Mesenchymal Stem Cells: Case Report of an Adjuvant Ambulatory Therapy for a COVID-19 High-Risk and steroid-hypersensitive Patient.

INTRODUCTION: Due to the rapid progression of COVID-19 to severe and critical stages, thousands of patients have required the use of intensive care unit (ICU) treatment, placing an excessive strain on health systems. Immunomodulatory effects of Wharton's Jelly Mesenchymal Stem Cells (WJ-MSCs) have shown promising results on the treatment of patients with COVID-19. However, the effect of promptly applied cell therapy on ambulatory patient prognosis has not been described. This case report presents the clinical outcome of a multimorbid, steroid-hypersensitive, COVID-19 patient treated with WJ-MSCs transplantation. CASE PRESENTATION: A 67-year-old woman with Type 2 diabetes, overweight (82 kg, 168 cm, BMI = 29.053), hypertension (60/190 mmHg) and steroid-hypersensitivity, tested positive for COVID-19 after presenting typical symptoms such as fatigue, chest pain, myalgia, nasal congestion, dysgeusia, anosmia and oxygen saturation (SpO2) 94% - 96%, with normal body temperature (36°C). The patient received pharmacologic treatment but, when symptoms worsened, WJ-MSCs were transplanted to modulate the suspected onset of the cytokine release syndrome. Significant improvement of symptoms and clinical parameters (inflammatory markers and CT score) were observed, and the patient fully recovered within a short period of time. CONCLUSION: The present case report exhibits the favorable outcome of using Wharton's Jelly Mesenchymal Stem Cells (WJ-MSCs) as an ambulatory and adjuvant therapy for COVID-19. Prompt WJ-MSCs infusion can be a safe ambulatory adjuvant therapy in COVID-19 infection care, preventing disease progression to critical stages and avoiding hospital overcrowding.

Respiratory Viral Infections in Recipients of Cellular Therapies: A Review of Incidence, Outcomes, Treatment, and Prevention.

Respiratory viral infections (RVIs) are of major clinical importance in immunocompromised patients and represent a substantial cause of morbidity and mortality in patients with hematologic malignancies and those who have undergone hematopoietic cell transplantation. Similarly, patients receiving immunotherapy with CD19-targeted chimeric antigen receptor-modified T cells, natural killer cells, and genetically modified T-cell receptors are susceptible to RVIs and progression to lower respiratory tract infections. In adoptive cellular therapy recipients, this enhanced susceptibility to RVIs results from previous chemotherapy regimens such as lymphocyte-depleting chemotherapy conditioning regimens, underlying B-cell malignancies, immune-related toxicities, and secondary prolonged, profound hypogammaglobulinemia. The aggregated risk factors for RVIs have both immediate and long-term consequences. This review summarizes the current literature on the pathogenesis, epidemiology, and clinical aspects of RVIs that are unique to recipients of adoptive cellular therapy, the preventive and therapeutic options for common RVIs, and appropriate infection control and preventive strategies.

Cell Therapy: cGMP Facilities and Manufacturing: Second Edition

This new edition presents a fully-updated and expanded look at current Good Manufacturing Practice (cGMP) for cell therapy products. It provides a complete discussion of facility design and operation including details specific to cord blood banking, cell processing, vector production and qualification of a new facility. Several chapters cover facility infrastructure including cleaning and maintenance, vendor qualification, writing a Standard Operating Procedure, staff training, and process validation. The detailed and invaluable product information covers topics like labelling, release and administration, transportation and shipment, et al. Further chapters cover relevant topics like writing and maintaining investigational new drug applications, support opportunities in North America and the European Union, commercial cell processing and quality testing services, and financial considerations for academic GMP facilities. A chapter on future directions rounds out Cell Therapy: cGMP Facilities and Manufacturing making it essential reading for any cell therapy professional involved in the development, use, or management of this type of facility. © Springer Nature Switzerland AG 2009, 2022, Corrected Publication 2022.

Registered clinical trials investigating treatment with cell-derived extracellular vesicles: a scoping review.

BACKGROUND AIMS: Interest in cell-based therapy using extracellular vesicles (EVs) is intensifying, building upon promising preclinical research and a handful of published clinical studies. Registered clinical trials remain small, heterogeneous in design and underpowered to determine safety and efficacy on their own. A scoping review of registered studies can identify opportunities to pool data and perform meta-analysis. METHODS: Registered trials were identified by searching clinical trial databases (Clinicaltrials.gov, the World Health Organization International Clinical Trials Registry Platform and the Chinese Clinical Trial Registry) on June 10, 2022. RESULTS: Seventy-three trials were identified and included for analysis. Mesenchymal stromal cells (MSCs) were the most common cell type from which EVs were derived (49 studies, 67%). Among the 49 identified MSC-EV studies, 25 were controlled trials (51%) with a combined total of 3094 participants anticipated to receive MSC-derived EVs (2225 in controlled studies). Although EVs are being administered to treat a broad range of conditions, trials treating patients with coronavirus disease-2019 and/or acute respiratory distress syndrome were observed most commonly. Despite heterogeneity between studies, we anticipate that at least some of the studies could be combined in meaningful meta-analysis and that a combined sample size of 1000 patients would provide the ability to detect a ≥5% difference in mortality with MSC-EVs compared to controls and could be achieved by December 2023. CONCLUSIONS: This scoping review identifies potential barriers that may stall clinical translation of EV-based treatment, and our analysis calls for more standardized product characterization, use of quantifiable product quality attributes and consistent outcome reporting in future clinical trials.

4 - Bayesian Statistical Methods in Stem Cell Transplantation and Cellular Therapy

A brief overview of Bayesian statistics is given, followed by illustrative applications of Bayesian methods in allogeneic hematopoietic cell transplantation (allo-HCT) and cellular therapy. Three clinical trial designs are described, including a study to evaluate safety and efficacy of cytotoxic T-lymphocytes for posttransplant viral infections, a trial to optimize chimeric antigen receptor T-cell dose for hematologic malignancies based on efficacy-toxicity trade-offs, and a randomized study of cord blood derived regulatory T-cells for COVID-19 induced acute respiratory distress syndrome. Three data analyses are described, including a sensitivity analysis of preparative regimen effects for allo-HCT that are confounded with institutional effects, regression-based estimation of the effects on survival of antigens in convalescent plasma therapy for COVID-19, and precision pharmacokinetic-guided dosing of intravenous busulfan in allo-HCT.

Effect and safety of mesenchymal stem cells for patients with COVID-19: Systematic review and meta-analysis with trial sequential analysis.

The objective of this study was to assess whether mesenchymal stem cells (MSCs) therapy could offer survival advantages for patients with novel coronavirus disease 2019 (COVID-19). An electronic search of PubMed, Embase, Cochrane Library, Web of Science, WanFang, and CNKI was performed from December 1, 2019 to December 25, 2022. The primary outcome was all-cause mortality. Trial sequential analysis (TSA) was conducted in this meta analysis. Besides, subgroup analysis and meta-regression was performed using a random-effects model to find the potential sources of heterogeneity. Seventeen randomized controlled trials (RCTs) involving a total of 1073 patients with COVID-19 were included in this study. Compared with the control group, patients in the MSCs groups were associated with significantly reduced all-cause mortality (MSCs 18.4% vs. control 25.5%; risk ratio [RR] 0.73; 95% confidence interval [CI] 0.59-0.90; p = 0.004; I² = 0%). For all secondary outcomes, there wasn't significant improvement in the experimental group versus the control group regarding symptom remission rate (53.2%, 201/378 vs. 46.5%, 164/353; RR 1.15; 95% CI 1.00-1.32; p = 0.05; I² = 43%), but the pooled analysis revealed significant differences between the groups in length of hospital stay (MD: -3.82, 95% CI: -5.87 to -1.77; p = 0.0003, I2 = 0%), requirement of invasive mechanical ventilation (RR 0.52; 95% CI 0.33-0.82; p = 0.005; I2 = 0%) and post-CRP level (MD: -31.61; 95% CI -46.74 to -16.49; p < 0.0001). Moreover, regarding the incidence of adverse events (AEs) (RR 0.73; 95% CI 0.35-1.52; p = 0.39; I² = 44%) and serious adverse events (sAEs) (RR 0.87; 95% CI 0.40-1.92; p = 0.73; I² = 39%), no significant differences were observed between MSCs and control groups. The TSA analysis showed that the result of all-cause mortality might be false-positive result. Based on the pooled results in this study, compared with standard treatment, MSCs therapy may reduce all-cause mortality of patients with COVID-19 with no increase risk of AEs and sAEs, but may not improve symptom remission rate. Further more high-quality and large-sample RCTs should be performed to confirm these findings.

Response to COVID-19 Vaccination Post-CAR T Therapy in Patients With Non-Hodgkin Lymphoma and Multiple Myeloma.

COVID-19 adversely affects individuals with cancer. Several studies have found that seroconversion rates among patients with hematologic malignancies are suboptimal when compared to patients without cancer. Patients with non-Hodgkin lymphoma (NHL) and multiple myeloma (MM) are immunocompromised due to impaired humoral and cellular immunity in addition to prescribed immunosuppressive therapy. Chimeric antigen receptor T-cell (CAR T) therapy is now widely used for NHL and MM, but little is known about seroconversion rates after COVID-19 vaccination among these populations. We evaluated SARS-CoV-2 spike-binding IgG antibody levels following COVID-19 vaccination among NHL and MM CAR T therapy recipients. Out of 104 CAR T infusions, 19 patients developed known COVID-19 infection post-CAR T. We tested 17 patients that received CAR T for antibody spike titers post COVID-19 vaccination, only 29 % (n = 5) were able to mount a clinically relevant antibody response (>250 IU/mL).

How do I save cell therapy product's storage space?

BACKGROUND: Availability of liquid nitrogen (LN2) freezer storage space is a major challenge for many transplant programs as they continue to grow and accumulate products. The recent trend of allogeneic grafts cryopreservation that started during the COVID-19 pandemic, made the situation even worse requiring an increase in storage capacity. Multi-compartment cryopreservation bags can help save storage space but can be tricky to use. Here, we describe the validation of muti-compartment cryopreservation bags for the purpose of donor lymphocyte infusion (DLI) aliquots. METHODS: We validated the use of five compartment cryobags for cryopreservation of cell therapy products. Four products were cryopreserved using these bags and each compartment was tested post-thaw for product volume distribution, total cell count recovery, and viability. Additionally, the integrity of both bag compartments and labels was assessed as well. RESULTS: All tested specimens met post-thaw viability and TNC recovery acceptability criteria. Fill volume was optimized at 24-25 mL for acceptable volume distribution between aliquots. With proper heat sealing between compartments, all aliquots retain their integrity and cryopreservation labels were adherent and legible. CONCLUSIONS: Muti-compartment bags can be used successfully for cryopreservation of cell therapy products and increase storage capacity.

Emerging immunomodulatory strategies for cell therapeutics.

Cellular therapies are poised to transform the field of medicine by restoring dysfunctional tissues and treating various diseases in a dynamic manner not achievable by conventional pharmaceutics. Spanning various therapeutic areas inclusive of cancer, regenerative medicine, and immune disorders, cellular therapies comprise stem or non-stem cells derived from various sources. Despite numerous clinical approvals or trials underway, the host immune response presents a critical impediment to the widespread adoption and success of cellular therapies. Here, we review current research and clinical advances in immunomodulatory strategies to mitigate immune rejection or promote immune tolerance to cellular therapies. We discuss the potential of these immunomodulatory interventions to accelerate translation or maximize the prospects of improving therapeutic outcomes of cellular therapies for clinical success.

Assessing deviations for HPCs obtained during COVID-19 (ADHOC): Evaluating impact of the COVID-19 pandemic on cellular therapy products and processes, the BEST collaborative study.

BACKGROUND: The success of allogeneic hematopoietic stem cell transplantation is dependent on a world-wide network of collection centers providing donations that predominantly have been infused as fresh cells. The logistics chain that supports the just-in-time delivery model for stem cell and immunotherapy products was severely stressed by the COVID pandemic, and in early 2020 a number of national and international bodies recommended that cells should be cryopreserved at the collection or transplant center to avoid interruptions in their acquisition or delivery to patients who had started conditioning. STUDY DESIGN: To assess the potential consequences of such pandemic-related deviations to normal practice, we surveyed nine international laboratories to determine if the characteristics or transplant outcomes of allogeneic stem cell donations differed in the immediate periods before and after the switch to routine cryopreservation. RESULTS: Nine centers on two continents provided data for 72 HSC donations just before, and 71 just after, switching to cryopreservation for allogeneic HSC products. No statistically significant differences between the period before and after cryopreservation were noted for time from product collection to receipt, product temperature at receipt, or CD34+ cell viability at receipt. There was an indication of slower absolute neutrophil count recovery after cryopreservation was required (mean time of 15 vs. 17.6 days). DISCUSSION: While there were no apparent changes to most parameters studied, there was an indication of slower neutrophil engraftment that will need to be examined in larger, longer term studies.

Safety and efficacy of mesenchymal stem cells in severe/critical patients with COVID-19: A systematic review and meta-analysis.

Background: The present study aims to better understand the efficacy and safety of mesenchymal stromal cells (MSCs) in treating severe/critical patients with COVID-19. Methods: PubMed, the Cochrane Library, and the Chinese electronic database CNKI were searched from inception up to Dec 19, 2021. Original comparative studies for MSC treatment + standard treatment for severe/critical patients with COVID-19, with placebo or standard treatment as the control group, were included. The primary outcomes were in-hospital mortality and adverse events (AEs). A meta-analysis was performed to compare the mortality rates between the two groups. Then, a subgroup analysis was performed according to the category of the disease (severe or critical) and MSC dose. Afterwards, a descriptive analysis was performed for AEs and secondary outcomes. The funnel plot and Egger's test were used for the publication bias assessment. Findings: Compared to placebo or standard care, MSCs provide significant benefit in the treatment of patients with severe/critical COVID-19, in terms of in-hospital mortality rate (odds ratio: 0.52, 95% CI 0.32-0.84), with very low heterogeneity (P=0.998 [Q test], I 2=0.0%) and less AEs. No significant difference was found in mortality rate due to the different disease categories or MSC doses. Furthermore, no publication bias was found. Interpretation: The present study demonstrates that MSCs are highly likely to reduce mortality and are safe to use for patients with severe or critical COVID-19, regardless of whether 1-3 doses are applied. However, due to the small sample size of the included studies, further high-quality, large-scale trials are needed to confirm this statement in the future. Funding: The National Key Research and Development Program of China (No. 2020YFC0860900), the Science and Technology Project of Wuhan (No. 2020020602012112), the Tianjin Science and Technology Research Program (18PTSYJC00070 and 16PTWYHZ00030), Haihe Laboratory of Cell Ecosystem Innovation Fund (HH22KYZX0046), and the Tianjin Free Trade Zone Innovation Development Project (ZMCY-03-2021002-01) funded the study. We are also grateful for the support from the 3551 Talent Plan of China Optics Valley.

Revised Guidelines for Coronavirus Disease 19 Management in Hematopoietic Cell Transplantation and Cellular Therapy Recipients (August 2022).

This document is intended as a guide for diagnosis and management of Coronavirus Disease 2019 (COVID-19), caused by the virus SARS-CoV-2, in adult and pediatric HCT and cellular therapy patients. This document was prepared using available data and with expert opinion provided by members of the (ASTCT) Infectious Diseases Special Interest Group (ID-SIG) and is an update of pervious publication. Since our original publication in 2020, the NIH and IDSA have published extensive guidelines for management of COVID-19 which are readily accessible ( NIH Guidelines , IDSA Guidelines ). This update focuses primarily on issues pertaining specifically to HCT/cellular therapy recipients. Information provided in this manuscript may change as new information becomes available.

CIMT 2022: Report on the 19th Annual Meeting of the Association for Cancer Immunotherapy.

The 19th Annual Meeting of the Association for Cancer Immunotherapy (CIMT), Europe's cancer immunotherapy meeting, was the first in-person event organized by CIMT since the beginning of the COVID-19 pandemic. As a hybrid event from May 10-12, the meeting attracted 920 academic and clinical professionals from over 40 countries, who met to discuss the latest advances in cancer immunology and immunotherapy research. This report summarizes the highlights of CIMT2022.

COVID-19 Vaccination in Cancer Patients: A Review Article.

Coronavirus disease 2019 (COVID-19) infection is caused by severe acute respiratory syndrome coronavirus 2. Adults with cancer are immunocompromised due to several causes including cancer itself and immunosuppressive therapy. Thus, cancer patients are more susceptible to develop COVID-19 infection. As COVID-19 vaccines became available, patients with cancer would benefit from receiving the vaccine. This article aims to review the recent evidences and recommendations about COVID-19 vaccination in cancer patients.Current guidelines recommend that patients with cancer should have the priority to receive the vaccine given their immunocompromised state. The timing of administration varies depending on cancer type and treatment. Generally, the vaccine should be given before starting the chemotherapy if possible or in between chemotherapy cycles and away from nadir phase. For other cancer treatments, it is recommended to give the vaccine when there is evidence of blood count recovery. In general, induction therapy and treatment for newly diagnosed patients should not be delayed for the vaccination purpose. It is noteworthy to mention that cancer patients especially those with hematologic malignancies might have absented or attenuated response to the vaccine due to their pathophysiological status.On the other hand, the current vaccine guidelines have been criticized for lacking evidence on some important topics that need to be addressed. Firstly, some vaccines have been granted an emergency use authorization, prior to the usual comprehensive safety and efficacy evaluation process. Secondly, specific populations including cancer patients were excluded from the approval trials for safety reasons. Finally, some recommendations regarding the COVID-19 vaccines are extrapolated from other vaccines studies. Further studies are required to fill these gaps and observational studies that include cancer patients are warranted to have a better understanding of the safety and efficacy of the vaccines in cancer patients.

Bone Marrow-Derived Mesenchymal Stromal Cell Therapy in Severe COVID-19: Preliminary Results of a Phase I/II Clinical Trial.

Background: Treatment of acute respiratory distress syndrome (ARDS) associated with COronaVIrus Disease-2019 (COVID-19) currently relies on dexamethasone and supportive mechanical ventilation, and remains associated with high mortality. Given their ability to limit inflammation, induce immune cells into a regulatory phenotype and stimulate tissue repair, mesenchymal stromal cells (MSCs) represent a promising therapy for severe and critical COVID-19 disease, which is associated with an uncontrolled immune-mediated inflammatory response. Methods: In this phase I-II trial, we aimed to evaluate the safety and efficacy of 3 intravenous infusions of bone marrow (BM)-derived MSCs at 3-day intervals in patients with severe COVID-19. All patients also received dexamethasone and standard supportive therapy. Between June 2020 and September 2021, 8 intensive care unit patients requiring supplemental oxygen (high-flow nasal oxygen in 7 patients, invasive mechanical ventilation in 1 patient) were treated with BM-MSCs. We retrospectively compared the outcomes of these MSC-treated patients with those of 24 matched control patients. Groups were compared by paired statistical tests. Results: MSC infusions were well tolerated, and no adverse effect related to MSC infusions were reported (one patient had an ischemic stroke related to aortic endocarditis). Overall, 3 patients required invasive mechanical ventilation, including one who required extracorporeal membrane oxygenation, but all patients ultimately had a favorable outcome. Survival was significantly higher in the MSC group, both at 28 and 60 days (100% vs 79.2%, p = 0.025 and 100% vs 70.8%, p = 0.0082, respectively), while no significant difference was observed in the need for mechanical ventilation nor in the number of invasive ventilation-free days, high flow nasal oxygenation-free days, oxygen support-free days and ICU-free days. MSC-treated patients also had a significantly lower day-7 D-dimer value compared to control patients (median 821.0 µg/L [IQR 362.0-1305.0] vs 3553 µg/L [IQR 1155.0-6433.5], p = 0.0085). Conclusions: BM-MSC therapy is safe and shows very promising efficacy in severe COVID-19, with a higher survival in our MSC cohort compared to matched control patients. These observations need to be confirmed in a randomized controlled trial designed to demonstrate the efficacy of BM-MSCs in COVID-19 ARDS. Clinical Trial Registration: (www.ClinicalTrials.gov), identifier NCT04445454.

Outcomes of Tisagenlecleucel in Lymphoma Patients With Predominant Management in an Ambulatory Setting.

INTRODUCTION: Chimeric antigen receptor T-cell therapy (CAR T) is a revolutionary adoptive immunotherapy approach in lymphoma; however, substantial resources are necessary for administration and care of these patients. Our institution has administered tisagenlecleucel primarily in an outpatient setting, and here we report our clinical outcomes. PATIENTS AND METHODS: We conducted a single institution, retrospective study investigating outcomes of adult lymphoma patients treated with commercial tisagenlecleucel between 10/2017 and 12/2020. We analyzed patient characteristics and outcomes of efficacy and safety including overall response rate, progression-free survival, overall survival and cytokine-release syndrome, neurotoxicity, and hospitalizations. RESULTS: Seventy-two patients with relapsed or refractory non-Hodgkin lymphoma (NHL) who received commercial tisagenlecleucel were identified; 68 (94.4%) patients received outpatient tisagenlecleucel. The overall response rate was 43% with a complete response observed in 25 patients (34.7%). At a median follow-up of 9.1 months, the median progression-free survival was 3.3 months. Grade 3-4 cytokine release syndrome was not observed in the study group and two patients had grade 3-4 neurotoxicity. Twenty-six patients (36.1%) were admitted within 30 days after infusion with a median length of stay of 5 days. Fourteen patients (19.4%) were admitted within 72 hours of infusion. No patient died of CAR T cell-related toxicity. CONCLUSION: Our experience affirms treatment with tisagenlecleucel in the outpatient setting is safe and feasible with close supervision and adequate institutional experience. After infusion, adverse events were manageable and the majority of patients did not require hospitalization.

The Viability of Hematopoietic Progenitor Cell Grafts after Cryopreservation Does Not Predict Delayed Engraftment in Allogeneic Hematopoietic Stem Cell Transplantation.

OBJECTIVE: Due to the COVID-19 pandemic, more peripheral blood stem cell (PBSC) allogeneic grafts are being frozen and infused thawed. Our objective was to study the influence of graft viability on engraftment outcome in patients treated with PBSCs. METHODS: Using trypan blue stain, we compared total nucleated cell (TNC) viability of both fresh and thawed grafts in allogeneic PBSCs. RESULTS: The viability of thawed PBSC grafts median was 74%, and fresh was 99.0%. The median number of CD34 + cells/kg infused thawed was 6.3 × 106/kg and median time to neutrophil and platelet engraftment was 17.5 and 20 days. Median number of CD34 + cells/kg infused fresh was 5.1 × 106/kg and median time to neutrophil and platelet engraftment was 18 and 19 days. There were no statistically significant differences in the time to engraftment between the 2 groups. CONCLUSION: A low TNC viability of thawed PBSC grafts does not have an effect on time to neutrophil and platelet engraftment when more than 2.85 × 106 CD34 + cells/kg are infused.