Report on Webinar Series Cell and Gene Therapy: From Concept to Clinical Use

With the launch of the UK Academy of Pharmaceutical Sciences Advanced Therapy Medicinal Products Focus Group in late 2020, a webinar series reviewing the current and emerging trends in cell and gene therapy was held virtually in May 2021. This webinar series was timely given the recent withdrawal of the United Kingdom from the European Union and the global COVID-19 pandemic impacting all sectors of the pharmaceutical sciences research landscape globally and in the UK. Delegates from the academic, industry, regulatory and NHS sectors attended the session where challenges and opportunities in the development and clinical implementation of cell and gene therapies were discussed. Globally, the cell and gene therapy market has reached a value of 4.3 billion dollars in 2020, having increased at a compound annual growth rate of 25.5% since 2015. This webinar series captured all the major developments in this rapidly evolving area and highlighted emerging concepts warranting cross-sector efforts from across the community in the future.

Process development and validation of expanded regulatory T cells for prospective applications: an example of manufacturing a personalized advanced therapy medicinal product

Background A growing number of clinical trials have shown that regulatory T (Treg) cell transfer may have a favorable effect on the maintenance of self-tolerance and immune homeostasis in different conditions such as graft-versus-host disease (GvHD), solid organ transplantation, type 1 diabetes, and others. In this context, the availability of a robust manufacturing protocol that is able to produce a sufficient number of functional Treg cells represents a fundamental prerequisite for the success of a cell therapy clinical protocol. However, extended workflow guidelines for nonprofit manufacturers are currently lacking. Despite the fact that different successful manufacturing procedures and cell products with excellent safety profiles have been reported from early clinical trials, the selection and expansion protocols for Treg cells vary a lot. The objective of this study was to validate a Good Manufacturing Practice (GMP)-compliant protocol for the production of Treg cells that approaches the whole process with a risk-management methodology, from process design to completion of final product development. High emphasis was given to the description of the quality control (QC) methodologies used for the in-process and release tests (sterility, endotoxin test, mycoplasma, and immunophenotype). Results The GMP-compliant protocol defined in this work allows at least 4.11 × 109 Treg cells to be obtained with an average purity of 95.75 ± 4.38% and can be used in different clinical settings to exploit Treg cell immunomodulatory function. Conclusions These results could be of great use for facilities implementing GMP-compliant cell therapy protocols of these cells for different conditions aimed at restoring the Treg cell number and function, which may slow the progression of certain diseases.

Recycling Apparent Waste Into Biologicals: The Case of Umbilical Cord Blood in Italy and Spain

Most public cord blood banking programs are currently facing financial difficulties due to a progressive decline in the number of cord blood transplants performed worldwide and to a high discard rate of the donated units caused by progressively increasing thresholds of the stem cell dose required to perform safe and effective hemopoietic cord blood transplants. Recycling a proportion of unused cord blood units to prepare novel cord blood components obtained with minimal manipulation (platelets, plasma, red blood cells) and to develop more technologically complex products regulated in the US as Cellular and Gene Therapy Products and in Europe as Advanced Therapy Medicinal Products [e.g. virus-specific T cells (VST), natural killer (NK) cells, induced pluripotent stem cells (iPSCs) is a promising strategy to increase the therapeutic value and reduce the financial deficits of public cord blood banking. Based on encouraging preliminary evidences reported in the literature, additional laboratory studies, large multicenter clinical trials and international regulatory harmonization are necessary to achieve these important goals. This article describes organizational, methodological and regulatory advancements developed in Italy and Spain to promote the clinical use of cord blood platelets, plasma and red blood cells.

Pulsed magnetic stimulation in combination with pneumomassage in the therapy of patients with professional sensorineural hearing loss

Introduction. There are many methods for treating sensorineural hearing loss (SHL) of the occupational origin, which indicates insufficient effectiveness and an active search for more advanced therapy methods. Objective of the study: to evaluate changes in the state of the central nervous system pathways under the influence of a magnetic field and the long-term period. Materials and Methods. There were treated fifty two aviation workers with SHL of the occupational origin with moderate hearing loss. Pulsed magnetic stimulation (MS) and pneumatic massage of the tympanic membrane were used. Before and after treatment, electroencephalography was performed with the registration of visual and auditory evoked potentials (EP), somatosensory evoked potentials (SSEP), psychological testing, and the study of higher mental functions in terms of short-term and delayed verbal memory, attention function. Results. After treatment, there was an improvement in speech intelligibility in 62% of cases, a decrease in the intensity of the tinnitus and head noise in 44% of cases, there was an improvement in the indicators of audiometric research and acumetry data from both sides. There was a statistically significant increase in the α-rhythm, the time of the pulse passing through the central afferent structures increased, the indicators of operative verbal memory, and the productivity of long-term memorization, the volume and stability of attention increased. Conclusion. The effectiveness of pulse MS in treating patients with occupational SHL has been proven. The prospects of using pulsed MS in combination with pneumatic massage in occupational pathology were shown, which was confirmed by positive changes in objective and subjective indicators characterizing the condition of patients immediately after the therapy sessions and a year after treatment.

Clinical significance of collchicine in pharmacotherapy of cardiovascular pathology in patients with hyperuricemia in rheumatic diseases

For a long time, there has been scientific debate about the appropriateness of prescribing drugs to lower the level of uric acid in patients without clinical manifestations of gout. Long-term hyperuricemia is known to be the cause of gout and gouty arthritis. However, an increased level of uric acid is often found in a number of other diseases (metabolic syndrome, kidney disease, cardiovascular disease, psoriasis). Clinical evidence suggests that uric acid-lowering therapy slows the progression of cardiovascular disease and chronic kidney disease. And, if in rheumatological practice this issue still remains a subject of discussion, then the cardiological community by 2019 has clearly defined the indications for starting urate-lowering therapy. The Consensus on the Management of Patients with Hyperuricemia and High Cardiovascular Risk strongly recommends that the practitioner prescribe drugs to control hyperuricemia in hypertensive patients. The need to control the level of uric acid is reflected in the relevant sections of the Clinical Guidelines for the Management of Patients with Arterial Hypertension, 2020. This article provides a review of the literature on the etiology, pathophysiology, pharmacotherapy of hyperuricemia in patients with cardiovascular and rheumatic diseases. A separate section is devoted to scientific studies of the effects of colchicine in advanced therapy for CVD and RD. A clinical case of observation of a patient with newly diagnosed psoriatic arthritis, hyperuricemia, high cardiovascular risk is presented. The peculiarity of this clinical case is the onset of the disease after orthopedic surgery on the knee joints, high comorbidity and poor tolerance of standard basic therapy. The use of colchicine stabilized the patient’s condition. Thus, in clinical practice, it is necessary to take into account the role of hyperuricemia in the pathogenesis of inflammation in cardiovascular pathology. Colchicine may be the drug of choice for patients with hyperuricemia at high cardiovascular risk.

Methodological Characteristics of Clinical Trials Supporting the Marketing Authorisation of Advanced Therapies in the European Union

Several advanced therapy medicinal products (ATMPs) have been approved in the European Union (EU). The aim of this study is to analyse the methodological features of the clinical trials (CT) that supported the marketing authorization (MA) of the approved ATMPs in the EU. A systematic review of the characteristics of pivotal CT of ATMPs approved in the EU until January 31st, 2021 was carried out. A total of 17 ATMPs were approved and 23 CT were conducted to support the MA (median, 1, range, 1–3). Of those studies, 8 (34.78%) were non-controlled and 7 (30.43%) used historical controls. Only 7 (30.4%) were placebo or active-controlled studies. Among all CT, 21 (91.3%) were open-label and 13 (56.52%) had a single-arm design. To evaluate the primary endpoint, 18 (78.26%) studies used an intermediate and single variable. The median (IQR) number of patients enrolled in the studies was 75 (22–118). To date, ATMPs’ approval in the EU is mainly supported by uncontrolled, single-arm pivotal CT. Although there is a trend toward an adaptive or a life cycle approach, a switch to more robust clinical trial designs is expected to better define the benefit and the therapeutic added value of ATMPs.