell elutriation using expanded T cells and freshly isolated human amniotic epithelial cells (hAECs). The efficiency of dead cell removal, cell function and post-thaw viability were compared.Elutriation using a low flow rate allowed better control of viable cell recovery from both low and high dead cell burden cultures of Jurkat cells. The viability of T cells and hAECs was improved by counterflow centrifugal processing, from 80.67% ± 2.33 to 94.73% ± 1.19 and 79.19% ± 5.35 to 90.34% ± 3.59, respectively. Processing increased the proliferation rate of T cells, while the metabolic activity of hAECs was unchanged.Counterflow centrifugal elutriation can be added as an integrated step to the automated wash-and-concentrate protocol for cell manufacturing to remove dead cells and improve cell viability of the final product.

The 1990s saw rapid growth in international activity in hematopoietic cell transplantation. As national donor registries were established and international collaboration increased, a need to transfer cellular therapy products across national borders emerged. A lack of international standards for identification, terminology and labeling resulted in significant challenges for import and export. Twenty years of effort by a large group of experts supported by professional societies and accreditation bodies has today achieved a high degree of standardization. This review highlights the main landmarks in this journey and serves as a reminder of the importance of taking the "long view" when working toward international standardization. It demonstrates the need for continual maintenance and enhancement of standards to meet the changing needs of the cell therapy industry and highlights recent developments in ISBT 128.

Allograft rejection is one of the obstacles in achieving a successful vascularized composite allotransplantation (VCA). Treatments of graft rejection with lifelong immunosuppression (IS) subject the recipients to a lifelong risk of cancer development and opportunistic infections. Cell therapy has recently emerged as a promising strategy to modulate the immune system, minimize immunosuppressant drug dosages, and induce allograft tolerance. In this review, the recent works regarding the use of cell therapy to improve allograft outcomes are discussed. The current data supports the safety of cell therapy. The suitable type of cell therapy in allotransplantation is clinically dependent. Bone marrow cell therapy is more suitable for the induction phase, while other cell therapies are more feasible in either the induction or maintenance phase, or for salvage of allograft rejection. Immune cell therapy focuses on modulating the immune response, whereas stem cells may have an additional role in promoting structural regenerations, such as nerve regeneration. Source, frequency, dosage, and route of cell therapy delivery are also dependent on the specific need in the clinical setting.

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.

Cell-based therapeutics are an emerging modality with the potential to treat many currently intractable diseases through uniquely powerful modes of action. Despite notable recent clinical and commercial successes, cell-based therapies continue to face numerous challenges that limit their widespread translation and commercialization, including identification of the appropriate cell source, generation of a sufficiently viable, potent and safe product that meets patient- and disease-specific needs, and the development of scalable manufacturing processes. These hurdles are being addressed through the use of cutting-edge basic research driven by next-generation engineering approaches, including genome and epigenome editing, synthetic biology and the use of biomaterials.

MSC (a.k.a. mesenchymal stem cell or medicinal signaling cell) cell therapies show promise in decreasing mortality in acute respiratory distress syndrome (ARDS) and suggest benefits in treatment of COVID-19-related ARDS. We performed a meta-analysis of published trials assessing the efficacy and adverse events (AE) rates of MSC cell therapy in individuals hospitalized for COVID-19. Systematic searches were performed in multiple databases through November 3, 2021. Reports in all languages, including randomized clinical trials (RCTs), non-randomized interventional trials, and uncontrolled trials, were included. Random effects model was used to pool outcomes from RCTs and non-randomized interventional trials. Outcome measures included all-cause mortality, serious adverse events (SAEs), AEs, pulmonary function, laboratory, and imaging findings. A total of 736 patients were identified from 34 studies, which included 5 RCTs (n = 235), 7 non-randomized interventional trials (n = 370), and 22 uncontrolled comparative trials (n = 131). Patients aged on average 59.4 years and 32.2% were women. When compared with the control group, MSC cell therapy was associated with a reduction in all-cause mortality (RR = 0.54, 95% CI: 0.35-0.85, I 2 = 0.0%), reduction in SAEs (IRR = 0.36, 95% CI: 0.14-0.90, I 2 = 0.0%) and no significant difference in AE rate. A sub-group with pulmonary function studies suggested improvement in patients receiving MSC. These findings support the potential for MSC cell therapy to decrease all-cause mortality, reduce SAEs, and improve pulmonary function compared with conventional care. Large-scale double-blinded, well-powered RCTs should be conducted to further explore these results.

CD4

Chimeric antigen receptor T-cell (CAR-T) therapy is a promising immunotherapy approved for hematological malignancies. Despite its effectiveness, clinically significant rates of toxicity, including immune effector cell associated neurotoxicity syndrome (ICANS), limit its widespread use. In certain contexts, ICANS may occur in up to one-third of patients using commercially available CAR-T therapies. The syndrome presents with a range of neurological signs and symptoms, as well as a variety of neuroimaging manifestations reported in the literature. A systematic review of the literature was performed. The systematic search strategy identified 24 studies discussing the neuroimaging appearances associated with ICANS. Imaging findings are more common in patients with higher grade neurotoxicity. The neuroimaging findings are heterogeneous, but can be grouped either anatomically (white matter, gray matter, brainstem, or leptomeninges) or pathologically (ischemic changes, hemorrhages, or cerebral edema). An understanding of the imaging manifestations of ICANS has the potential to impact the management of patients.

It is not clear if all Americans have benefitted equally from the availability of chimeric antigen receptor T-cell (CART) therapy. We aimed to evaluate if demographic differences existed among adult patients who received CART therapy and to assess predictors of CART treatment outcomes.Records of patients ≥18 years who received CART therapy for non-Hodgkin's lymphoma, acute lymphoblastic leukemia, and multiple myeloma in 2018 were evaluated in the National Inpatient Sample. Acute complications and inhospital mortality were compared between two groups of CART recipients: Whites and non-Whites. Logistic regression analysis was used to evaluate the association between sociodemographic factors and inhospital mortality.Of 1275 CART recipients that met inclusion criteria, there were 40.4% of females, 66.9% of Whites, Blacks (4.2%), Hispanics (13.3%), Asians or Pacific Islanders (4.2%), and Native Americans (1.3%). Up to 96.8% of CART procedures were performed in urban teaching hospitals, and 85.3% of CART recipients lived in metropolitan counties. Non-Whites, compared to Whites, were younger at the time of CART therapy (p 0.001). The inhospital mortality rate was higher in non-Whites, though not statistically significant (5.4% vs. 4.4%, p = 0.764). There were no differences in length of hospital stay, hospital charges, or rates of acute toxicities between the two race groups. We found no association between race and treatment outcomes. Gender, neurotoxicity, and Charlson Comorbidity Index were significant predictors of inhospital mortality.CART therapy recipients in the United States were more likely to be Whites and more likely to be residents of metropolitan areas. These observed demographic differences were not associated with treatment outcomes or inhospital mortalities.

In this open-label, single-arm, phase I/II clinical trial, we evaluated the efficacy of anti-B cell maturation antigen (BCMA) chimeric antigen receptor (CAR)-T cell (HDS269B) therapy in 49 relapsed/refractory multiple myeloma (RRMM) patients, including 20 with Eastern Cooperative Oncology Group (ECOG) grade 3-4. After HDS269B infusion (9 × 10