The Art of Stem Cell-Based Therapy.

Potency assays represent crucial experiments at the hub of the comprehensive complexity surrounding cell therapy. Moreover, numerous factors beyond biological and scientific considerations are involved in achieving successful potency assays that fulfil regulatory authority approval for a new advanced therapy medicinal product. Though this can mean a frustratingly long period of discovery and development, progress in cell therapy is nowadays proceeding remarkably quickly, assisted by the potency assay rigorously placing emphasis on the need to critically analyse the key factor/s responsible for the therapeutic mechanism of action. History has shown that it can take many decades for there to be an improved understanding of a mechanism of action. Yet the chasing of precise targets has revolutionised medicine, with no clearer example than approaches to viral pandemics. The centuries involved in the eradication of smallpox have paved the way for an unprecedented pace of vaccine development for the Covid-19 pandemic. Such extraordinary accomplishments foster encouragement that similarly for stem cell-based therapy, our scientific knowledge will continue to improve apace. This chapter focuses on the art of experimentation and discovery, introducing potency assay requisites and numerous factors that can influence potency assay outcomes. A comprehensive understanding of potency assays and their development can hasten the provision of new cell therapies to help resolve burdensome diseases of unmet medical need.

Creating the Hematology/Oncology/Stem Cell Transplant Advancing Resiliency Team: A Nurse-Led Support Program for Hematology/Oncology/Stem Cell Transplant Staff.

Background: Burnout, moral distress, compassion fatigue, and posttraumatic stress disorder are concerns for health-care staff. Due to the high mental, physical, and emotional demands of the pediatric hematology/oncology profession, workplace supports should be in place to address the needs of the staff. A nurse-led support program is one strategy to enhance staff well-being. Methods: The Hematology/Oncology/Stem Cell Transplant Advancing Resiliency Team (HART) is a nurse-led peer-to-peer on-site support program for multidisciplinary staff caring for hematology/oncology patients. HART coaches, working 8-hour shifts, covering both day and night shift hours, are present 3 days a week on the unit. HART offers a confidential space for one on one or group interactions, educational sessions, assistance with work related, patient-care based, or personal concerns, and various forms of integrative therapies. Results: There have been over 1,100 coach consults and 98 HART shifts worked. The most commonly reported changes since HART began include staff feeling more supported by leadership and staff making time for breaks during the work shift. A 25.6% increase in staff reporting to be extremely satisfied with unit support was found. Discussion: Cultivating a culture of staff support is important. Due to COVID-19, physical HART coach presence was put on hold for 4 weeks and virtual interventions were trialed. Since its return, coach consult numbers have been steadily rising. Having a support program led by coaches with direct experience understanding the emotional toll of caring for the pediatric hematology/oncology patient population was found to be well utilized, feasible through donor funding, and measurable via staff report.

Stem cell therapy: a novel approach against emerging and re-emerging viral infections with special reference to SARS-CoV-2.

The past several decades have witnessed the emergence and re-emergence of many infectious viral agents, flaviviruses, influenza, filoviruses, alphaviruses, and coronaviruses since the advent of human deficiency virus (HIV). Some of them even become serious threats to public health and have raised major global health concerns. Several different medicinal compounds such as anti-viral, anti-malarial, and anti-inflammatory agents, are under investigation for the treatment of these viral diseases. These therapies are effective improving recovery rates and overall survival of patients but are unable to heal lung damage caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Therefore, there is a critical need to identify effective treatments to combat this unmet clinical need. Due to its antioxidant and immunomodulatory properties, stem cell therapy is considered a novel approach to regenerate damaged lungs and reduce inflammation. Stem cell therapy uses a heterogeneous subset of regenerative cells that can be harvested from various adult tissue types and is gaining popularity due to its prodigious regenerative potential as well as immunomodulatory and anti-inflammatory properties. These cells retain expression of cluster of differentiation markers (CD markers), interferon-stimulated gene (ISG), reduce expression of pro-inflammatory cytokines and, show a rapid proliferation rate, which makes them an attractive tool for cellular therapies and to treat various inflammatory and viral-induced injuries. By examining various clinical studies, this review demonstrates positive considerations for the implications of stem cell therapy and presents a necessary approach for treating virally induced infections in patients.

Outcome of COVID-19 in allogeneic stem cell transplant recipients: Results from the EPICOVIDEHA registry.

Background: The outcome of COVID-19 in allogeneic hematopoietic stem cell transplantation (HSCT) recipients is almost uniformely considered poor. The aim of present study was to retrospectively analyse the outcome and risk factors for mortality in a large series of patients who developed COVID-19 infection after an allogeneic HSCT. Methods: This multicenter retrospective study promoted by the European Hematology Association - Infections in Hematology Study Working Group, included 326 adult HSCT patients who had COVID-19 between January 2020 and March 2022. Results: The median time from HSCT to the diagnosis of COVID-19 was 268 days (IQR 86-713; range 0-185 days). COVID-19 severity was mild in 21% of the patients, severe in 39% and critical in 16% of the patients. In multivariable analysis factors associated with a higher risk of mortality were, age above 50 years, presence of 3 or more comorbidities, active hematologic disease at time of COVID-19 infection, development of COVID-19 within 12 months of HSCT, and severe/critical infections. Overall mortality rate was 21% (n=68): COVID-19 was the main or secondary cause of death in 16% of the patients (n=53). Conclusions: Mortality in HSCT recipients who develop COVID-19 is high and largely dependent on age, comorbidities, active hematologic disease, timing from transplant and severity of the infection.

Universal masking in hospitals in the COVID-19 era: Is it time to consider shielding?

With concerns for presymptomatic transmission of COVID-19 and increasing burden of contact tracing and employee furloughs, several hospitals have supplemented pre-existing infection prevention measures with universal masking of all personnel in hospitals. Other hospitals are currently faced with the dilemma of whether or not to proceed with universal masking in a time of critical mask shortages. We summarize the rationale behind a universal masking policy in healthcare settings, important considerations before implementing such a policy and the challenges with universal masking. We also discusses proposed solutions such as universal face shields.

Development and regulation of stem cell-based therapies in China.

BACKGROUND: Clinical researches of stem cell-based therapies are highly active in China, while it was arduous to determine the most effective way of clinical translation of those advanced therapies. METHODS: This article briefly introduced the regulatory framework development, the progress in stem cell clinical researches and clinical trials of commercially developed stem cell-based products, as well as the clinical review concerns of stem cell-based products in China. MAIN FINDINGS: The current regulatory framework of stem cell clinical researches in China was launched in 2015, when regulatory authorities issued "Administrative Measures on Stem Cell Clinical Research" (AMSCCR) detailing the rules of stem cell clinical research. Thereafter, the rapidly growing stem cell clinical researches were rigorously managed and clinical use of stem cell therapy was halted. Meanwhile, commercially developed stem cell-based products are supervised by Drug Administration Law (DAL). CONCLUSION: The regulatory framework of stem cell-based therapy in China has progressed in the last few decades, which is currently regulated according to AMSCCR and DAL. Well-designed and patient-focused clinical trial is required for commercially developed stem cell-based products, and definite clinical benefit evidence is crucial to obtain marketing authorization.

The impact of COVID-19 on autologous stem cell transplantation in multiple myeloma: A single-centre, qualitative evaluation study.

Autologous stem cell transplantation (ASCT) is standard of care in biologically fit, newly diagnosed multiple myeloma (MM) patients, offering better therapeutic outcomes and improved quality of life (QoL). However, with the UK's 1st national lockdown on 23/03/2020, several guidelines recommended deferring ASCT due to risks of infection, with resource limitations forcing some units to suspend ASCT entirely. Such changes to patients' treatment plans inevitably altered their lived experience during these uncertain times with expected impact on QoL. We conducted a qualitative study using semi-structured interviews to gain insight into MM patients' understanding of their disease, initial therapy and ASCT, and their response to therapy changes. A clinical snapshot of how COVID-19 affected the MM ASCT service in a single UK institution is also provided, including changes to chemotherapy treatment plans, timing, and prioritisation of ASCT. Framework analysis identified 6 overarching themes: (1) beliefs about ASCT, (2) perceptions of information provided about MM and ASCT, (3) high levels of fear and anxiety due to COVID-19, (4) feelings about ASCT disruption or delay due to COVID-19, (5) perceptions of care, and (6) importance of social support. Example subthemes were beliefs that ASCT would provide a long-remission/best chance of normality including freedom from chemotherapy and associated side-effects, disappointment, and devastation at COVID-related treatment delays (despite high anxiety about infection) and exceptionally high levels of trust in the transplant team. Such insights will help us adjust our service and counselling approaches to be more in tune with patients' priorities and expectations.

The role of autologous micrografts injection from the scalp tissue in the treatment of COVID-19 associated telogen effluvium: Clinical and trichoscopic evaluation.

The clinical presentation of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2 COVID-19) varies from asymptomatic infection to a life-threatening, multiorgan disease. One of these manifestations is telogen effluvium (TE) which is characterized by diffuse hair loss occurring in patients previously infected with SARS-CoV-2 and lasts ~3 months, after which excessive hair loss follows. Hair follicles are known to contain a well-characterized niche for adult stem cells which is the bulge containing epithelial and melanocytic stem cells. Stem cells in the hair bulge, a demarcated structure within the lower permanent portion of hair follicles, can generate the interfollicular epidermis, hair follicle structures, and sebaceous glands. This study aims to evaluate autologous micrografts from scalp tissues as a therapeutic modality in the management of TE caused by COVID-19. Twenty patients of previous COVID-19 infection suffered from TE were included in this study for human follicle stem cells micrograft scalp treatment and they were evaluated after 3 months of treatment and after 6 months. There was significant improvement of the hair thickness and density compared with the start of the treatment and 6 months of follow-up. Autologous micrograft of the scalp showed marked improvement in the treatment of COVID-19 TE.

Evaluation of the Durability of the Immune Humoral Response to COVID-19 Vaccines in Patients With Cancer Undergoing Treatment or Who Received a Stem Cell Transplant.

Importance: The durability of the antibody response to COVID-19 vaccines in patients with cancer undergoing treatment or who received a stem cell transplant is unknown and may be associated with infection outcomes. Objective: To evaluate anti-SARS-CoV-2 spike protein receptor binding domain (anti-RBD) and neutralizing antibody (nAb) responses to COVID-19 vaccines longitudinally over 6 months in patients with cancer undergoing treatment or who received a stem cell transplant (SCT). Design, Setting, and Participants: In this prospective, observational, longitudinal cross-sectional study of 453 patients with cancer undergoing treatment or who received an SCT at the University of Kansas Cancer Center in Kansas City, blood samples were obtained before 433 patients received a messenger RNA (mRNA) vaccine (BNT162b2 or mRNA-1273), after the first dose of the mRNA vaccine, and 1 month, 3 months, and 6 months after the second dose. Blood samples were also obtained 2, 4, and 7 months after 17 patients received the JNJ-78436735 vaccine. For patients receiving a third dose of an mRNA vaccine, blood samples were obtained 30 days after the third dose. Interventions: Blood samples and BNT162b2, mRNA-1273, or JNJ-78436735 vaccines. Main Outcomes and Measures: Geometric mean titers (GMTs) of the anti-RBD; the ratio of GMTs for analysis of demographic, disease, and treatment variables; the percentage of neutralization of anti-RBD antibodies; and the correlation between anti-RBD and nAb responses to the COVID-19 vaccines. Results: This study enrolled 453 patients (mean [SD] age, 60.4 [13,1] years; 253 [56%] were female). Of 450 patients, 273 (61%) received the BNT162b2 vaccine (Pfizer), 160 (36%) received the mRNA-1273 vaccine (Moderna), and 17 (4%) received the JNJ-7846735 vaccine (Johnson & Johnson). The GMTs of the anti-RBD for all patients were 1.70 (95% CI, 1.04-2.85) before vaccination, 18.65 (95% CI, 10.19-34.11) after the first dose, 470.38 (95% CI, 322.07-686.99) at 1 month after the second dose, 425.80 (95% CI, 322.24-562.64) at 3 months after the second dose, 447.23 (95% CI, 258.53-773.66) at 6 months after the second dose, and 9224.85 (95% CI, 2423.92-35107.55) after the third dose. The rate of threshold neutralization (≥30%) was observed in 203 of 252 patients (80%) 1 month after the second dose and in 135 of 166 patients (81%) 3 months after the second dose. Anti-RBD and nAb were highly correlated (Spearman correlation coefficient, 0.93 [0.92-0.94]; P < .001). Three months after the second dose, anti-RBD titers were lower in male vs female patients (ratio of GMTs, 0.52 [95% CI, 0.34-0.81]), patients older than 65 years vs patients 50 years or younger (ratio of GMTs, 0.38 [95% CI, 0.25-0.57]), and patients with hematologic malignant tumors vs solid tumors (ratio of GMTs, 0.40 [95% CI, 0.20-0.81]). Conclusions and Relevance: In this cross-sectional study, after 2 doses of an mRNA vaccine, anti-RBD titers peaked at 1 month and remained stable over the next 6 months. Patients older than 65 years of age, male patients, and patients with a hematologic malignant tumor had low antibody titers. Compared with the primary vaccine course, a 20-fold increase in titers from a third dose suggests a brisk B-cell anamnestic response in patients with cancer.

"Smoldering" Rejection of Keratolimbal Allograft.

PURPOSE: The purpose of this study was to report a case of "smoldering" keratolimbal allograft (KLAL) rejection in a patient with subtherapeutic levels of systemic immunosuppression in temporal association with BNT162b2 messenger RNA vaccination for severe acute respiratory syndrome coronavirus 2. METHODS: This was a case report. OBSERVATIONS: A 72-year-old man presented with circumferential perilimbal engorgement, stagnation, and tortuosity of vessels with mild chemosis in his right eye KLAL segments 1 month after receiving the BNT162b2 messenger RNA vaccine while his tacrolimus trough blood levels were subtherapeutic measuring <2 ng/mL. He had undergone KLAL 6.5 years before for total limbal stem cell deficiency from a chemical injury and had been stable without any history of rejection. The donor was blood type O, and the patient had no systemic comorbidities. The patient was treated with hourly difluprednate 0.05% and increasing of his oral tacrolimus dose to 2 mg twice a day with improvement of rejection signs. CONCLUSIONS: There may be a temporal association between KLAL rejection after immunization against severe acute respiratory syndrome coronavirus 2 in patients with subtherapeutic levels of systemic immunosuppression. Patients should be on alert for any ocular signs or symptoms postimmunization and present for treatment immediately.

Is hypoimmunogenic stem cell therapy safe in times of pandemics?

The manipulation of human leukocyte antigens (HLAs) and immune modulatory factors in "universal" human pluripotent stem cells (PSCs) holds promise for immunological tolerance without HLA matching. This paradigm raises concerns should "universal" grafts become virally infected. Furthermore, immunological manipulation might functionally impair certain progeny, such as hematopoietic stem cells. We discuss the risks and benefits of hypoimmunogenic PSCs, and the need to further advance HLA matching and autologous strategies.

Patient Understanding of Nonapproved Stem Cell Therapies for Retinal Disease.

This prospective survey study demonstrates a lack of retina clinic patient knowledge about appropriate stem cell therapy applications for retinal disease.

Extending human healthspan and longevity: a symposium report.

For many years, it was believed that the aging process was inevitable and that age-related diseases could not be prevented or reversed. The geroscience hypothesis, however, posits that aging is, in fact, malleable and, by targeting the hallmarks of biological aging, it is indeed possible to alleviate age-related diseases and dysfunction and extend longevity. This field of geroscience thus aims to prevent the development of multiple disorders with age, thereby extending healthspan, with the reduction of morbidity toward the end of life. Experts in the field have made remarkable advancements in understanding the mechanisms underlying biological aging and identified ways to target aging pathways using both novel agents and repurposed therapies. While geroscience researchers currently face significant barriers in bringing therapies through clinical development, proof-of-concept studies, as well as early-stage clinical trials, are underway to assess the feasibility of drug evaluation and lay a regulatory foundation for future FDA approvals in the future.

Online seminars as an information source for direct-to-consumer stem cell therapy.

Aim: To attend stem cell (SC) seminars hosted by US-based direct-to-consumer SC businesses either in person or via online 'webinars' to determine accuracy and regulatory oversight of the advertised SC therapies. Methods: The therapeutic claims, costs, risks, scientific evidence in support of a therapy and any regulatory oversight were collated using pre-established checklists. Participation consisted of one live attendance of a seminar, and following COVID-19 restrictions, review of seven recorded presentations available on the internet from SC businesses. Results & conclusion: None of the SC therapies advertised by direct-to-consumer clinics reviewed were supported by proper clinical evidence nor substantiated by peer reviewed literature.