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Cytokine release syndrome (CRS) is a frequently observed side effect of chimeric antigen receptor (CAR)-T cell therapy. Here, we report self-regulating T cells that reduce CRS severity by secreting inhibitors of cytokines associated with CRS. With a humanized NSG-SGM3 mouse model, we show reduced CRS-related toxicity in mice treated with CAR-T cells secreting tocilizumab-derived single-chain variable fragment (Toci), yielding a safety profile superior to that of single-dose systemic tocilizumab administration. Unexpectedly, Toci-secreting CD19 CAR-T cells exhibit superior in vivo antitumor efficacy compared with conventional CD19 CAR-T cells. scRNA-seq analysis of immune cells recovered from tumor-bearing humanized mice revealed treatment with Toci-secreting CD19 CAR-T cells enriches for cytotoxic T cells while retaining memory T-cell phenotype, suggesting Toci secretion not only reduces toxicity but also significantly alters the overall T-cell composition. This approach of engineering T cells to self-regulate inflammatory cytokine production is a clinically compatible strategy with the potential to simultaneously enhance safety and efficacy of CAR-T cell therapy for cancer.

The current paradigm of medicine is mostly designed to block or prevent pathological events. Once the disease-led tissue damage occurs, the limited endogenous regeneration may lead to depletion or loss of function for cells in the tissues. Cell therapy is rapidly evolving and influencing the field of medicine, where in some instances attempts to address cell loss in the body. Due to their biological function, engineerability, and their responsiveness to stimuli, cells are ideal candidates for therapeutic applications in many cases. Such promise is yet to be fully obtained as delivery of cells that functionally integrate with the desired tissues upon transplantation is still a topic of scientific research and development. Main known impediments for cell therapy include mechanical insults, cell viability, host's immune response, and lack of required nutrients for the transplanted cells. These challenges could be divided into three different steps: 1) Prior to, 2) during the and 3) after the transplantation procedure. In this review, we attempt to briefly summarize published approaches employing biomaterials to mitigate the above technical challenges. Biomaterials are offering an engineerable platform that could be tuned for different classes of cell transplantation to potentially enhance and lengthen the pharmacodynamics of cell therapies.

Peripheral artery disease is an atherosclerotic disease associated with limb ischemia that necessitates limb amputation in severe cases. Cell therapies comprised of adult mononuclear or stromal cells have been clinically tested and show moderate benefits. Bioengineering strategies can be applied to modify cell behavior and function in a controllable fashion. Using mechanically tunable or spatially controllable biomaterials, we highlight examples in which biomaterials can increase the survival and function of the transplanted cells to improve their revascularization efficacy in preclinical models. Biomaterials can be used in conjunction with soluble factors or genetic approaches to further modulate the behavior of transplanted cells and the locally implanted tissue environment in vivo. We critically assess the advances in bioengineering strategies such as 3-dimensional bioprinting and immunomodulatory biomaterials that can be applied to the treatment of peripheral artery disease and then discuss the current challenges and future directions in the implementation of bioengineering strategies.

Adoptive cell therapy with autologous, ex vivo-expanded, tumor-infiltrating lymphocytes (TILs) is being investigated for treatment of solid tumors and has shown robust responses in clinical trials. Based on the encouraging efficacy, tolerable safety profile, and advancements in a central manufacturing process, lifileucel is now the first US Food and Drug Administration (FDA)-approved TIL cell therapy product. To this end, treatment management and delivery practice guidance is needed to ensure successful integration of this modality into clinical care. This review includes clinical and toxicity management guidelines pertaining to the TIL cell therapy regimen prepared by the TIL Working Group, composed of internationally recognized hematologists and oncologists with expertize in TIL cell therapy, and relates to patient care and operational aspects. Expert consensus recommendations for patient management, including patient eligibility, screening tests, and clinical and toxicity management with TIL cell therapy, including tumor tissue procurement surgery, non-myeloablative lymphodepletion, TIL infusion, and IL-2 administration, are discussed in the context of potential standard of care TIL use. These recommendations provide practical guidelines for optimal clinical management during administration of the TIL cell therapy regimen, and recognition of subsequent management of toxicities. These guidelines are focused on multidisciplinary teams of physicians, nurses, and stakeholders involved in the care of these patients.

A major limitation to developing chimeric antigen receptor (CAR)-T cell therapies for solid tumors is identifying surface proteins highly expressed in tumors but not in normal tissues. Here, we identify Tyrosinase Related Protein 1 (TYRP1) as a CAR-T cell therapy target to treat patients with cutaneous and rare melanoma subtypes unresponsive to immune checkpoint blockade. TYRP1 is primarily located intracellularly in the melanosomes, with a small fraction being trafficked to the cell surface via vesicular transport. We develop a highly sensitive CAR-T cell therapy that detects surface TYRP1 in tumor cells with high TYRP1 overexpression and presents antitumor activity in vitro and in vivo in murine and patient-derived cutaneous, acral and uveal melanoma models. Furthermore, no systemic or off-tumor severe toxicities are observed in an immunocompetent murine model. The efficacy and safety profile of the TYRP1 CAR-T cell therapy supports the ongoing preparation of a phase I clinical trial.

Purpose The recent coronavirus disease 2019 (COVID-19) pandemic and vaccine mandates have increased the number of patient questions related to how fetal cell lines are used during drug development and final manufacturing. This article describes our literature search and review of COVID-19 vaccines, transplant medications, and biologics whose development included use of fetal cell lines. Summary A detailed literature search was conducted to identify the common fetal cell lines used in COVID-19 vaccine development; the two most prevalent fetal cell lines identified were HEK-293 and PER.C6. Subsequent literatures searches were conducted to identify transplant medications and biologics whose development included use of the HEK-293 or PER.C6 cell lines. For the COVID-19 vaccines, only the viral vector vaccine by Janssen was found to contain proteins produced by PER.C6 in the final preparation administered to patients, and Novavax is the only vaccine for which fetal cell lines were not directly involved in any portion of drug development. For transplant medications, many medications were studied in fetal cell lines in postmarketing studies after Food and Drug Administration approval; however, none of these medications contained fetal cells or would expose a patient to a fetal cell line. Many new biologics and cellular therapies for genetic diseases and malignancies have been directly developed from HEK-293 fetal cells or contain proteins produced directly from fetal cell lines. Conclusion There were very few drugs reviewed that were found to contain HEK-293 or PER.C6 fetal cells or proteins derived directly from fetal cell lines; however, use of fetal cell lines in biologics and gene therapies will continue to increase. Healthcare providers should be mindful of patients' beliefs while also correcting common misconceptions about how these fetal cell lines are used throughout drug development and manufacturing. [ABSTRACT FROM AUTHOR]

Mucopolysaccharidosis type I (MPS I) is a metabolic disorder characterized by a deficiency in α-l-iduronidase (IDUA), leading to impaired glycosaminoglycan degradation. Current approved treatments seek to restore IDUA levels via enzyme replacement therapy (ERT) and/or hematopoietic stem cell transplantation (HSCT). The effectiveness of these treatment strategies in preventing neurodegeneration is limited due to the inability of ERT to penetrate the blood-brain barrier (BBB) and HSCT’s limited CNS reconstitution of IDUA levels. We reprogrammed human cord blood cells into induced pluripotent stem cells (iPSCs), differentiated them into human induced neural stem cells (hiNSCs), and sorted them using fluorescence-activated cell sorting (FACS). Our in vitro studies showed that these hiNSCs can migrate and cross-correct IDUA deficiency. Purified hiNSCs were then transplanted into neonatal immunodeficient MPS I mice (Idua−/−). Analysis of brain tissue obtained 8 months after transplantation showed partially restored IDUA activity, with distribution and differentiation of engrafted hiNSCs throughout the brain into glial cell types. The presence of engrafted hiNSCs was associated with decreased levels of biomarkers commonly elevated in the Idua−/− mouse brain, such as β-hexosaminidase, CD68, and LAMP1, suggesting physiological efficacy. These results highlight the potential of hiNSCs for use as a patient-specific cellular therapy for MPS I.

Nanorobots, also known as nanobots, are promising medical structures with significant potential for revolutionizing medical treatments and preventing their onset. Nanorobotics shows promise for diagnosing, treating, and regenerating age-related diseases. These tiny machines can repair cellular damage, deliver drugs, stimulate tissue regeneration, and monitor treatments. However, their application in controlling cellular aging is in its early stages, requiring more research to fully understand their potential and address safety concerns. Despite this, the benefits of nanorobots in age-related disease management justify further investigation. This narrative review article provides an overview of recent developments in nanorobotics, specifically focusing on its medical applications. PubMed and Google Scholar were utilized to conduct a comprehensive search using relevant keywords including "nanorobots", "cellular aging", "drug delivery systems", "cellular repair", "therapeutics", and "diagnosis". Only articles published between 2005-2023 were selected to support the arguments with up-to-date evidence. The extracted information includes nanorobot design, fabrication methods, applications, and key findings. A quality assessment was performed, and the data were categorized thematically to identify patterns and trends. The article concludes with an examination of the current state and future prospects of nanorobotics in different fields. Our research showed that nanorobots have significant potential in the diagnosis, treatment, and regenerative medicine of age-related diseases. They can detect and repair cellular damage caused by aging, targeting DNA damage and cellular protein misfolding. Nanorobots can also deliver drugs directly to affected areas, reducing side effects. Furthermore, they stimulate tissue regeneration and the growth of new blood vessels by delivering growth factors. Nanorobots can also monitor treatment effectiveness by measuring drug concentration in tumor cells. However, there are concerns about their safety in long-term use that require further research. Overall, nanorobots present an innovative approach to addressing cellular changes in aging, but more research is needed to understand their full potential and address safety concerns. The use of nanorobots in treating cellular aging has opened new possibilities in diagnosing and treating age-related diseases and it is a rapidly evolving field with the potential to revolutionize age-related disease treatment and improve the quality of life globally.

Nanorobots, also known as nanobots, are promising medical structures with significant potential for revolutionizing medical treatments and preventing their onset. Nanorobotics shows promise for diagnosing, treating, and regenerating age-related diseases. These tiny machines can repair cellular damage, deliver drugs, stimulate tissue regeneration, and monitor treatments. However, their application in controlling cellular aging is in its early stages, requiring more research to fully understand their potential and address safety concerns. Despite this, the benefits of nanorobots in age-related disease management justify further investigation. This narrative review article provides an overview of recent developments in nanorobotics, specifically focusing on its medical applications. PubMed and Google Scholar were utilized to conduct a comprehensive search using relevant keywords including "nanorobots", "cellular aging", "drug delivery systems", "cellular repair", "therapeutics", and "diagnosis". Only articles published between 2005-2023 were selected to support the arguments with up-to-date evidence. The extracted information includes nanorobot design, fabrication methods, applications, and key findings. A quality assessment was performed, and the data were categorized thematically to identify patterns and trends. The article concludes with an examination of the current state and future prospects of nanorobotics in different fields. Our research showed that nanorobots have significant potential in the diagnosis, treatment, and regenerative medicine of age-related diseases. They can detect and repair cellular damage caused by aging, targeting DNA damage and cellular protein misfolding. Nanorobots can also deliver drugs directly to affected areas, reducing side effects. Furthermore, they stimulate tissue regeneration and the growth of new blood vessels by delivering growth factors. Nanorobots can also monitor treatment effectiveness by measuring drug concentration in tumor cells. However, there are concerns about their safety in long-term use that require further research. Overall, nanorobots present an innovative approach to addressing cellular changes in aging, but more research is needed to understand their full potential and address safety concerns. The use of nanorobots in treating cellular aging has opened new possibilities in diagnosing and treating age-related diseases and it is a rapidly evolving field with the potential to revolutionize age-related disease treatment and improve the quality of life globally. [ABSTRACT FROM AUTHOR]

Objective: Platelet‐rich plasma (PRP) is recognized as a safe and effective therapy for regenerative skin healing and rejuvenation, utilizing autologous blood enriched with various growth factors. This review aims to assess the efficacy of PRP treatments for skin rejuvenation. Methods: Keywords such as "platelet‐rich plasma," "rejuvenation," "skin aging," and "wrinkles" were queried on Ovid, PubMed, and MEDLINE to identify pertinent studies on PRP treatment for skin rejuvenation. Results: Analysis revealed that PRP treatment led to significant enhancements in multiple facial parameters after one to three sessions. Improvements were noted in skin pore size, texture, wrinkle reduction, pigmented spots, collagen density, hyaluronic acid levels, and protection against ultraviolet damage. Combining PRP with hyaluronic acid demonstrated a synergistic effect, particularly enhancing skin elasticity in patients with lower body mass index and firmness in individuals aged 50s and 60s. Incorporating both physical and biometric data for assessment proved superior to relying solely on physical observations for evaluating subtle skin quality and structural changes. Conclusion: This study underscores the efficacy of PRP monotherapy for skin rejuvenation and emphasizes the necessity of standardizing PRP preparation protocols in future investigations. Heightened awareness and advancements in technology have contributed to the emergence of higher‐quality, less biased studies supporting PRP as a reliable and safe therapeutic option for skin rejuvenation. [ABSTRACT FROM AUTHOR]

Exosomes are nano-sized membrane-bound extracellular vesicles containing various biological molecules, such as nucleic acids, proteins, and lipids, which can be used to modulate physiological processes. The exosomal molecules secreted by cells can be extensively used as tools for diagnosis and therapy. Exosomes carry specific molecules released by the cells they originate from, which can be transferred to surrounding cells or tissues by the exosome. For these reasons, exosomes can be exploited as biomarkers for diagnosis, carriers for drug delivery, as well as therapeutics. In stem cell technology, exosomes have been an attractive option because they can be used as safer therapeutic agents for stem cell-based cell-free therapy. Recently, studies have demonstrated the safety and efficacy of mesenchymal stem cell-derived exosomes in alleviating symptoms associated with coronavirus disease 2019 as they have anti-inflammatory and immunomodulatory potential. Performing multiple studies on exosomes would provide innovative next-generation options for clinical diagnostics and therapy. This review summarizes the use of exosomes focusing on their diverse roles. In addition, the potential of exosomes is illustrated with a focus on how exosomes can be exploited as powerful tools in the days to come.

Abstract Background Chimeric antigen receptor CAR-T cell therapies have ushered in a new era of treatment for specific blood cancers, offering unparalleled efficacy in cases of treatment resistance or relapse. However, the emergence of cytokine release syndrome (CRS) as a side effect poses a challenge to the widespread application of CAR-T cell therapies. Melatonin, a natural hormone produced by the pineal gland known for its antioxidant and anti-inflammatory properties, has been explored for its potential immunomodulatory effects. Despite this, its specific role in mitigating CAR-T cell-induced CRS remains poorly understood. Methods In this study, our aim was to investigate the potential of melatonin as an immunomodulatory agent in the context of CD19-targeting CAR-T cell therapy and its impact on associated side effects. Using a mouse model, we evaluated the effects of melatonin on CAR-T cell-induced CRS and overall survival. Additionally, we assessed whether melatonin administration had any detrimental effects on the antitumor efficacy and persistence of CD19 CAR-T cells. Results Our findings demonstrate that melatonin effectively mitigated the severity of CAR-T cell-induced CRS in the mouse model, leading to improved overall survival outcomes. Remarkably, melatonin administration did not compromise the antitumor effectiveness or persistence of CD19 CAR-T cells, indicating its compatibility with therapeutic goals. These results suggest melatonin's potential as an immunomodulatory compound to alleviate CRS without compromising the therapeutic benefits of CAR-T cell therapy. Conclusion The study's outcomes shed light on melatonin's promise as a valuable addition to the existing treatment protocols for CAR-T cell therapies. By attenuating CAR-T cell-induced CRS while preserving the therapeutic impact of CAR-T cells, melatonin offers a potential strategy for optimizing and refining the safety and efficacy profile of CAR-T cell therapy. This research contributes to the evolving understanding of how to harness immunomodulatory agents to enhance the clinical application of innovative cancer treatments.

Recapitulation of the natural healing process is receiving increasing recognition as a strategy to induce robust tissue regeneration. Endochondral ossification has been recognized as an essential reparative approach in natural jawbone defect healing. However, such an approach has been overlooked in the recent development of cell-based therapeutics for jawbone repair. Therefore, this study aimed to explore a bioinspired stem cell–based strategy for jawbone repair by mimicking the mesenchymal condensation of progenitor cells during the early endochondral ossification process. For this purpose, passage 3 of jawbone periosteum-derived cells (jb-PDCs) was cultured in our previously reported nonadherent microwells (200 µm in diameter, 148 µm in depth, and 100 µm space in between) and self-assembled into spheroids with a diameter of 96.4 ± 5.8 µm after 48 h. Compared to monolayer culture, the jb-PDC spheroids showed a significant reduction of stemness marker expression evidenced by flow cytometry. Furthermore, a significant upregulation of chondrogenic transcription factor SOX9 in both gene and protein levels was observed in the jb-PDC spheroids after 48 h of chondrogenic induction. RNA sequencing and Western blotting analysis further suggested that the enhanced SOX9-mediated chondrogenic differentiation in jb-PDC spheroids was attributed to the activation of the p38 MAPK pathway. Impressively, inhibition of p38 kinase activity significantly attenuated chondrogenic differentiation jb-PDC spheroids, evidenced by a significant decline of SOX9 in both gene and protein levels. Strikingly, the jb-PDC spheroids implanted in 6- to 8-wk-old male C57BL/6 mice with critical-size jawbone defects (1.8 mm in diameter) showed an evident contribution to cartilaginous callus formation after 1 wk, evidenced by histological analysis. Furthermore, micro–computed tomography analysis showed that the jb-PDC spheroids significantly accelerated bone healing after 2 wk in the absence of exogenous growth factors. In sum, the presented findings represent the successful development of cell-based therapeutics to reengineer the endochondral bone repair process and illustrate the potential application to improve bone repair and regeneration in the craniofacial skeleton. [ABSTRACT FROM AUTHOR]

Exposure to ionizing radiation can induce harmful biological effects on the human body, particularly in cases of high-dose γ-irradiation affecting the gastrointestinal tract, bone marrow, skin and lung. Such exposures lead to lethal outcomes as individuals experience a breakdown in their immune system's ability to defend against pathogens, predisposing them to sepsis-induced multiple organ failures. Mesenchymal stromal/stem cells (MSCs) possess diverse biological characteristics, including immunomodulation, anti-inflammation and tissue regeneration. Off-the-shelf culture-expanded human bone marrow- or adipose tissue-derived MSCs are clinically available to treat graft-versus-host disease following hematopoietic cell transplantation and perianal fistulas in Crohn's disease in Japan. While preclinical studies showcase encouraging outcomes in radiation-induced injuries, the effectiveness of MSC transplantation in addressing acute radiation syndrome affecting organs in irradiated individuals is limited. Recent studies have highlighted MSC-releasing extracellular vesicles as nanoparticle substances responsible for outlining the mechanism of action and have identified various components, including proteins and microRNA, that serve as functional molecules. MSC-releasing extracellular vesicle-based therapy emerges as a promising avenue, offering a potential solution to the challenges posed by radiation-induced injuries. However, further investigation is required, especially regarding whether MSC-releasing extracellular vesicles have regenerative effects on tissue-resident stem cells. These unresolved issues represent key aspects that need to be addressed to optimize the therapeutic potential of cell-based and extracellular vesicle-based MSC therapies for interventions in the context of radiation-induced injuries., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Inflammatory bowel diseases (IBD) are chronic inflammatory and pathological conditions of the gastrointestinal tract, which include two main clinical subtypes: Crohn's disease (CD) and ulcerative colitis (UC). IBDs show an increase in their age-standardized global incidence rate worldwide, with no gender differences, although the age-standardized mortality rate has decreased over the years. Indeed, thanks to recent therapies with novel mechanisms of action, including those with biologics and small molecules, it has been possible to reduce the mortality rate of IBDs. However, a significant percentage of IBD patients remain refractory to these multiple advanced therapies. Therefore, another challenge of IBD research remains the development of novel therapies with novel agents or cells that could improve the quality of life and outcome of IBD patients. Furthermore, another aspect to be studied in IBDs is not only the high risk of progression not only to neoplastic transformation but also to the development of cardiovascular disease (CVD). Consequently, 25-40 % of IBD patients present with cardiovascular manifestations. Here, we propose that the altered number and functions of endothelial progenitor cells (EPCs) may represent one of the crucial mechanisms associated with incomplete/delayed healing of IBD and may offer the possibility of using them, as well as their vesicles and content, as novel biomarkers and potential candidates of cell therapy for IBD. The advantages and limitations are extensively described and discussed., (Copyright © 2024 Elsevier B.V. All rights reserved.)

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.)

Background: Advanced practice providers (APPs), which include physician assistants/associates and advanced practice nurses, are critical members of the transplant and cellular therapy (TCT) care team. Despite broad utilization in transplant centers, there is little published literature on the clinical roles and responsibilities, staffing models, compensation structure, and job satisfaction of TCT APPs. This study represents the results of a national survey administered by the APP Special Interest Group to better characterize the TCT APP workforce., Objective: To characterize the TCT APP workforce by investigating clinical roles and responsibilities, compensation and institutional support, and job satisfaction., Methods: A 25-item web-based survey addressing four domains (transplant center data, APP roles and responsibilities, compensation and institutional support, and job satisfaction). Surveys were sent to participants through a chain-referral sampling method. Data were analyzed using descriptive statistics and multinomial logistic regression., Results: A total of 198 responses were analyzed, representing 64 transplant centers of varying size from 29 states. APPs report working in inpatient and outpatient settings and performing a broad array of TCT-associated procedures including bone marrow biopsy (78%), lumbar puncture (43.2%), intrathecal chemotherapy (47.0%), and cellular infusions (45.9%). Median salary of respondents was $110,000-$119,000 and was significantly associated with geographic location of transplant center and years of experience. A minority of respondents reported no funding (4.2%) or time (9.8%) supporting continuing education. A majority of APPs (55.1%) do not feel they are appropriately paid. A majority (54.3%) did not feel that their center supported a good work-life balance. Nearly 35.4% of respondents did not feel valued in their role., Conclusions: This survey represents the first to characterize the TCT APP workforce in the United States. APPs are highly integrated into the TCT care team and can serve as means to improve patient access to TCT therapies given a worsening physician shortage. However, the lack of satisfaction with compensation and work-life balance could represent barriers to recruitment and retention of TCT APPs and warrant future studies to better characterize., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Aims: This study aimed to determine the efficacy and safety of iltamiocel investigational autologous muscle cell therapy in females with stress urinary incontinence (SUI)., Methods: Adult females were randomized 2:1 to iltamiocel (150 × 10 6  cells) or placebo and stratified by severity and prior SUI surgery. The primary objective was efficacy based on the frequency of stress incontinence episodes (SIE) recorded in a 3-day diary at 12 months posttreatment. After 12 months, placebo participants could elect to receive open-label iltamiocel. Efficacy and safety analyses were performed using all patients as treated populations., Results: The study enrolled 311 patients, 297 were randomized to either iltamiocel (n = 199) or placebo (n = 98). Of the 295 participants that completed 12 months blinded follow-up, the proportion achieving the primary endpoint of ≥ 50% SIE reduction was not statistically different between treatment groups (52% vs. 53.6%; p = 0.798). A significantly greater proportion of iltamiocel participants in the prior SUI surgery stratum group achieved ≥ 75% SIE reduction compared with placebo, (40% vs. 16%; p = 0.037). Treatment response was maintained at 24 months in 78.4% and 64.9% of iltamiocel participants who achieved ≥ 50% and ≥ 75% SIE reduction, respectively, at Month 12. Adverse events related to the treatment were reported in 19 (9.5%) iltamiocel participants and 6 (6.1%) placebo participants., Conclusion: The study did not meet its primary endpoint however, iltamiocel cell therapy is safe and may be ideally suited to female patients who have undergone prior surgery for SUI. Additional study in this group of patients with high unmet medical needs is warranted., Trial Registration: ClinicalTrials.gov identifier: NCT01893138; EudraCT number: 2014-002919-41., (© 2024 The Author(s). Neurourology and Urodynamics published by Wiley Periodicals LLC.)

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.)

Introduction: Regenerative endodontic procedures (REPs) using cell-based approaches have emerged as novel treatment modalities. This clinical study aimed to present the outcomes and explore factors influencing REPs with minced pulp tissue (MP) grafts in a mature tooth., Methods: Healthy patients requiring non-surgical root canal treatment were enrolled. MP obtained from the third molar was grafted into the instrumented, disinfected, and blood-filled root canal. After treatment, patients were evaluated clinically and radiographically., Results: Follow-ups for 6 cases (male patients aged 20-27) ranged from 19 to 42 months. Radiographically, all the teeth showed favorable outcomes. Among the 6 teeth, 2 showed neither intracanal calcification nor recovery in sensibility tests, and one had no intracanal calcification with an inapplicable sensibility test evaluation. In 2 teeth, intracanal calcification was observed in the apical third; however, there was no recovery in the sensibility tests. One tooth exhibited intracanal calcification in the apical third and showed recovery in the sensibility tests. Considering these outcomes and clinical variables, the size of the apical foramen and the composition of the transplanted pulp tissue were identified as tentative influencing factors., Conclusions: This exploratory clinical study on simplified cell-based REPs using autologous MP grafts for pulp/dentin regeneration in adult teeth not only enhances our understanding of REPs but also suggests its potential as an alternative treatment option to conventional endodontic treatment., (Copyright © 2024 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

TCR-T cell therapy represents a promising advancement in adoptive immunotherapy for cancer treatment. Despite its potential, the development and preclinical testing of TCR-T cells face significant challenges. This review provides a structured overview of the key stages in preclinical testing, including in silico, in vitro, and in vivo methods, within the context of the sequential development of novel therapies. This review aimed to systematically outline the processes for evaluating TCR-T cells at each stage: from in silico approaches used to predict target antigens, assess cross-reactivity, and minimize off-target effects, to in vitro assays designed to measure cell functionality, cytotoxicity, and activation. Additionally, the review discusses the limitations of in vivo testing in animal models, particularly in accurately reflecting the human tumor microenvironment and immune responses. Performed analysis emphasizes the importance of these preclinical stages in the safe and effective development of TCR-T cell therapies. While current models provide valuable insights, we identify critical gaps, particularly in in vivo biodistribution and toxicity assessments, and propose the need for enhanced standardization and the development of more representative models. This structured approach aims to improve the predictability and safety of TCR-T cell therapy as it advances towards clinical application., (© 2024. The Author(s).)

Hyperthermia is known to enhance the effects of radiotherapy and chemotherapy. We have previously shown that hyperthermia also enhances the effects of molecular targeted therapy, immune cell therapy, and immune checkpoint inhibitors (ICI). Here, we present the recent clinical data and research results that suggest the mechanism of enhancement. Clinical data: We treated 3,419 advanced or recurrent cancer patients between June 2005 to December 2023. The effective rate (CR+PR+long term SD)was 19.7%. The effective rate of 2,329 patients treated with dendritic cells was 25.4%. The effective rate of 140 patients treated with combined dendritic cell therapy and ICI was high at 56.4%, and increased from 40.0 to 57.7% by the addition of hyperthermia. Clinical tissue: Hyperthermia promoted immune cell infiltration and enhanced MHC-class Ⅰ and PD-L1. Animal experiments: We have previously reported that hyperthermia promotes immune cell infiltration and increases MHC-class Ⅰ and PD-L1. We showed that hyperthermia increased p-STAT1 and IRF1 followed by PD-L1 expression. This study suggested that hyperthermia increased ICI through immune cell infiltration and expression of p-STAT1 and IRF1 pathways.

All Food and Drug Administration-approved noncoding RNA (ncRNA) drugs (n≈20) target known disease-causing molecular pathways by mechanisms such as antisense. In a fortuitous evolution of work on regenerative medicine, my coworkers and I inverted the RNA drug discovery process: first we identified natural disease-modifying ncRNAs, then used them as templates for new synthetic RNA drugs. Mechanism was probed only after bioactivity had been demonstrated. The journey began with the development of cardiosphere-derived cells (CDCs) for cardiac regeneration. While testing CDCs in a first-in-human trial, we discovered they worked indirectly: ncRNAs within CDC-secreted extracellular vesicles mediate the therapeutic benefits. The vast majority of such ncRNAs are fragments of unknown function. We chose several abundant ncRNA species from CDC-secreted extracellular vesicles, synthesized and screened each of them in vitro and in vivo. Those with exceptional disease-modifying bioactivity inspired new chemical entities that conform to the structural conventions of the Food and Drug Administration-approved ncRNA armamentarium. This discovery arc-Cell-Derived RNA from Extracellular vesicles for bioinspired Drug develOpment, or CREDO-has yielded various promising lead compounds, each of which works via a unique, and often novel, mechanism. The process relies on emergent insights to shape therapeutic development. The initial focus of our inquiry-CDCs-are now themselves in phase 3 testing for Duchenne muscular dystrophy and its associated cardiomyopathy. But the intravenous delivery strategy and the repetitive dosing protocol for CDCs, which have proven key to clinical success, both arose from systematic mechanistic inquiry. Meanwhile, emergent insights have led to multiple cell-free therapeutic candidates: CDC-secreted extracellular vesicles are in preclinical development for ventricular arrhythmias, while the CREDO-conceived RNA drugs are in translation for diseases ranging from myocarditis to scleroderma., Competing Interests: E. Marbán holds founder’s equity in Capricor, Inc.

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.)

The Center for International Blood and Marrow Transplant Research (CIBMTR) prepares an annual set of summary slides to summarize the trends in transplantation and cellular therapies. For the first time in the 2023 summary slides, the CIBMTR incorporated data for patients receiving chimeric antigen receptor T cell (CAR-T) infusions. In addition, data on patient-reported outcomes (PROs) are included. This report aims to update the annual trends in US hematopoietic cell transplantation (HCT) activity and incorporate data on the use of CAR-T therapies. A second aim is to present and describe the development, implementation, and current status of PRO data collection. In August 2020, the CIBMTR launched the Protocol for Collection of Patient-Reported Outcomes Data (CIBMTR PRO Protocol). The CIBMTR PRO Protocol operates under a centralized infrastructure to reduce the burden to centers. Specifically, PRO data are collected from a prospective convenience sample of adult HCT and CAR-T recipients who received treatment at contributing centers and consented for research. Data are merged and stored with the clinical data and used under the governance of the CIBMTR Research Database Protocol. Participants answer a series of surveys developed by the Patient Reported Outcomes Measurement Information System (PROMIS) focusing on physical, social and emotional, and other measures assessing financial well-being, occupational functioning, and social determinants of health. To complement traditionally measured clinical outcomes, the surveys are administered at the same time points at which clinical data are routinely collected. As of September 2023, PRO data have been collected from 993 patients across 25 different centers. With the goal of incorporating these important patient perspectives into standard clinical care, the CIBMTR has added the PRO data to Data Back to Centers (DBtC). Through expanding the data types represented in the registry, the CIBMTR aims to support holistic research accounting for the patients' perspective in improving patient outcomes. CIBMTR PRO data aim to provide a foundation for future large-scale, population-level evaluations to identify areas for improvement, emerging disparities in access and health outcomes (eg, by age, race, and ethnicity), and new therapies that may impact current treatment guidelines. Continuing to collect and grow the PRO data is critical for understanding these changes and identifying methods for improving patients' quality of life., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Human Immunodeficiency Virus (HIV) remains a significant global health challenge with approximately 38 million people currently having the virus worldwide. Despite advances in treatment development, the virus persists in the human population and still leads to new infections. The virus has a powerful ability to mutate and hide from the human immune system in reservoirs of the body. Current standard treatment with antiretroviral therapy effectively controls viral replication but requires lifelong adherence and does not eradicate the virus. This review explores the potential of Advanced Therapy Medicinal Products as novel therapeutic approaches to HIV, including cell therapy, immunisation strategies and gene therapy. Cell therapy, particularly chimeric antigen receptor T cell therapy, shows promise in preclinical studies for targeting and eliminating HIV-infected cells. Immunisation therapies, such as broadly neutralising antibodies are being investigated to control viral replication and reduce reservoirs. Despite setbacks in recent trials, vaccines remain a promising avenue for HIV therapy development. Gene therapy using technologies like CRISPR/Cas9 aims to modify cells to resist HIV infection or eliminate infected cells. Challenges such as off-target effects, delivery efficiency and ethical considerations persist in gene therapy for HIV. Future directions require further research to assess the safety and efficacy of emerging therapies in clinical trials. Combined approaches may be necessary to achieve complete elimination of the HIV reservoir. Overall, advanced therapies offer new hope for advancing HIV treatment and moving closer to a cure.

Traditional therapeutic approaches such as chemotherapy and radiation therapy have burdened cancer patients with onerous physical and psychological challenges. Encouragingly, the landscape of tumor treatment has undergone a comprehensive and remarkable transformation. Emerging as fervently pursued modalities are small molecule targeted agents, antibody-drug conjugates (ADCs), cell-based therapies, and gene therapy. These cutting-edge treatment modalities not only afford personalized and precise tumor targeting, but also provide patients with enhanced therapeutic comfort and the potential to impede disease progression. Nonetheless, it is acknowledged that these therapeutic strategies still harbour untapped potential for further advancement. Gaining a comprehensive understanding of the merits and limitations of these treatment modalities holds the promise of offering novel perspectives for clinical practice and foundational research endeavours. In this review, we discussed the different treatment modalities, including small molecule targeted drugs, peptide drugs, antibody drugs, cell therapy, and gene therapy. It will provide a detailed explanation of each method, addressing their status of development, clinical challenges, and potential solutions. The aim is to assist clinicians and researchers in gaining a deeper understanding of these diverse treatment options, enabling them to carry out effective treatment and advance their research more efficiently., (© 2024. The Author(s).)

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.)

Introduction: CMML is a rare neoplasm with overlapping myelodysplastic and myeloproliferative features whose only potential cure is allogeneic hematopoietic cell transplantation (allo-HCT)., Methods: This retrospective study examined 27 CMML patients with high-risk clinical features who underwent first allo-HCT at our institution between 2004 and 2022., Results: Nineteen patients were diagnosed with the proliferative subtype (CMML-MPN) and 8 with the dysplastic subtype (CMML-MDS). Median OS was 15 months post-HCT (95% CI: 5-71); OS at 1, 3, and 5 years was 52%, 35%, and 35%, respectively. Compared to those with CMML-MPN, patients with CMML-MDS had longer OS (median, 8.6 vs. 0.9 years; p = 0.025), RFS (4.4 vs. 0.5 years; p = 0.021), and GVHD-free, relapse-free survival (GRFS, 9.4 vs. 3.4 months; p = 0.033) as well as lower 1-year NRM (13 vs. 47%; p = 0.043), with the statistical significance of this CMML subtype effect maintained in multivariable models. High-risk cytogenetics were associated with shorter GRFS in the univariable (median, 3.1 vs. 6.2 months; p = 0.013) and multivariable (HR = 4.88; p = 0.006) settings., Conclusions: Patients who underwent transplant for CMML-MDS experienced substantially better outcomes than those transplanted for CMML-MPN. Future studies are needed for transplantation optimization in CMML, especially CMML-MPN., (© 2024 S. Karger AG, Basel.)

Dr. Shinya Yamanaka is recognized for his discovery of the induction of pluripotent stem cells from fibroblasts by a combination of defined factors. In this interview with Cell, he discusses the progress of the field, what's next for clinical applications of iPS cells, and the state of science in Japan and the rest of the world., Competing Interests: Declaration of interests S.Y. holds multiple advisory roles related to this topic: Altos Labs, Inc. (Scientific Advisory Board), iPS Academia Japan, Inc. (Scientific Advisor), Med, Elsevier Inc. (Scientific Advisory Board), Cell Press (Advisory Board), Orizuru Therapeutics, Inc. (Scientific Advisory Board), and The Uehiro Foundation on Ethics and Education (Scientific Advisor)., (Copyright © 2024.)

Subcutaneous delivery of cell therapy is an appealing minimally-invasive strategy for the treatment of various diseases. However, the subdermal site is poorly vascularized making it inadequate for supporting engraftment, viability, and function of exogenous cells. In this study, we developed a 3D bioprinted scaffold composed of alginate/gelatin (Alg/Gel) embedded with mesenchymal stem cells (MSCs) to enhance vascularization and tissue ingrowth in a subcutaneous microenvironment. We identified bio-ink crosslinking conditions that optimally recapitulated the mechanical properties of subcutaneous tissue. We achieved controlled degradation of the Alg/Gel scaffold synchronous with host tissue ingrowth and remodeling. Further, in a rat model, the Alg/Gel scaffold was superior to MSC-embedded Pluronic hydrogel in supporting tissue development and vascularization of a subcutaneous site. While the scaffold alone promoted vascular tissue formation, the inclusion of MSCs in the bio-ink further enhanced angiogenesis. Our findings highlight the use of simple cell-laden degradable bioprinted structures to generate a supportive microenvironment for cell delivery., (© 2024. The Author(s).)

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.)

Workforce education and development are key cornerstones in advancing and maturing the Cell & Gene Therapy sector. A skilled worker shortage can significantly impact and delay progress as well as the quality of output for any developer, thereby negatively impacting a patient's access to life-saving treatments. Several roundtable discussions were held at the International Society for Cell & Gene Therapy (ISCT) 2023 Annual Meeting to dive deeper into the current state of workforce development and solutions to address this bottleneck. One roundtable discussion was co-hosted by the Alliance for Regenerative Medicine (ARM) and ISCT, which focused on the gap analysis provided for the United States Cell & Gene Therapy (CGT) sector, highlighting the lack of skilled workers in manufacturing and quality control. In this manuscript, the roundtable participants continue this conversation, review the roles and staffing requirements in both academic and industry as well as small and large company settings. The adoption of increased manufacturing automation is one promising solution to propel the sector forward. However, automation alone won't replace on-site staff, but will lower the bar to entry for a larger pool of people and require different training. This paper also addresses the workforce development and training paradigm shift as advanced manufacturing techniques are implemented, which will differ considerably based on the type of manufacturing efforts, thus emphasizing the need for a well-thought-out strategy to up-skill and re-skill the technical workforce to adapt to these advancements. Organizations such as ISCT and ARM have a role to play in propelling the field forward, providing awareness and education to stakeholders at all levels, as well as acting as a convener and participating as a key stakeholder in discussions and partnerships between academia and industry towards solutions for training the best personnel for CGT manufacturing. This scope includes novel digital tools and technologies to simplify training to increase access to new talent pools interested in careers in a rapidly advancing sector., (Copyright © 2024 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Objective: The objectives of this study were to isolate, characterize progenitor cells from blood in the root canals of necrotic immature permanent teeth evoked from periapical tissues and evaluate the applicable potential of these isolated cells in Regenerative Endodontics., Design: Ten necrotic immature permanent teeth from seven patients were included. Evoked bleeding from periapical tissues was induced after chemical instrumentation of the root canals. Cells were isolated from the canal blood and evaluated for cell surface marker expression, multilineage differentiation potential, proliferation ability, and target protein expression. Cell sheets formed from these cells were transferred into human root segments, and then transplanted into nude mice. Histological examination was performed after eight weeks. Data analysis was conducted using one-way ANOVA followed by Tukey's post-hoc comparison, considering p < 0.05 as statistically significant., Results: The isolated cells exhibited characteristics typical of fibroblastic cells with colony-forming efficiency, and displayed Ki67 positivity and robust proliferation. Flow cytometry data demonstrated that at passage 3, these cells were positive for CD73, CD90, CD105, CD146, and negative for CD34 and CD45. Vimentin expression indicated a mesenchymal origin. Under differentiation media specific differentiation media, the cells demonstrated osteogenic, adipogenic, and chondrogenic differentiation potential. Subcutaneous root canals with cell sheets of isolated cells in nude mice showed the formation of pulp-like tissues., Conclusions: This study confirmed the presence of progenitor cells in root canals following evoked bleeding from periapical tissues of necrotic immature teeth. Isolated cells exhibited similar immunophenotype and regenerative potential with dental mesenchymal stromal cells in regenerative endodontic therapy., Competing Interests: Declaration of Competing Interest The authors deny any conflicts of interest., (Copyright © 2024. Published by Elsevier Ltd.)

A shortage of transplant and cellular therapy (TCT) physicians is expected given the expansion of TCT indications and the scope of practice of TCT programs in recent years. American Society of Transplantation and Cellular Therapy (ASTCT) conducted a survey of early career transplant physicians and trainees to assess the factors that prompted them to pursue to career in TCT. This was a cross-sectional survey conducted via emails sent to the ASTCT membership. Fifty-nine respondents completed the survey. The vast majority of respondents decided to pursue a career in TCT during their hematology/oncology fellowship (41%), followed by during residency (25%) or medical school (18%), and a majority of them had some exposure to TCT in their clinical training already. The most common reason for choosing to specialize in TCT was interest in the clinical practice of TCT (81%) closely followed by the scientific allure of the field (75%). Most respondents were extremely committed to remaining in this field of practice. We found that those in the field report high levels of satisfaction despite factors that would otherwise predispose them to burnout. A systematic and sustained effort to promote trainee engagement that could result in improved recruitment and retention in the field of TCT is needed. Professional societies in partnership with educational institutions could conduct outreach and help attract trainees from diverse backgrounds., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Chimeric antigen receptor (CAR) T-cell therapy is a promising immunotherapy based on genetically engineered T cells derived from patients. The introduction of CAR T-cell therapy has changed the treatment paradigm of patients with B-cell lymphoid malignancies. However, challenging issues including managing life-threatening toxicities related to CAR T-cell infusion and resistance to CAR T-cell therapy, leading to progression or relapse, remain. This review summarizes the issues with currently approved CAR T-cell therapies for patients with relapsed or refractory B-cell lymphoid malignancies, including lymphoma and myeloma. We focus on unique toxicities after CAR T-cell therapy, such as cytokine-related events and hematological toxicities, and the mechanisms underlying post-CAR T-cell failure.

Chimeric antigen receptor (CAR) T-cell therapy has become a commercially available treatment option for relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL) with two or more lines of prior therapies, and recently for high-risk r/r DLBCL with one prior line of therapy. The successful development of CAR T-cell therapy for multiple relapsed DLBCL has led to a boom in subsequent trials that investigated its utility in patients with other r/r B-cell lymphoma subtypes. However, CAR T-cell therapy is a multistep process that includes leukapheresis and manipulation which take several weeks. Therefore, patients with rapidly progressing or bulky disease may not be able to complete the therapeutic regimen involving CAR T-cell products. This raises the question of the generalizability of the results of pivotal studies to the entire population. In this review, we summarize the development of CAR-T cell therapy for B-cell lymphoma and discuss strategies to further improve the clinical outcomes of this treatment., (© 2024 The Authors. European Journal of Haematology published by John Wiley & Sons 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.)

Background: Cancer stem cells (CSCs) induce therapeutic resistance and may be an important barrier to cancer immunotherapy. Chimeric antigen receptor T (CAR-T) cell therapy has demonstrated remarkable efficacy in clinical settings. However, CAR-T cell therapy fails in a large proportion of patients, especially in those with solid tumors. It is unclear how CSCs mediate resistance to CAR-T cells, and whether CAR-T cells can more effectively eradicate CSCs., Methods: In this study, the effect of CSCs on CAR-T cell therapy was determined using in vitro and in vivo assays. Subsequently, Interleukin-24 (IL-24) was expressed along with CAR in T cells. Further in vitro and in vivo tests were performed to determine the effects of IL-24 on CSCs and CAR-T cell therapy., Results: IL-24 induced apoptosis in CSCs and contributed to T cell activation, differentiation, and proliferation. CAR.IL-24-T cells inhibited CSC enrichment and exhibited stronger antitumor activity in vitro and in vivo., Conclusions: IL-24 helps eliminate CSCs and endows CAR-T cells with improved antitumor reactivity., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose of Review: This review presents an update on completed stem cell therapy trials aimed at retinal diseases., Recent Findings: In recent years, several clinical trials have been conducted examining the safety and role of cell therapy in diseases, including age-related macular degeneration, Stargardt's macular dystrophy, and retinitis pigmentosa. Studies have utilized a variety of cell lines, modes of delivery, and immunosuppressive regimens. The prevalence of fraudulent cell therapy clinics poses threats to patients., Summary: Clinical trials have begun to characterize the safety of cell therapy in retinal disease. While studies have described the potential benefits of cell therapy, larger studies powered to evaluate this efficacy are required to continue progressing toward preventing retinal disease. Nonapproved cell therapy clinics require regulation and patient education to avoid patient complications., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

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.)