Preliminary assessment of cardiotoxicity in chimeric antigen receptor T cell therapy: a systematic review and meta-analysis.

As a novel anticancer therapy, chimeric antigen receptor T (CAR T) cell therapy may lead to cardiotoxic reactions. However, the exact incidence remains unclear. Our study aimed to preliminarily assess the prevalence of cardiotoxicity after CAR T cell treatment using a systematic review and meta-analysis. PubMed, Embase, Web of Science, and Cochrane databases were searched for potentially relevant studies. All types of relevant clinical studies were screened and assessed for risk bias. In most instances, random-effect models were used for data analysis, and heterogeneity between studies was evaluated. Standard quality assessment tools were used to assess quality. The study was registered with PROSPERO (CRD42022304611). Eight eligible studies comprising 3567 patients, including seven observational studies and one controlled study, were identified. The incidence of cardiovascular events was 16.7% [95% confidence interval (CI) 0.138-0.200, P < 0.01)]. Arrhythmia was the most common disorder, with an incidence of 6.5% (95% CI 0.029-0.115, P < 0.01). The occurrence of cardiotoxicity was associated with cytokine release syndrome (CRS), with a prevalence of 18.7% (95% CI 0.107-0.315, P < 0.01). Moreover, such adverse reactions were more common when CRS > 2 (OR = 0.07, 95% CI 0.02-0.29, P < 0.01). The risk of cardiotoxicity was not notably higher in patients receiving CAR T cell therapy than in those receiving traditional anticancer treatment. However, sufficient attention should be paid to this. And further evidence from large-scale clinical trials are needed.

Imaging-based Toxicity and Response Pattern Assessment Following CAR T-Cell Therapy.

Background Chimeric antigen receptor (CAR) T-cell immunotherapy is increasingly used for refractory lymphoma but may lead to cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Imaging may assist in clinical management. Associations between CRS or ICANS grade and imaging findings remain not fully established. Purpose To determine associations between imaging findings and clinical grade of CRS or ICANS, evaluate response patterns, and assess imaging use following CAR T-cell treatment. Materials and Methods Patients with refractory B-cell lymphoma who received CAR T-cell infusion between 2018 and 2020 at a single center were analyzed retrospectively. Clinical CRS or ICANS toxicity grade was assessed using American Society for Transplantation and Cellular Therapy, or ASTCT, consensus grading. Thoracic and head images (radiographs, CT scans, MRI scans) were evaluated. Associations between imaging findings and clinical CRS or ICANS grade were analyzed. Wilcoxon signed-rank and χ2 tests were used to assess associations between thoracic imaging findings, clinical CRS toxicity grade, and imaging-based response. Response to therapy was evaluated according to Deauville five-point scale criteria. Results A total of 38 patients (mean age ± standard deviation, 59 years ± 10; 23 men) who received CAR T-cell infusion were included. Of these, 24 (63% [95% CI: 48, 79]) and 11 (29% [95% CI: 14, 44]) experienced clinical grade 1 or higher CRS and ICANS, respectively. Patients with grade 2 or higher CRS were more likely to have thoracic images with abnormal findings (10 of 14 patients [71%; 95% CI: 47, 96] vs five of 24 patients [21%; 95% CI: 4, 37]; P = .002) and more likely to have imaging evidence of pleural effusions (five of 14 [36%; 95% CI: 10, 62] vs two of 24 [8.3%; 95% CI: 0, 20]; P = .04) and atelectasis (eight of 14 [57%; 95% CI: 30, 84] vs six of 24 [25%; 95% CI: 7, 43]; P = .048). Positive imaging findings were identified in three of seven patients (43%) with grade 2 or higher ICANS who underwent neuroimaging. The best treatment response included 20 of 36 patients (56% [95% CI: 39, 72]) with complete response, seven of 36 (19% [95% CI: 6, 33]) with partial response, one of 36 (2.8% [95% CI: 0, 8]) with stable disease, and eight of 36 (22% [95% CI: 8, 36]) with progressive disease. Conclusion Thoracic imaging findings, including pleural effusions and atelectasis, correlated with cytokine release syndrome grade following chimeric antigen receptor (CAR) T-cell infusion. CAR T-cell therapy yielded high response rates. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Langer in this issue.

Harnessing T Cells to Control Infections After Allogeneic Hematopoietic Stem Cell Transplantation.

Dramatic progress in the outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT) from alternative sources in pediatric patients has been registered over the past decade, providing a chance to cure children and adolescents in need of a transplant. Despite these advances, transplant-related mortality due to infectious complications remains a major problem, principally reflecting the inability of the depressed host immune system to limit infection replication and dissemination. In addition, development of multiple infections, a common occurrence after high-risk allo-HSCT, has important implications for overall survival. Prophylactic and preemptive pharmacotherapy is limited by toxicity and, to some extent, by lack of efficacy in breakthrough infections. T-cell reconstitution is a key requirement for effective infection control after HSCT. Consequently, T-cell immunotherapeutic strategies to boost pathogen-specific immunity may complement or represent an alternative to drug treatments. Pioneering proof of principle studies demonstrated that the administration of donor-derived T cells directed to human herpesviruses, on the basis of viral DNA monitoring, could effectively restore specific immunity and confer protection against viral infections. Since then, the field has evolved with implementation of techniques able to hasten production, allow for selection of specific cell subsets, and target multiple pathogens. This review provides a brief overview of current cellular therapeutic strategies to prevent or treat pathogen-related complications after HSCT, research carried out to increase efficacy and safety, including T-cell production for treatment of infections in patients with virus-naïve donors, results from clinical trials, and future developments to widen adoptive T-cell therapy access in the HSCT setting.

The environmental risk assessment of cell-processing facilities for cell therapy in a Japanese academic institution.

Cell therapy is a promising treatment. One of the key aspects of cell processing products is ensuring sterility of cell-processing facilities (CPFs). The objective of this study was to assess the environmental risk factors inside and outside CPFs. We monitored the temperature, humidity, particle number, colony number of microorganisms, bacteria, fungi, and harmful insects in and around our CPF monthly over one year. The temperature in the CPF was constant but the humidity fluctuated depending on the humidity outside. The particle number correlated with the number of entries to the room. Except for winter, colonies of microorganisms and harmful insects were detected depending on the cleanliness of the room. Seven bacterial and two fungal species were identified by PCR analyses. Psocoptera and Acari each accounted for 41% of the total trapped insects. These results provide useful data for taking the appropriate steps to keep entire CPFs clean.

Tumorigenicity assessment of cell therapy products: The need for global consensus and points to consider.

Pluripotent stem cells offer the potential for an unlimited source for cell therapy products. However, there is concern regarding the tumorigenicity of these products in humans, mainly due to the possible unintended contamination of undifferentiated cells or transformed cells. Because of the complex nature of these new therapies and the lack of a globally accepted consensus on the strategy for tumorigenicity evaluation, a case-by-case approach is recommended for the risk assessment of each cell therapy product. In general, therapeutic products need to be qualified using available technologies, which ideally should be fully validated. In such circumstances, the developers of cell therapy products may have conducted various tumorigenicity tests and consulted with regulators in respective countries. Here, we critically review currently available in vivo and in vitro testing methods for tumorigenicity evaluation against expectations in international regulatory guidelines. We discuss the value of those approaches, in particular the limitations of in vivo methods, and comment on challenges and future directions. In addition, we note the need for an internationally harmonized procedure for tumorigenicity assessment of cell therapy products from both regulatory and technological perspectives.

Towards Automated Manufacturing for Cell Therapies.

PURPOSE OF REVIEW: Many cell therapy products are beginning to reach the commercial finish line and a rapidly escalating pipeline of products are in clinical development. The need to develop manufacturing capability that will support a successful commercial business model has become a top priority as many cell therapy developers look to secure long-term visions to enable both funding and treatment success. RECENT FINDINGS: Manufacturing automation is both highly compelling and very challenging at the same time as a key tactic to address quality, cost of goods, scale, and sustainability that are fundamental drivers for commercially viable manufacturing. This paper presents an overview and strategic drivers for application of automation to cell therapy manufacturing. It also explores unique automation considerations for patient-specific cell therapy (PSCT) where each full-scale lot is for one patient vs off-the-shelf cell therapy (OTSCT) where a full-scale lot will treat many patients, and finally some practical considerations for implementing automation.

Renewed assessment of the risk of emergent advanced cell therapies to transmit neuroproteinopathies.

The inadvertent transmission of long incubating, untreatable and fatal neurodegenerative prionopathies, notably iatrogenic Creutzfeldt-Jakob disease, following transplantation of cadaver-derived corneas, pituitary growth, hormones and dura mater, constitutes a historical precedent which has underpinned the application of precautionary principles to modern day advanced cell therapies. To date these have been reflected by geographic or medical history risk-based deferral of tissue donors. Emergent understanding of other prion-like proteinopathies, their potential independence from prions as a transmissible agent and the variable capability of scalably manufacturable stem cells and derivatives to take up and clear or to propagate prions, substantiate further commitment to qualifying neurodegenerative proteinopathy transmission risks. This is especially so for those involving direct or facilitated access to a recipient's brain or connected visual or nervous system such as for the treatment of stroke, retinal and adult onset neurodegenerative diseases, treatments for which have already commenced. In this review, we assess the prospective global dissemination of advanced cell therapies founded on transplantation or exposure to allogeneic human cells, recap lessons learned from the historical precedents of CJD transmission and review recent advances and current limits in understanding of prion and other neurodegenerative disease prion-like susceptibility and transmission. From these we propose grounds for a reassessment of the risks of emergent advanced cell therapies to transmit neuroproteinopathies and suggestions to ACT developers and regulators for risk mitigation and extension of criteria for deferrals.

Science-based assessment of source materials for cell-based medicines: report of a stakeholders workshop.

Human pluripotent stem cells (hPSCs) have the potential to transform medicine. However, hurdles remain to ensure safety for such cellular products. Science-based understanding of the requirements for source materials is required as are appropriate materials. Leaders in hPSC biology, clinical translation, biomanufacturing and regulatory issues were brought together to define requirements for source materials for the production of hPSC-derived therapies and to identify other key issues for the safety of cell therapy products. While the focus of this meeting was on hPSC-derived cell therapies, many of the issues are generic to all cell-based medicines. The intent of this report is to summarize the key issues discussed and record the consensus reached on each of these by the expert delegates.

Direct-to-consumer marketing of stem cell interventions by Canadian businesses.

AIM: This study examines marketing claims of Canadian businesses engaged in direct-to-consumer advertising of putative stem cell treatments. METHODS: Internet searches were used to locate Canadian businesses selling stem cell interventions. Company websites were subjected to detailed analysis. RESULTS: In total, 30 Canadian businesses sell stem cell interventions provided at 43 clinics. Autologous stem cells are the most common types of products promoted by such businesses. Company websites minimize risks while making strong claims about benefits of stem cell interventions. DISCUSSION: Businesses' representations could result in patients making health-related decisions informed by marketing claims rather than best available scientific evidence. CONCLUSION: Although there is absent development of new regulations and guidance, the Canadian direct-to-consumer marketplace for stem cell interventions appears poised for expansion.

EU decision-making for marketing authorization of advanced therapy medicinal products: a case study.

A comparative analysis of assessment procedures for authorization of all European Union (EU) applications for advanced therapy medicinal products (ATMPs) shows that negative opinions were associated with a lack of clinical efficacy and identified severe safety risks. Unmet medical need was often considered in positive opinions and outweighed scientific uncertainties. Numerous quality issues illustrate the difficulties in this domain for ATMP development. Altogether, it suggests that setting appropriate standards for ATMP authorization in Europe, similar to elsewhere, is a learning experience. The experimental characteristics of authorized ATMPs urge regulators, industry, and clinical practice to pay accurate attention to post-marketing risk management to limit patient risk. Methodologies for ATMP development and regulatory evaluations need to be continuously evaluated for the field to flourish.

[Specific aspects for virus safety of raw materials for cellular-based medicinal products]. / Spezifische Aspekte zur Virussicherheit von Produktionshilfsstoffen für somatische Zelltherapie-Arzneimittel.

Virus safety of cell-based medicinal products is a particular challenge. These products are frequently manufactured using various human- or animal-derived starting and raw materials (serum and feeder-cells) in cell culture, which are possible sources for viral contamination. For living or proliferating cells, no methods for virus inactivation (such as heat or chemical treatment) can be used and the options for testing these medicinal products for all possible viral contaminations are very limited. As a consequence, other safety measures, in particular careful selection and testing of starting and raw materials, are very important. For raw materials, attention should be paid to cell-culture additives of biological origin, such as human and bovine serum and porcine trypsin. Whenever possible, manufacturing steps for inactivation and removal of viruses should be introduced as an additional safety measure. In addition, recombinant products from animal cell cultures (such as growth factors, monoclonal antibodies for cell sorting, viral vectors) are used and have to be tested for virus safety.

Aurigon's point of view on the safety assessment of cell-based therapies: an experience based on the participation in 15 ATMPs projects.

Cell-based medicinal products (CBMP) require the use of a case-by-case, risk-based, and scientifically justified nonclinical safety testing approach. The challenge is to translate regulatory requirements into concrete testing designs while overcoming technical limitations inherent to animal models and the CBMP and assaying combination strategies to reduce animal use and save time and budget.

Proceedings: international regulatory considerations on development pathways for cell therapies.

Regenerative medicine is a rapidly evolving field that faces novel scientific and regulatory challenges. In September 2013, the International Workshop on Regulatory Pathways for Cell Therapies was convened to discuss the nature of these challenges and potential solutions and to highlight opportunities for potential convergence between different regulatory bodies that might assist the field's development. The workshop discussions generated potentially actionable steps in five main areas that could mitigate cell therapy development pathway risk and accelerate moving promising therapies to patients. These included the need for convergence of regulatory guidelines on donor eligibility and suitability of lines for use in clinical trials and subsequent commercialization for cell therapies to move forward on a global basis; the need to challenge and encourage investigators in the regenerative medicine field to share information and provide examples of comparability studies related to master cell banks; the need for convergence of guidelines across regulatory jurisdictions on requirements for tumorigenicity studies, based on particular cell types and on biodistribution studies; the need to increase transparency in sharing clinical trial information more broadly and disseminating results more rapidly; and the need to establish a forum for sharing the experiences of various approaches being developed to expedite regulatory approvals and access for patients to innovative cell and regenerative therapies in the different regulatory jurisdictions and to assess their potential strengths and weaknesses.

Path to the clinic: assessment of iPSC-based cell therapies in vivo in a nonhuman primate model.

Induced pluripotent stem cell (iPSC)-based cell therapies have great potential for regenerative medicine but are also potentially associated with tumorigenic risks. Current rodent models are not optimal predictors of efficiency and safety for clinical application. Therefore, we developed a clinically relevant nonhuman primate model to assess the tumorigenic potential and in vivo efficacy of both undifferentiated and differentiated iPSCs in autologous settings without immunosuppression. Undifferentiated autologous iPSCs indeed form mature teratomas in a dose-dependent manner. However, tumor formation is accompanied by an inflammatory reaction. On the other hand, iPSC-derived mesodermal stromal-like cells form new bone in vivo without any evidence of teratoma formation. We therefore show in a large animal model that closely resembles human physiology that undifferentiated autologous iPSCs form teratomas, and that iPSC-derived progenitor cells can give rise to a functional tissue in vivo.

Assessment of a symptomatic Duchenne muscular dystrophy carrier 20 years after myoblast transplantation from her asymptomatic identical twin sister.

Because it is due to a mutation on the X-chromosome, Duchenne muscular dystrophy rarely affects women, unless there is an unequal lyonisation of the X-chromosome containing the normal dystrophin gene. We report here the unique situation of a symptomatic Duchenne muscular dystrophy woman who was transplanted with myoblasts received from her asymptomatic monozygotic twin sister 20 years ago. Specific dynamometry was performed to possibly detect a long-term effect of this cell therapy. Long-term safety of myoblast transplantation was established by this exceptional case. However, long-term efficacy could not be definitively asserted for this patient, in spite of several clues suggesting beneficial effects.