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Cell therapy manufacturing requires precise monitoring of critical parameters to ensure product quality, consistency and to facilitate the implementation of cost-effective processes. While conventional analytical methods offer limited real-time insights, integration of process analytical technology tools such as Raman spectroscopy in bioprocessing has the potential to drive efficiency and reliability during the manufacture of cell-based therapies while meeting stringent regulatory requirements. The non-destructive nature of Raman spectroscopy, combined with its ability to be integrated on-line with scalable platforms, allows for continuous data acquisition, enabling real-time correlations between process parameters and critical quality attributes. Herein, we review the role of Raman spectroscopy in cell therapy bioprocessing and discuss how simultaneous measurement of distinct parameters and attributes, such as cell density, viability, metabolites and cell identity biomarkers can streamline on-line monitoring and facilitate adaptive process control. This, in turn, enhances productivity and mitigates process-related risks. We focus on recent advances integrating Raman spectroscopy across various manufacturing stages, from optimizing culture media feeds to monitoring bioprocess dynamics, covering downstream applications such as detection of co-isolated contaminating cells, cryopreservation, and quality control of the drug product. Finally, we discuss the potential of Raman spectroscopy to revolutionize current practices and accelerate the development of advanced therapy medicinal products., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Purpose: To assess the scope of U.S.-based companies advertising and administering non-Federal Drug Administration (FDA) approved cell-based therapy (herein called NFACT) for ocular conditions based on information from companies' public websites after the FDA's legal actions against specific NFACT clinics in 2018 and 2019. Current findings are compared to previously published data from 2017., Design: Trend study looking at U.S.-based companies that use direct-to-consumer marketing and have websites advertising therapy for ocular conditions., Methods: A systematic and extensive keyword-based Internet search was utilized to identify, document, and analyze U.S. business websites offering NFACT for ocular conditions as of August 2022. Main outcomes measured include, clinic locations, marketed ocular conditions, types of NFACT offered, source of stem cells used, routes of administration, and treatment costs., Results: From the prior analysis in 2017 to the 2019 analysis, there was a decrease in the number of NFACT clinics from 76 to 62 and companies from 40 to 39. Given the concerning persistence of NFACTs in August 2019 an additional analysis was performed in 2022 which showed a drastic decrease in NFACT clinics from 62 in 2019 to 18 in 2023 and from 39 companies to 13 in 2023. In both 2019 and 2022, the most commonly referenced ocular condition was age-related macular degeneration (2019-72%, 2022-92%). The state with the most clinics was in Texas (2019-12; 2022-5). Autologous adipose-derived stem cells were the most common cell type used in both analyses., Conclusions: In 2019 U.S.-based direct-to-consumer companies marketing NFACT persisted despite (1) a lack of high-quality clinical evidence supporting the efficacy of these procedures, (2) the association of some of these treatments with severe vision loss, and (3) increasing FDA oversight and recent legal action. In 2022 the number of clinics and companies decreased, but their persistence is a reminder that continued concern is necessary and ophthalmic associations need to continue advocacy efforts to protect patients from these potentially predatory organizations., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The field of organ transplantation is experiencing a transformative shift with the rise of Advanced Therapy Medicinal Products (ATMPs), which include gene therapies, somatic cell therapies, and tissue-engineered products. These therapies offer new, potentially curative treatments for longstanding medical challenges, impacting numerous patients. However, their adoption is hindered by complex regulatory frameworks, high production costs, and inconsistent access across Europe. The ESOT ATMP Task Force's position paper analyzes these challenges from research to clinical application, advocating for a coordinated strategy to position Europe as a leader in ATMP development. It proposes specific actions such as streamlining regulatory pathways to accelerate approvals, boosting funding for ATMP research, and creating specialized facilities for development and implementation. The paper also highlights the critical roles of patient engagement and real-world evidence in optimizing clinical and regulatory practices., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Berishvili, Piemonti, de Koning, Lindstedt, Scholz, Scott, Auxenfans, Johnson, Martin, Gunther, Mey, Potena and Thaunat.)

Technological and scientific innovations in the area of gene and cell therapies, so-called advanced therapy medicinal products (ATMPs), have contributed to the steep increase in treatment options for patients with rare diseases. They offer opportunities to address the underlying genetic defect by gene addition, i.e., the delivery of the gene of interest to the target cells, or by genome editing approaches through direct repair of disease-causing mutations. This paper outlines clinical evidence requirements in the context of marketing authorisations for rare diseases. Two out of fifteen gene therapies that have been approved in the European Union since 2018 are used as case studies: Libmeldy (atidarsagen autotemcel) for the treatment of patients with metachromatic leukodystrophy, and Roctavian (valoctocogen roxaparvovec) for the treatment of patients with haemophilia A. Special aspects of the evaluation of single-arm trials with small sample size and requirements with regard to the isolation and causal attribution of the treatment effect are discussed. The role of clinical data obtained under everyday conditions (real world data) to support the generation of evidence in the pre- and post authorisation phase is critically examined. Furthermore, the paper outlines aspects related to conditional versus standard marketing authorisations as well as aspects related to registry-based non-interventional studies in the context of market and patient access to urgently needed drugs., (Copyright © 2024. Published by Elsevier GmbH.)

Increasing numbers of cell and gene therapies (CGTs) are emerging to treat and cure pediatric diseases. However, small market sizes limit the potential return on investment within the traditional biopharmaceutical drug development model, leading to a market failure. In this Perspective, we discuss major factors contributing to this failure, including high manufacturing costs, regulatory challenges, and licensing practices that do not incorporate pediatric development milestones, as well as potential solutions. We propose the creation of a new entity, the Pediatric Advanced Medicines Biotech, to lead late-stage development and commercialize pediatric CGTs outside the traditional biopharmaceutical model in the United States-where organized efforts to solve this problem have been lacking. The Pediatric Advanced Medicines Biotech would partner with the academic ecosystem, manufacture products in academic good manufacturing practice facilities and work closely with regulatory bodies, to ferry CGTs across the drug development 'valley of death' and, ultimately, increase access to lifesaving treatments for children in need., (© 2024. Springer Nature America, Inc.)

Toward the translation of allogeneic cell therapy products, cell banks are needed not only to manufacture the final human product but also during the preclinical evaluation of an animal-based analogous cellular product (ACP). These cell banks need to be established at both the master cell bank (MCB) level and the working cell bank (WCB) level. Inasmuch as most of the development of cell therapy products is at academic centers, it is imperative that academic researchers understand how to establish MCBs and WCBs within an academic environment. To illustrate this process, using articular cartilage as the model, a cell bank for an ACP was developed (MCBs at passage 2, WCBs at passage 5) to produce self-assembled neocartilage for preclinical evaluation (constructs at passage 7). The cell bank system is estimated to be able to produce between 160 000 and 400 000 constructs for each of the six MCBs. Overall, the ACP cell bank yielded constructs that are analogous to the intended human product, which is critical toward conducting preclinical evaluations of the ACP for inclusion in an Investigational New Drug application to the FDA., (© 2024 IOP Publishing Ltd.)

Competing Interests: Declaration of competing interest None.

Optimizing complex bioprocesses poses a significant challenge in several fields, particularly in cell therapy manufacturing. The development of customized, closed, and automated processes is crucial for their industrial translation and for addressing large patient populations at a sustainable price. Limited understanding of the underlying biological mechanisms, coupled with highly resource-intensive experimentation, are two contributing factors that make the development of these next-generation processes challenging. Bayesian optimization (BO) is an iterative experimental design methodology that addresses these challenges, but has not been extensively tested in situations that require parallel experimentation with significant experimental variability. In this study, we present an evaluation of noisy, parallel BO for increasing noise levels and parallel batch sizes on two in silico bioprocesses, and compare it to the industry state-of-the-art. As an in vitro showcase, we apply the method to the optimization of a monocyte purification unit operation. The in silico results show that BO significantly outperforms the state-of-the-art, requiring approximately 50% fewer experiments on average. This study highlights the potential of noisy, parallel BO as valuable tool for cell therapy process development and optimization., (© 2024 Wiley Periodicals LLC.)

Lifileucel (AMTAGVI™), a one-time autologous T cell therapy derived and expanded from tumour-infiltrating lymphocytes (TIL) from a patient's own tumour, is being developed by Iovance Biotherapeutics, Inc. for the treatment of cancer. Lifileucel was granted accelerated approval based on objective response rate (ORR) in February 2024 in the USA for use in adult patients with unresectable or metastatic melanoma previously treated with a PD-1 blocking antibody, and if BRAF V600 mutation positive, a BRAF inhibitor with or without a MEK inhibitor. This article summarizes the milestones in the development of lifileucel leading to this first approval for the treatment of patients with unresectable or metastatic melanoma who have progressed on or after prior anti-PD-1/L1 therapy and targeted therapy., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Chimeric antigen receptor-T (CAR-T) cell therapy has made remarkable strides in treating hematological malignancies. However, the widespread adoption of CAR-T cell therapy is hindered by several challenges. These include concerns about the long-term and complex manufacturing process, as well as efficacy factors such as tumor antigen escape, CAR-T cell exhaustion, and the immunosuppressive tumor microenvironment. Additionally, safety issues like the risk of secondary cancers post-treatment, on-target off-tumor toxicity, and immune effector responses triggered by CAR-T cells are significant considerations. To address these obstacles, researchers have explored various strategies, including allogeneic universal CAR-T cell development, infusion of non-activated quiescent T cells within a 24-hour period, and in vivo induction of CAR-T cells. This review comprehensively examines the clinical challenges of CAR-T cell therapy and outlines strategies to overcome them, aiming to chart pathways beyond its current Achilles heels., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li, Hu, Li and Wu.)

A major aim in the field of synthetic biology is developing tools capable of responding to user-defined inputs by activating therapeutically relevant cellular functions. Gene transcription and regulation in response to external stimuli are some of the most powerful and versatile of these cellular functions being explored. Motivated by the success of chimeric antigen receptor (CAR) T-cell therapies, transmembrane receptor-based platforms have been embraced for their ability to sense extracellular ligands and to subsequently activate intracellular signal transduction. The integration of transmembrane receptors with transcriptional activation platforms has not yet achieved its full potential. Transient expression of plasmid DNA is often used to explore gene regulation platforms in vitro. However, applications capable of targeting therapeutically relevant endogenous or stably integrated genes are more clinically relevant. Gene regulation may allow for engineered cells to traffic into tissues of interest and secrete functional proteins into the extracellular space or to differentiate into functional cells. Transmembrane receptors that regulate transcription have the potential to revolutionize cell therapies in a myriad of applications, including cancer treatment and regenerative medicine. In this review, we will examine current engineering approaches to control transcription in mammalian cells with an emphasis on systems that can be selectively activated in response to extracellular signals. We will also speculate on the potential therapeutic applications of these technologies and examine promising approaches to expand their capabilities and tighten the control of gene regulation in cellular therapies., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Sebastian Vega reports financial support was provided by National Science Foundation. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The separation of specific cell populations is instrumental in gaining insights into cellular processes, elucidating disease mechanisms, and advancing applications in tissue engineering, regenerative medicine, diagnostics, and cell therapies. Microfluidic methods for cell separation have propelled the field forward, benefitting from miniaturization, advanced fabrication technologies, a profound understanding of fluid dynamics governing particle separation mechanisms, and a surge in interdisciplinary investigations focused on diverse applications. Cell separation methodologies can be categorized according to their underlying separation mechanisms. Passive microfluidic separation systems rely on channel structures and fluidic rheology, obviating the necessity for external force fields to facilitate label-free cell separation. These passive approaches offer a compelling combination of cost-effectiveness and scalability when compared to active methods that depend on external fields to manipulate cells. This review delves into the extensive utilization of passive microfluidic techniques for cell separation, encompassing various strategies such as filtration, sedimentation, adhesion-based techniques, pinched flow fractionation (PFF), deterministic lateral displacement (DLD), inertial microfluidics, hydrophoresis, viscoelastic microfluidics, and hybrid microfluidics. Besides, the review provides an in-depth discussion concerning cell types, separation markers, and the commercialization of these technologies. Subsequently, it outlines the current challenges faced in the field and presents a forward-looking perspective on potential future developments. This work hopes to aid in facilitating the dissemination of knowledge in cell separation, guiding future research, and informing practical applications across diverse scientific disciplines., Competing Interests: Declaration of competing Interest The authors declare no competing interests. K.G. is a shareholder of CYBO, LucasLand, and FlyWorks., (Copyright © 2024. Published by Elsevier Inc.)

Cell-based therapy, as a promising regenerative medicine approach, has been a promising and effective strategy to treat or even cure various kinds of diseases and conditions. Generally, two types of cells are used in cell therapy, the first is the stem cell, and the other is a fully differentiated cell. Initially, all cells in the body are derived from stem cells. Based on the capacity, potency and differentiation potential of stem cells, there are four types: totipotent (produces all somatic cells plus perinatal tissues), pluripotent (produces all somatic cells), multipotent (produces many types of cells), and unipotent (produces a particular type of cells). All non-totipotent stem cells can be used for cell therapy, depending on their potency and/or disease state/conditions. Adult fully differentiated cell is another cell type for cell therapy that is isolated from adult tissues or obtained following the differentiation of stem cells. The cells can then be transplanted back into the patient to replace damaged or malfunctioning cells, promote tissue repair, or enhance the targeted organ's overall function. With increasing science and knowledge in biology and medicine, different types of techniques have been developed to obtain efficient cells to use for therapeutic approaches. In this study, the potential and opportunity of use of all cell types, both stem cells and fully differentiated cells, are reviewed., Competing Interests: Declaration of competing interest Authors have no conflict of interest to declare., (Copyright © 2024. Published by Elsevier B.V.)

The clinical application of cell therapies is becoming increasingly important for the treatment of cancer, congenital immune deficiencies, and hemoglobinopathies. These therapies have been primarily manufactured and used at academic medical centers. However, cell therapies are now increasingly being produced in centralized manufacturing facilities and shipped to medical centers for administration. Typically, these cell therapies are produced from a patient's own cells, which are the critical starting material. For these therapies to achieve their full potential, more medical centers must develop the infrastructure to collect, label, cryopreserve, test, and ship these cells to the centralized laboratories where these cell therapies are manufactured. Medical centers must also develop systems to receive, store, and infuse the finished cell therapy products. Since most cell therapies are cryopreserved for shipment and storage, medical centers using these therapies will require access to liquid nitrogen product storage tanks and develop procedures to thaw cell therapies. These services could be provided by the hospital pharmacy or transfusion service, but the latter is likely most appropriate. Another barrier to implementing these services is the variability among providers of these cell therapies in the processes related to handling cell therapies. The provision of these services by medical centers would be facilitated by establishing a national coordinating center and a network of apheresis centers to collect and cryopreserve the cells needed to begin the manufacturing process and cell therapy laboratories to store and issue the cells. In addition to organizing cell collections, the coordinating center could establish uniform practices for collecting, labeling, shipping, receiving, thawing, and infusing the cell therapy., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Sham surgery is often required for cell therapies adopting a randomized placebo-controlled double-blinded trial design. Using the case of dopamine neuron therapy for Parkinson's disease, we argue that alternative trial designs should be considered instead, for several reasons relating to ethics, patient burden, ease of unblinding, and cost., Competing Interests: Declaration of interests V.T. is a co-founder, advisor, and recipient of research support from BlueRock Therapeutics. R.A.B. is a consultant for NovoNordisk, Aspen Neuroscience, Bayer, Transine Therapeutics, Rinri Therapeutics, and UCB on patient-related outcome measures., (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)

This paper presents an innovative approach to wireless cellular stimulation therapy through the design of a magnetoelectric (ME) microdevice. Traditional electrophysiological stimulation techniques for neural and deep brain stimulation face limitations due to their reliance on electronics, electrode arrays, or the complexity of magnetic induction. In contrast, the proposed ME microdevice offers a self-contained, controllable, battery-free, and electronics-free alternative, holding promise for targeted precise stimulation of biological cells and tissues. The designed microdevice integrates core shell ME materials with remote coils which applies magnetic temporal interference (MTI) signals, leading to the generation of a bipolar local electric stimulation current operating at low frequencies which is suitable for precise stimulation. The nonlinear property of the magnetostrictive core enables the demodulation of remotely applied high-frequency electromagnetic fields, resulting in a localized, tunable, and manipulatable electric potential on the piezoelectric shell surface. This potential, triggers electrical spikes in neural cells, facilitating stimulation. Rigorous computational simulations support this concept, highlighting a significantly high ME coupling factor generation of 550 V/m·Oe. The high ME coupling is primarily attributed to the operation of the device in its mechanical resonance modes. This achievement is the result of a carefully designed core shell structure operating at the MTI resonance frequencies, coupled with an optimal magnetic bias, and predetermined piezo shell thickness. These findings underscore the potential of the engineered ME core shell as a candidate for wireless and minimally invasive cellular stimulation therapy, characterized by high resolution and precision. These results open new avenues for injectable material structures capable of delivering effective cellular stimulation therapy, carrying implications across neuroscience medical devices, and regenerative medicine., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Narayanan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

GvHD still remains, despite the continuous improvement of transplantation platforms, a fearful complication of transplantation from allogeneic donors. Being able to separate GvHD from GvL represents the greatest challenge in the allogeneic transplant setting. This may be possible through continuous improvement of cell therapy techniques. In this review, current cell therapies are taken into consideration, which are based on the use of TCR alpha/beta depletion, CD45RA depletion, T regulatory cell enrichment, NK-cell-based immunotherapies, and suicide gene therapies in order to prevent GvHD and maximally amplify the GvL effect in the setting of haploidentical transplantation.

Leading causes of blindness worldwide include neurodegenerative diseases of the retina, which cause irreversible loss of retinal pigment epithelium (RPE) and photoreceptors, and optic neuropathies, which result in retinal ganglion cell (RGC) death. Because photoreceptor and RGCs do not spontaneously regenerate in mammals, including humans, vision loss from these conditions is, at present, permanent. Recent advances in gene and cell-based therapies have provided new hope to patients affected by these conditions. This chapter reviews the current state and future of these approaches to treating ocular neurodegenerative disease. Gene therapies for retinal degeneration and optic neuropathies primarily focus on correcting known pathogenic mutations that cause inherited conditions to halt progression. There are multiple retinal and optic neuropathy gene therapies in clinical trials, and one retinal gene therapy is approved in the United States, Canada, Europe, and Australia. Cell-based therapies are mutation agnostic and have the potential to repopulate neurons regardless of the underlying etiology of degeneration. While photoreceptor cell replacement is nearing a human clinical trial, RPE transplantation is currently in phase I/II clinical trials. RGC replacement faces numerous logistical challenges, but preclinical research has laid the foundation for functional repair of optic neuropathies to be feasible., (Copyright © 2024 Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Encapsulated cell therapy (ECT) shows significant potential for treating neurodegenerative disorders including Alzheimer's and Parkinson's, which currently lack curative medicines and must be managed symptomatically. This novel technique encapsulates functional cells with a semi-permeable membrane, providing protection while enabling critical nutrients and therapeutic substances to pass through. Traditional ECT procedures, on the other hand, pose difficulties in terms of cell survival and retrieval. We introduce the Microtube Array Membrane (MTAM), a revolutionary technology that solves these constraints, in this comprehensive overview. Microtube Array Membrane has distinct microstructures that improve encapsulated cells' long-term viability by combining the advantages of macro and micron scales. Importantly, the MTAM platform improves biosafety by allowing the entire encapsulated unit to be retrieved in the event of an adverse reaction. Our findings show that MTAM-based ECT has a great potential in a variety of illness situations. For cancer treatment, hybridoma cells secreting anti-CEACAM 6 antibodies inhibit triple-negative breast cancer cell lines for an extended period of time. In animal brain models of Alzheimer's disease, hybridoma cells secreting anti-pTau antibodies successfully reduce pTau buildup, accompanied by improvements in memory performance. In mouse models, MTAM-encapsulated primary cardiac mesenchymal stem cells dramatically improve overall survival and heart function. These findings illustrate the efficacy and adaptability of MTAM-based ECT in addressing major issues such as immunological isolation, cell viability, and patient safety. We provide new possibilities for the treatment of neurodegenerative illnesses and other conditions by combining the potential of ECT with MTAM. Continued research and development in this subject has a lot of promise for developing cell therapy and giving hope to people suffering from chronic diseases., (© 2023 Wiley Periodicals LLC.)

Mitochondria's role as engines and beacons of metabolism and determinants of cellular health is being redefined through their therapeutic application as "Living Drugs" (LDs). Artificial mitochondrial transfer/transplant (AMT/T), encompassing various techniques to modify, enrich, or restore mitochondria in cells and tissues, is revolutionizing acellular therapies and the future of medicine. This article proposes a necessary definition for LDs within the Advanced Therapeutic Medicinal Products (ATMPs) framework. While recognizing different types of LDs as ATMPs, such as mesenchymal stem cells (MSCs) and chimeric antigen receptor T (CAR T) cells, we focus on mitochondria due to their unique attributes that distinguish them from traditional cell therapies. These attributes include their inherent living nature, diverse sources, industry applicability, validation, customizability for therapeutic needs, and their capability to adapt and respond within recipient cells. We trace the journey from initial breakthroughs in AMT/T to the current state-of-the-art applications by emerging innovative companies, highlighting the need for manufacturing standards to navigate the transition of mitochondrial therapies from concept to clinical practice. By providing a comprehensive overview of the scientific, clinical, and commercial landscape of mitochondria as LDs, this article contributes to the essential dialogue among regulatory agencies, academia, and industry to shape their future in medicine., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Andrés Caicedo is the leader of the Dragon BioMed Initiative. Keshav Singh is the scientific founder of Yuva Biosciences and serves as Chief Scientific Advisor., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Human platelet lysate (hPL) is a supplement for cell culture media that can be derived from platelet concentrates. As not-for-profit blood establishments, we endorse the evolution of maximally exploiting the potential of donated blood and its derived components, including platelets. The decision to use platelet concentrates to supply hPL as a cell culture supplement should align with the principles and values that blood establishments hold towards the use of donated blood components in transfusion. As a consequence, questions on ethics, practical standardization of hPL production and logistics as well as on assuring hPL quality and safety need careful consideration. We therefore propose an opinion on some of these matters based on available literature and on discussions within the proceedings of the Working Group on Innovation and New Products of the European Blood Alliance. In addition, we propose collaboration among European blood establishments to streamline efforts of hPL supply to maximize the potential of hPL and its application in the wider field of medicine., (© 2023 International Society of Blood Transfusion.)

The 17 th Workshop on Recent Issues in Bioanalysis (17 th WRIB) took place in Orlando, FL, USA on June 19-23, 2023. Over 1000 professionals representing pharma/biotech companies, CROs, and multiple regulatory agencies convened to actively discuss the most current topics of interest in bioanalysis. The 17 th WRIB included 3 Main Workshops and 7 Specialized Workshops that together spanned 1 week to allow an exhaustive and thorough coverage of all major issues in bioanalysis of biomarkers, immunogenicity, gene therapy, cell therapy and vaccines.Moreover, in-depth workshops on "EU IVDR 2017/746 Implementation and impact for the Global Biomarker Community: How to Comply with this NEW Regulation" and on "US FDA/OSIS Remote Regulatory Assessments (RRAs)" were the special features of the 17 th edition.As in previous years, WRIB continued to gather a wide diversity of international, industry opinion leaders and regulatory authority experts working on both small and large molecules as well as gene, cell therapies and vaccines to facilitate sharing and discussions focused on improving quality, increasing regulatory compliance, and achieving scientific excellence on bioanalytical issues.This 2023 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2023 edition of this comprehensive White Paper has been divided into three parts for editorial reasons.This publication covers the recommendations on Mass Spectrometry Assays, Regulated Bioanalysis/BMV (Part 1A) and Regulatory Inputs (Part 1B). Part 2 (Biomarkers, IVD/CDx, LBA and Cell-Based Assays) and Part 3 (Gene Therapy, Cell therapy, Vaccines and Biotherapeutics Immunogenicity) are published in volume 16 of Bioanalysis, issues 7 and 8 (2024), respectively.

The magnetic microrobots promise benefits in minimally invasive cell-based therapy. However, they generally suffer from an inevitable compromise between their magnetic responsiveness and biomedical functions. Herein, we report a modularized microrobot consisting of magnetic actuation (MA) and cell scaffold (CS) modules. The MA module with strong magnetism and pH-responsive deformability and the CS module with cell loading-release capabilities were fabricated by three-dimensional printing technique. Subsequently, assembly of modules was performed by designing a shaft-hole structure and customizing their relative dimensions, which enabled magnetic navigation in complex environments, while not deteriorating the cellular functionalities. On-demand disassembly at targeted lesion was then realized to facilitate CS module delivery and retrieval of the MA module. Furthermore, the feasibility of proposed system was validated in an in vivo rabbit bile duct. Therefore, this work presents a modular design-based strategy that enables uncompromised fabrication of multifunctional microrobots and stimulates their development for future cell-based therapy.

Progress in the understanding of human diseases has coincided with the advent of precision medicine, whereby the underlying genetic and molecular contributors can be used as diagnostic and therapeutic biomarkers. To address these, drug developers have designed a range of different treatment strategies, including gene therapy, which the American Society of Gene and Cell Therapy defines as the use of genetic material to treat or prevent disease. A number of approaches exist, including the delivery of genetic material in vivo or ex vivo, as well as the use of RNA species to alter gene expression in particular disease states. Through the end of the first quarter of 2023, there were more than 100 different approved gene, cell, and RNA therapies throughout the world, with over 3,700 more in clinical and preclinical development. This review comprehensively captures the landscape for such advanced therapies, including the different genetic technologies used and diseases targeted in clinical trials., Competing Interests: Declaration of interests D.B. is an employee of ASGCT. S.M., D.C., and F.E. are employees of Citeline. L.N.-J. is a former employee of Citeline. ASGCT and Citeline are partners in the development of the underlying data, which is derived from Citeline products and made available in the Gene, Cell & RNA Therapy Landscape quarterly data report., (Copyright © 2023. Published by Elsevier Inc.)

As research associates in clinical experiments, we have an obligation to disclose clinical methodologies and findings in full transparency in ethics. However, inadequate disclosure in results reporting clinical trials registered on ClinicalTrials.gov has been revealed, with approximately half the trial results not being reported in an applicable manner. Our recent study in clinical trials of regenerative medicine for four kinds of neurological diseases revealed that the rate of result reporting to ClinicalTrials.gov is inadequate for gene and cell therapy (CT) trials. In this path, further curiosity emerged to see what the findings would be if the analysis was conducted for trials in all disease areas, and outcomes if gene therapy (GT) and CT were distinguished in terms. In this study, the scope of analysis was further expanded to include all disease areas, and the drug classification from the AdisInsight database was used for modality classification, with biologic drug trials classified as controls, CT, ex vivo GT, and in vivo GT. To begin, among all interventional clinical trials with registration in the ClinicalTrials.gov registry and with a primary completion between 2010 and 2019, we created a total of 5539 datasets corresponding to trials classified as GT and CT, while biologics (BLG) as controls in the AdisInsight drug classification. The status of reported results of these trials was identified by surveying posting status of ClinicalTrials.gov and publication in journals (PubMed), respectively. Based on the obtained dataset, multivariate analysis was performed on the data on the reporting rate of clinical trial results, aggregated by sponsor, phase, status, and modality (CT, ex vivo GT, in vivo GT, and BLG), respectively. The result shows that CT was identified as an independent factor restraining result reporting ratio in both ClinicalTrials.gov and total disclosures, whereas ex vivo GT as boosting result reporting ratio. Since the result reporting rate of CT results was notably poor, we discussed the causes and solutions in this regard.

Background Aims: The selection between centralized and point-of-care (POC) manufacturing supply-chain network design is a crucial consideration in the autologous cell therapy (AuCT) industry, as each approach offers its advantages and disadvantages., Methods: This study uses a simulation-based approach to compare and examine the two strategies using the supply chain for chimeric antigen receptor T-cell therapy manufacturing as an exemplar. When does it make sense to use one manufacturing strategy over another? Currently, major manufacturers in the AuCT industry use centralized supply-chain strategies predominantly in practice. The simulation results explain the reasons for this choice. To enhance the competitiveness of the POC strategy, two operation rules are proposed and tested with the simulation. The study uses key performance indicators such as cost, fulfillment time, service level, and resource utilization to provide generic guidelines based on the findings., Results: The results have revealed that (i) the centralized supply-chain strategy has a significant advantage at current demand levels of a few thousand products per year; (ii) "optimal capacity" exists for the POC strategy that minimizes the cost of goods and (iii) allowing part-time labor and order transshipment can significantly increase the competitiveness of the POC strategy., Conclusions: This study may be useful in helping commercial manufacturers make informed decisions about their manufacturing approach to enhance their competitiveness in the market and to ensure a high level of patient benefit., Competing Interests: Declaration of Competing Interest Bruec L. Levine reports personal fees from Akron, Avectas, Immuneel, Immusoft, In8bio, Ori Biotech, Oxford Biomedica, ThermoFisher Pharma Services, UTC Therapeutics, Vycellix and is a co-founder and equity holder in Tmunity Therapeutics (acquired by Kite Pharma) and Capstan Therapeutics, outside the submitted work. Andrew D. Fesnak reports a relationship with Achieve Clinics that is outside the scope of the submitted work. There is no conflict of interest for other co-authors., (Published by Elsevier Inc.)

To accelerate the development of Advanced Therapy Medicinal Products (ATMPs) for patients suffering from life-threatening cancer with limited therapeutic options, regulatory approaches need to be constantly reviewed, evaluated and adjusted, as necessary. This includes utilizing science and risk-based approaches to mitigate and balance potential risks associated with early clinical research and a more flexible manufacturing paradigm. In this paper, T2EVOLVE an Innovative Medicine Initiative (IMI) consortium explores opportunities to expedite the development of CAR and TCR engineered T cell therapies in the EU by leveraging tools within the existing EU regulatory framework to facilitate an iterative and adaptive learning approach across different product versions with similar design elements or based on the same platform technology. As understanding of the linkage between product quality attributes, manufacturing processes, clinical efficacy and safety evolves through development and post licensure, opportunities are emerging to streamline regulatory submissions, optimize clinical studies and extrapolate data across product versions reducing the need to perform duplicative studies. It is worth noting that this paper is focusing on CAR- and TCR-engineered T cell therapies but the concepts may be applied more broadly to engineered cell therapy products (e.g., CAR NK cell therapy products)., Competing Interests: Author DA was employed by Astellas. Author IS was employed by Bayer Vital GmbH. Author MM was employed by Immatics Biotechnologies GmbH. Author TT was employed by Century Therapeutics. Author BS was employed by Miltenyi Biotec B.V. & Co. KG. Author HN was employed by Institut de Recherches Internationales Servier, Gif-sur-Yvette, France. Author JA-C was employed by Bristol Myers Squibb. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Ammar, Schapitz, Luu, Hudecek, Meyer, Taps, Schröder, Ivics, Sanges, Franz, Koehl, Negre, Johanna and Awigena-Cook.)

Cell therapies are powerful technologies in which human cells are reprogrammed for therapeutic applications such as killing cancer cells or replacing defective cells. The technologies underlying cell therapies are increasing in effectiveness and complexity, making rational engineering of cell therapies more difficult. Creating the next generation of cell therapies will require improved experimental approaches and predictive models. Artificial intelligence (AI) and machine learning (ML) methods have revolutionized several fields in biology including genome annotation, protein structure prediction, and enzyme design. In this review, we discuss the potential of combining experimental library screens and AI to build predictive models for the development of modular cell therapy technologies. Advances in DNA synthesis and high-throughput screening techniques enable the construction and screening of libraries of modular cell therapy constructs. AI and ML models trained on this screening data can accelerate the development of cell therapies by generating predictive models, design rules, and improved designs., (© 2023 The Authors. Immunological Reviews published by John Wiley & Sons Ltd.)

Established in October 2021, the Cell and Gene Therapy (CGT) Consortium convened with the goal to bring together key CGT stakeholders - manufacturers, treatment centers, regulators, services providers, and ecosystem partners - to gain alignment on process definitions, terminology, challenges, and opportunities for process and data standardization from CGT program start-up and patient enrollment to therapy administration. With the recognition that the number of investigational and commercial cell and gene therapies will scale over the next several years, so will the number of manufacturer-specific processes and solutions (e.g., portals). As a result, this will increase the burden on academic medical centers, community hospitals, standalone clinics, collection facilities, and labs. Healthcare professionals (HCPs) and other industry stakeholders agree that a multiplicity of manufacturer portals with varying data requirements and nomenclature is unsustainable and adds unnecessary complexity - risk, cost, and time - in coordinating patient treatment. Following extensive discussions and multiple stakeholder meetings and interviews, we have developed a manuscript reporting on our activities and conclusions. Through the course of the manuscript, we delineate a framework for defining common principles, terminology, and user experiences for enrolling patients, ordering therapies, and collecting starting material in a standardized way. We also provide substantial background information on opportunities to streamline communications between manufacturing and healthcare organizations from the HCP end-user's perspective., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Cell therapy uses living cells as a drug to treat diseases. To develop a cell therapy drug product (DP), cryopreservation plays a central role in extending the shelf life of these living medicines by pausing their biological activities, especially preventing degradation, at a temperature as low as liquid nitrogen. This helps overcome the temporal and geographical gaps between centralized manufacturing and clinical administration, as well as allowing sufficient time for full release testing and flexibility in scheduling patients for administration. Cryopreservation determines or influences several key manufacturing, logistical, or clinical in-use processes, including formulation, filling, controlled rate freezing, cryogenic storage and transportation, thawing, and dose preparation. This article overviews the key technical aspects of cell therapy DP development and elucidates fundamental principles of cryobiology that should be considered when we design and optimize the relevant processes. This article also discusses the challenges that motivate continued innovation for cell therapy drug product development., Competing Interests: Declaration of Competing Interest The author declares that he has no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Owing to Karl Landsteiner's discovery of blood groups, blood transfusions became safe cellular therapies in the early 1900s. Since then, cellular therapy made great advances from transfusions with unmodified cells to today's commercially available chimeric antigen receptor (CAR) T cells requiring complex manufacturing. Modern cellular therapy products can be improved using basic knowledge of cell biology and molecular genetics. Emerging genome engineering tools are becoming ever more versatile and precise and thus catalyze rapid progress towards programmable therapeutic cells that compute input and respond with defined output. Despite a large body of literature describing important functions of non-coding RNAs including microRNAs (miRNAs), the vast majority of cell engineering efforts focuses on proteins. However, miRNAs form an important layer of posttranscriptional regulation of gene expression. Here, we highlight examples of how miRNAs can successfully be incorporated into engineered cellular therapies., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Lukas T. Jeker reports financial support was provided by European Research Council (ERC) grant agreement No. 818806. Lukas T. Jeker reports a relationship with Cimeio Therapeutics AG that includes: board membership, consulting or advisory, equity or stocks, and funding grants. Lukas T. Jeker has patent pending to University of Basel. LTJ is a co-founder and board member of Cimeio Therapeutics AG (Cimeio) and owns equity in Cimeio. LTJ and MD are inventors on a patent application related to using miRNAs for cellular therapies., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Biocapacitance measurement has emerged as a widely used technique for monitoring bioprocesses that involve living cells. Over time, hardware and software developments have enabled this method to move from food towards biopharma industries for improved characterisation, monitoring and control of the bioprocess, even in strictly regulated production environments. In alignment with the general trends in biopharma towards new modalities such as virus-based and cell-based therapies, biocapacitance measurement is entering this area and provides new opportunities for process development and control. Based on the recent progress, the authors strongly believe that even though biocapacitance measurement is a mature, established technology for online biomass monitoring, the nearest future will bring its new and exciting developments and applications that will enhance bioprocess understanding and bring new solutions for enhanced process understanding, monitoring and control., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The field of transplantation has witnessed the emergence of Advanced Therapy Medicinal Products (ATMPs) as highly promising solutions to address the challenges associated with organ and tissue transplantation. ATMPs encompass gene therapy, cell therapy, and tissue-engineered products, hold immense potential for breakthroughs in overcoming the obstacles of rejection and the limited availability of donor organs. However, the development and academic research access to ATMPs face significant bottlenecks that hinder progress. This opinion paper emphasizes the importance of addressing bottlenecks in the development and academic research access to ATMPs by implementing several key strategies. These include the establishment of streamlined regulatory processes, securing increased funding for ATMP research, fostering collaborations and partnerships, setting up centralized ATMP facilities, and actively engaging with patient groups. Advocacy at the policy level is essential to provide support for the development and accessibility of ATMPs, thereby driving advancements in transplantation and enhancing patient outcomes. By adopting these strategies, the field of transplantation can pave the way for the introduction of innovative and efficacious ATMP therapies, while simultaneously fostering a nurturing environment for academic research., Competing Interests: Authors MM, KP-K, and PK were employed by Kugelmeiers Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Piemonti, Scholz, de Jongh, Kerr-Conte, van Apeldoorn, Shaw, Engelse, Bunnik, Mühlemann, Pal-Kutas, Scott, Magalon, Kugelmeier and Berishvili.)

Chronic stimulation can cause T cell dysfunction and limit the efficacy of cellular immunotherapies. Improved methods are required to compare large numbers of synthetic knockin (KI) sequences to reprogram cell functions. Here, we developed modular pooled KI screening (ModPoKI), an adaptable platform for modular construction of DNA KI libraries using barcoded multicistronic adaptors. We built two ModPoKI libraries of 100 transcription factors (TFs) and 129 natural and synthetic surface receptors (SRs). Over 30 ModPoKI screens across human TCR- and CAR-T cells in diverse conditions identified a transcription factor AP4 (TFAP4) construct that enhanced fitness of chronically stimulated CAR-T cells and anti-cancer function in vitro and in vivo. ModPoKI's modularity allowed us to generate an ∼10,000-member library of TF combinations. Non-viral KI of a combined BATF-TFAP4 polycistronic construct enhanced fitness. Overexpressed BATF and TFAP4 co-occupy and regulate key gene targets to reprogram T cell function. ModPoKI facilitates the discovery of complex gene constructs to program cellular functions., Competing Interests: Declaration of interests F.B. received research awards (Gilead and Kite and Bristol Myers Squibb Foundation Immunonkologie). E.S. was an advisor for Arsenal Biosciences. J.E. is a compensated co-founder at Mnemo Therapeutics and compensated scientific advisor to Cytovia Therapeutics. J.E. owns stocks in Mnemo Therapeutics and Cytovia Therapeutics. J.E. has received a consulting fee from Casdin Capital. The Eyquem lab has received research support from Cytovia Therapeutics and Takeda. T.L.R. is a compensated co-founder, member of the scientific advisory board, and previously worked as the CSO of Arsenal Biosciences. A.T.S. is a founder of Immunai and Cartography Biosciences and receives research funding from Allogene Therapeutics and Merck Research Laboratories. C.T.M. is a compensated Bio+Health Venture Fellow at Andreessen Horowitz. C.J.Y. is founder for and holds equity in DropPrint Genomics (now ImmunAI) and Survey Genomics, a scientific advisory board member for and holds equity in Related Sciences and ImmunAI, a consultant for and holds equity in Maze Therapeutics, and a consultant for TReX Bio, HiBio, ImYoo, and Santa Ana. C.J.Y. has received research support from Chan Zuckerberg Initiative, Chan Zuckerberg Biohub, Genentech, BioLegend, ScaleBio, and Illumina. A.M. is a co-founder of Arsenal Biosciences, Spotlight Therapeutics, and Survey Genomics, serves on the boards of directors at Spotlight Therapeutics and Survey Genomics, is a board observer (and former member of the board of directors) at Arsenal Biosciences, is a member of the scientific advisory boards of Arsenal Biosciences, Spotlight Therapeutics, Survey Genomics, NewLimit, Amgen, Tenaya, and Lightcast, owns stock in Arsenal Biosciences, Spotlight Therapeutics, NewLimit, Survey Genomics, PACT Pharma, Tenaya, and Lightcast and has received fees from Arsenal Biosciences, Spotlight Therapeutics, Survey Genomics, NewLimit, 23andMe, PACT Pharma, Juno Therapeutics, Tenaya, Lightcast, GLG, Gilead, Trizell, Vertex, Merck, Amgen, Genentech, AlphaSights, Rupert Case Management, Bernstein, and ALDA. A.M. is an investor in and informal advisor to Offline Ventures and a client of EPIQ. The Marson laboratory received research support from Juno Therapeutics, Epinomics, Sanofi, GlaxoSmithKline, Gilead, and Anthem. T.L.R., F.B., A.M., R.A., Y.Y.C., C.T.M., and E.S. are listed on patent applications related to this work., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The development of viral vectors and recombinant DNA technology since the 1960s has enabled gene therapy to become a real therapeutic option for several inherited and acquired diseases. After several ups and downs in the gene therapy field, we are currently living a new era in the history of medicine in which several ex vivo and in vivo gene therapies have reached maturity. This is testified by the recent marketing authorization of several gene therapy medicinal products. In addition, many others are currently under evaluation after exhaustive investigation in human clinical trials. In this review, we summarize some of the most significant milestones in the development of gene therapy medicinal products that have already facilitated the treatment of a significant number of rare diseases. Despite progresses in the gene therapy field, the transfer of these innovative therapies to clinical practice is also finding important restrictions. Advances and also challenges in the progress of gene therapy for rare diseases are discussed in this opening review of a Human Gene Therapy issue dedicated to the 30th annual Congress of the European Society for Gene and Cell Therapy.

The field of regenerative medicine, including cellular immunotherapies, is on a remarkable growth trajectory. Dozens of cell-, tissue- and gene-based products have received marketing authorization worldwide while hundreds-to-thousands are either in preclinical development or under clinical investigation in phased clinical trials. However, the promise of regenerative therapies has also given rise to a global industry of direct-to-consumer offerings of prematurely commercialized cell and cell-based products with unknown safety and efficacy profiles. Since its inception, the International Society for Cell & Gene Therapy Committee on the Ethics of Cell and Gene Therapy has opposed the premature commercialization of unproven cell- and gene-based interventions and supported the development of evidence-based advanced therapy products. In the present Guide, targeted at International Society for Cell & Gene Therapy members, we analyze this industry, focusing in particular on distinctive features of unproven cell and cell-based products and the use of tokens of scientific legitimacy as persuasive marketing devices. We also provide an overview of reporting mechanisms for patients who believe they have been harmed by administration of unapproved and unproven products and suggest practical strategies to address the direct-to-consumer marketing of such products. Development of this Guide epitomizes our continued support for the ethical and rigorous development of cell and cell-based products with patient safety and therapeutic benefit as guiding principles., Competing Interests: Declaration of Competing Interest Hamid R. Bidkhori is the chancellor of the Biomedical Research Ethics Committee of Academic Center for Education, Culture and Research (ACECR) - Mashhad. He is a member of the International Society for Cell & Gene Therapy (ISCT), the International Society for Extracellular Vesicles (ISEV) and the ISCT Committee on the Ethics of Cell and Gene Therapy. Rachele Ciccocioppo is a member of the Advisory Board of Takeda (Italy) for the use of mesenchymal stromal cells in fistulizing Crohn's disease. Natividad Cuende is a member of the Governing Council of the Agencia Española de Medicamentos y Productos Sanitarios (Spanish Medicine and Medical Device Agency). She is member of the ISCT Committee on the Ethics of Cell and Gene Therapy and the ISCT Legal and Regulatory Affairs Committee–Europe. She is also member of the Spanish Guarantee Committee for Donation and Use of Human Cells and Tissues of the Spanish Ministry of Science and Innovation. She is not paid for these roles. Bambi Grilley is affiliated with QBRegulatory Consulting LLC that has provided regulatory affairs and project management support to AlloVir, Marker Therapeutics, LOKON Pharma, Tessa Therapeutics and March Biosciences. She is a member of ISCT and its Ethics of Cell and Gene Therapy (ECGT) Committee and is the incoming Chief Regulatory Officer of ISCT. She is not paid for her roles in ISCT. Conflict of interest is managed in accordance with Baylor College of Medicine policy and oversight. Laertis Ikonomou has written an expert report in a class action lawsuit filed against a business selling unproven “stem cell”-based interventions, and wrote the report on a pro bono basis. He is a member of the ISCT and the International Society for Stem Cell Research (ISSCR) and the chair of the ISCT Committee on the Ethics of Cell and Gene Therapy. He is not paid for these roles. Conflict of interest is managed in accordance with University at Buffalo policy and oversight. Aaron D. Levine is a member of ISCT and its ECGT committee. He is not paid for these roles. Levine's research program is supported by the National Science Foundation (NSF) (Grant No. EEC-1648035). Bruce Levine has received compensation for serving on the scientific advisory boards of Akron Bio, Avectas, Immuneel, Immusoft, In8bio, Ori Biotech, Oxford Biomedica, UTC Therapeutics and Vycellix. He has received compensation for consulting for GSK. He has received compensation and equity from Capstan Therapeutics as a co-founder and member of the Scientific Advisory Board. As co-founder of Tmunity Therapeutics, he received equity. Conflict of interest is managed in accordance with University of Pennsylvania policy and oversight. Megan Munsie is a member of the International Society for Stem Cell Research and its Ethics Committee and Public Policy Committee. She is also the President of the Australasian Society for Stem Cell Research. Munsie's research program is supported by the Novo Nordisk Foundation Center for Stem Cell Medicine (NNF21CC0073729). John E. J. Rasko: employment: Royal Prince Alfred Hospital; consultancy and honoraria: Rarecyte, Gilead, Roche, Novartis, Bluebird Bio, Spark therapeutics, Cynata, Pfizer; equity: Genea; shareholder: Rarecyte, Woke; DSMB: Diamond Fanconi anemia trial; research funding: National Health and Medical Research Council (NHMRC), New South Wales Cancer Council, Cancer Institute NSW (CINSW), Therapeutic Innovation Australia, Philanthropic foundations; Chair, Gene Technology Technical Advisory Committee, Office of The Gene Technology Regulator, Australian Government. Leigh Turner served as a compensated expert witness for the US government in a criminal case and as a pro bono expert witness in a class action lawsuit. He is a member of ISCT and its ECGT committee. He is also a member of the International Society for Stem Cell Research and its Ethics Committee and Membership Committee. Turner's research program is supported by the Pew Charitable Trusts. Daniel J. Weiss served as a compensated expert witness for the US government in a criminal case and as a pro bono expert witness in a class action lawsuit. He is a member of ISCT and its ECGT committee and is former Chief Scientific Officer of the ISCT. He is not paid for his roles in the ISCT. Dr. Weiss has received compensation for consulting with Mesoblast Inc., NextCell Inc., United Therapeutics. Inc. and Vertex Inc. Conflict of interest is managed in accordance with University of Vermont policy and oversight. Patricia J. Zettler reports serving as a consultant to the US Food & Drug Administration. All the other authors have no commercial, proprietary, or financial interest in the products or companies described in this article., (Copyright © 2023 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Cell and gene therapy (CGT) describes a broad category of medicinal products with potential applications to prevent and treat human disease in multiple therapeutic areas. These therapies leverage the use of modified nucleic acids, altered cells or tissue, or both. The modality, mechanism, route of administration, and therapeutic indication for a CGT product will influence the challenges and opportunities for early clinical development, some of which may be highly specific to the product under consideration. Both the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) encourage early interaction between sponsor and health authority to align on key elements of the CGT development program., (© 2023 The Authors. Clinical Pharmacology & Therapeutics © 2023 American Society for Clinical Pharmacology and Therapeutics.)

The increasing number of life-threatening infections caused by persister bacteria is associated with various issues, including antimicrobial resistance and biofilm formation. Infections due to persister cells are often difficult to suppress without the use of last-resort antibiotics. Throughout the world, bacterial persistence and resistance create an unmet clinical demand for the exploration of newly introduced therapeutic approaches. Mesenchymal stem / stromal cells (MSCs) have an antimicrobial activity to protect against bacterial infections, including those caused by bacterial persisters. MSCs have substantial potential to secrete antimicrobial peptides (AMPs), including cathelicidin, beta-defensins, lipocalin-2, hepcidin, indoleamine 2,3-dioxygenase (IDO), cysteine proteases, and inducible nitric oxide synthases (iNOS). MSCs possess the potential to contribute to innate immunity by regulating the immune response. Recently, MSCs and their secreted components have been reported to improve antimicrobial activity. Bactericidal activity by MSCs and their secretomes has been shown to be mediated in part by the secretion of AMPs. Even though they were discovered more than 80 years ago, therapeutic options for persisters are restricted, and there is an urgent need for alternative treatment regimens. Hence, this review intends to critically assess the current literature on the effects of MSCs and their secretomes on persister bacteria. MSCs and their secretome-based therapies could be preferred as an up-and-coming approach to reinforce the antimicrobial efficiency in persister infections., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Developing cellular therapies is not straightforward. This Perspective summarizes the experience of a group of academic stem cell investigators working in different clinical areas and aims to share insight into what we wished we knew before starting. These include (1) choosing the stem cell line and assessing the genome of both the starting and final product, (2) familiarity with GMP manufacturing, reagent validation, and supply chain management, (3) product delivery issues and the additional regulatory challenges, (4) the relationship between clinical trial design and preclinical studies, and (5) the market approval requirements, pathways, and partnerships needed., Competing Interests: Conflict of interests C.J. is a co-founder of Aspera Biomedicines and Impact Biomedicines and receives royalties from Forty Seven Inc. C.M. is a senior vice president and equity holder in Sana Biotechnology. G.P. is a consultant for J-TEC, Gamagori, Japan, a member of the board of directors, and R&D director of Holostem Terapie Avanzate, Modena, Italy. J.S. is the founder and CEO of iPS Bio, Inc. The remaining authors report no conflicts., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)