bims-carter Biomed News
on CAR-T Therapies
Issue of 2025–12–07
fifty-one papers selected by
Luca Bolliger, lxBio
  1. Sugar-coated CAR T for sweeter cell therapies.
  2. Cell and Gene Therapy: Transforming Treatment Paradigms for Patient-Centric Care.
  3. A new era in CAR-NK cell therapy: from technological innovations to clinical applications.
  4. CAR-T cell therapy in nephrology.
  5. CAR-T cell therapy for multiple myeloma: An update on the current state and future potential.
  6. Computational design of CAR-scFv linker variants for enhanced CD20 binding against B-cell malignancies.
  7. Metabolic reprogramming of CAR T cells: a new frontier in cancer immunotherapy.
  8. Mapping the experiences of adult cancer patients receiving chimeric antigen receptor T-cell (CAR-T) therapy: A scoping review protocol.
  9. Gene transfer and genome editing of T cells for cancer immunotherapy: from allogeneic HSCT to TCR gene editing.
  10. Progress and Future Perspectives of Treg Cell Therapy.
  11. Nanobody CAR-T cells in cancer: From molecular design to clinical translation.
  12. Advancing breast cancer treatment through dual targeting CAR T cell therapy.
  13. Harnessing single-domain antibodies for CAR-T and bispecific antibody development.
  14. Enabling access to genetically modified cell therapies through flexible approaches to manufacturing and cost recovery.
  15. Medical tourism for cellular therapy: a clinical perspective.
  16. The intersection of CAR-T immunotherapy with emerging technologies.
  17. The development of CAR T cells for patients with CNS malignancies.
  18. Efficacy and safety of chimeric antigen receptor T-cell in the treatment of hematologic malignancy: an umbrella review of systematic review and meta-analysis.
  19. The Pleiotropic Roles of Cytokines in Chimeric Antigen Receptor T-cell Therapy.
  20. Optimizing Natural Killer Cellular Therapy in Acute Myeloid Leukemia.
  21. Nanozymes: An emerging perspective in tumor diagnosis and treatment since the 21st century.
  22. Long-Term Follow-Up of Patients Receiving Cell and Gene Therapy Products.
  23. A comparative review of single-cell atlases: mapping cellular diversity across species and tissues.
  24. Advocacy in Theranostics: Expanding Access and Awareness Across Disciplines.
  25. Inducing ferroptosis to improve cancer therapy: a promising tool for enhancing immunotherapy.
  26. Natural killer cell therapies in cancer: innovations, challenges, and future directions.
  27. GMP-compliant manufacturing of iPSC-derived therapeutic cell products: Technologies, applications, risks and limitations.
  28. Narrative review on microbiota and sepsis: the host's betrayal?
  29. The status quo of the development of decentralized clinical trials.
  30. Challenges and Opportunities of Cosmeceutical Regulations: A Global Perspective.
  31. Navigating Solid Tumor Heterogeneity: The Promise and Challenges of Antibody-Drug Conjugates.
  32. Advancing through the blood-brain barrier: mechanisms, challenges and drug delivery strategies.
  33. Outpatient Administration of Bispecific Antibody Therapy for Hematologic Malignancies: A Practical Guide.
  34. Donor selection, graft engineering, and dosing oh my!
  35. The Neurocognitive Impact of CAR T Cell Therapy in Hematological Cancers: A Systematic Review of Cognitive Function, Quality of Life, and Psychological Outcomes.
  36. Dysbiosis and Therapeutic Modulation of the Gut Microbiota in Multiple Sclerosis: A Narrative Review.
  37. Bridging the digital divide in the pharmaceutical industry: A future research agenda.
  38. Reimbursement routes and past practices for advanced therapy medicinal products in the Netherlands.
  39. Estimands for long-term follow-up trials in gene therapy products.
  40. Immunological mechanisms underlying the novel application of mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) in graft-versus-host disease (GvHD) therapy.
  41. FDA Boxed Warnings: Should Package Inserts Include Levels of Evidence?
  42. The Role of Intestinal Microbiota and Immune System Interactions in Autoimmune Diseases.
  43. CAR T-cell-associated acute myelopathy: a rare but critical neurologic toxicity to recognize.
  44. Improvements in Data Quality Can Boost Efficiency and Reduce Development Costs: A Pharmacometric CRO's Perspective.
  45. Exploration of recent advancements of nanoparticle-based therapeutics emphasis on diabetic-related chronic wound management: a comprehensive review.
  46. Advances and future perspectives in chimeric antigen receptor T-cell and bispecific antibody therapies for multiple myeloma.
  47. When David Surrenders the Sling: The Misalignment of Science and Strategy in Biotech-Pharma Partnerships.
  48. Companion Diagnostic: An Overview of Regulatory Framework, Challenges, and Future Directions.
  49. Perovskite quantum dots in cancer diagnosis and therapy: from synthesis to biomedical applications.
  50. Superparamagnetic iron oxide nanoparticles in clinical applications: current status and future perspectives.
  51. Practical Considerations for Incorporating Equity More Explicitly in Australian Health Technology Assessment Processes.
  1. Sci Immunol. 2025 Dec 05. 10(114): eaee1941
    Sugar-coated CAR T for sweeter cell therapies.
    Dachuan Dong, Jonathan S Maltzman.
      Deletion of the SPPL3 sheddase improves allogeneic CAR T cell persistence.
    DOI:  https://doi.org/10.1126/sciimmunol.aee1941
  2. Clin Transl Sci. 2025 Dec;18(12): e70430
    Cell and Gene Therapy: Transforming Treatment Paradigms for Patient-Centric Care.
    Sojeong Yi, Chia-Yung Wu, Avery McIntosh, Maria E Santaella, Tara M Robinson, Michael Z Liao.
      Cell and gene therapies (CGTs) are transforming medicine by offering potential cures for diseases previously considered untreatable. Despite rapid advancements, challenges remain in optimizing efficacy and safety and ensuring patient accessibility and preference due to high costs and clinical uncertainties, particularly for rare diseases and one-time administration. The American Society of Clinical Pharmacology & Therapeutics (ASCPT) held a CGT satellite conference in 2025, titled "Cell and Gene Therapy: Transforming Treatment Paradigms for Patient-Centric Care." This manuscript summarizes the conference, covering gene therapies and T-cell immunotherapies from scientific, clinical, and patient-centered perspectives. Key topics on gene therapy included "platformization" to streamline development, lessons from adeno-associated virus-based gene therapies for hemophilia from patient and clinical perspectives, clinical pharmacology, and model-informed drug development (MIDD) considerations. The conference also highlighted T-cell immunotherapies including chimeric antigen receptor T therapy (CAR T), focusing on factors affecting cellular kinetics, efficacy, and safety, as well as emerging allogeneic CAR T for autoimmune diseases and MIDD strategies to optimize therapy design and clinical outcomes.
    Keywords:  cell‐ and tissue‐based therapy; gene editing; genetic therapy; immunotherapy; model informed drug development
    DOI:  https://doi.org/10.1111/cts.70430
  3. World J Pediatr. 2025 Dec 02.
    A new era in CAR-NK cell therapy: from technological innovations to clinical applications.
    Qing Ye, Wen-Xuan Li, Ming-Yu Lai, Zhi Li, Wen-Xia Shao, Yu Xia, Ti Zhang, Han-Yan Meng, Wen-Qin Jin, Jia-Xuan Chen, Rui-Ying Liu, Si-Miao Chen, Jia-Yu Zhang, Rui Gu, Xuan-Wen Ru, Jia-Yi Shen, Chen Zheng, Jin-Ai Gu, Ming Sun, Dong-Qing Cheng, Ting Zhang, Jian-Hua Mao.
       BACKGROUND: As an emerging type of immune cell therapy, chimeric antigen receptor natural killer (CAR-NK) cells have shown great potential in the treatment of both tumors and autoimmune diseases. Compared with CAR-T cells, CAR-NK cells have a lower risk of cytokine release syndrome and neurotoxicity and have the potential for "off-the-shelf" treatment from a wide range of sources including peripheral blood, umbilical cord blood, induction blood, and pluripotent stem cells (iPSCs).
    DATA SOURCES: We systematically review the basic biological characteristics of CAR-NK cells, strategies for CAR construct design and optimization, cell sources and expansion techniques, gene transfer methods and the latest progress in preclinical and clinical research.
    RESULTS: CAR-NKs have shown good safety and preliminary efficacy in treating hematological malignancies, solid tumors, autoimmune diseases and infectious diseases. Challenges relating to persistence in the body and adaptability to the microenvironment of solid tumors remain, With continuous optimization of the genetic engineering, combination therapy and personalized strategies, CAR-NK therapy is expected to be an important pillar of the next generation of immunotherapies and promote the development of precision medicine.
    CONCLUSIONS: CAR-NK cell therapy, with its superior safety profile and "off-the-shelf" potential, has emerged as a highly promising star in immunotherapy for tumors and autoimmune diseases. Although challenges remain in its in vivo persistence and efficacy against solid tumors, continuous engineering optimization and combination strategies are expected to advance the development of precision medicine.
    Keywords:  CAR-NK cells; Cancer therapy; Cell sources and expansion; Immunotherapy; Precision medicine; Safety
    DOI:  https://doi.org/10.1007/s12519-025-00998-0
  4. Ren Fail. 2025 Dec;47(1): 2594261
    CAR-T cell therapy in nephrology.
    Francesco Tondolo, Elisa Gessaroli, Federica Maritati, Irene Colombini, Marinela Shkjau, Gaetano La Manna, Giorgia Comai.
      In recent years, chimeric antigen receptor T-cell (CAR-T) therapy has emerged as a promising immunotherapeutic strategy beyond oncology, offering new treatment opportunities for immune-mediated kidney diseases. These conditions including systemic lupus erythematosus, ANCA-associated vasculitis, membranous nephropathy, and monoclonal gammopathy-related nephropathies are characterized by dysregulated B cell and plasma cell activity that often proves refractory to standard immunosuppression. CAR-T cells, engineered to target antigens such as CD19 or BCMA, enable potent and durable depletion of pathogenic lymphocyte subsets, with growing evidence of clinical efficacy in autoimmune settings. Recent clinical data suggest that CAR-T therapies can induce profound immunological remission, restore immune tolerance, and improve renal outcomes. Novel platforms such as chimeric autoantibody receptor (CAAR)-T cells and bispecific T-cell engagers (BiTEs) further refine antigen targeting and may offer scalable alternatives. Importantly, early studies also point to the potential use of these therapies in kidney transplantation, particularly desensitization therapy in highly sensitized patients and treatment of post-transplant lymphoproliferative disorders. Despite these advances, challenges remain regarding toxicity, patient selection, cost, and long-term safety. This review critically evaluates the current landscape of CAR-based therapies in nephrology, explores their immunopathological rationale, and outlines future directions for their integration into clinical practice.
    Keywords:  Cell therapy; autoimmunity; chimeric antigen receptor T; immune-mediated kidney diseases
    DOI:  https://doi.org/10.1080/0886022X.2025.2594261
  5. Best Pract Res Clin Haematol. 2025 Dec;pii: S1521-6926(25)00065-9. [Epub ahead of print]38(4): 101659
    CAR-T cell therapy for multiple myeloma: An update on the current state and future potential.
    Prateek Pophali, Jacalyn Rosenblatt, David Avigan.
      The field of multiple myeloma (MM) has seen significant therapeutic advances over the last decade including the recent advent of Chimeric Antigen Receptor T cell (CAR-T) therapy. Currently there are two FDA approved CAR-T products for MM, both targeting B cell maturation antigen (BCMA). These agents have demonstrated striking therapeutic efficacy in patients with advanced disease and are now also approved in earlier relapse. CAR-T therapy is associated with unique toxicities including cytokine release syndrome, neurotoxicity, hypogammaglobulinemia, risk of infections and cytopenias. While response rates are dramatic, most patients ultimately experience disease progression due to therapeutic resistance potentially arising from lack of persistence and exhaustion of CAR-T cells, emergence of antigen negative variants, and the immunosuppressive tumor microenvironment. Significant efforts in the field are dedicated towards improving the efficacy and mitigating the toxicity of CAR-T cell therapy. In this publication, we review the approved and investigational CAR-T models for MM.
    Keywords:  BCMA; CAR-T cell therapy; Cilta-cel; Ide-cel; Immunotherapy; Multiple myeloma
    DOI:  https://doi.org/10.1016/j.beha.2025.101659
  6. Comput Biol Med. 2025 Nov 29. pii: S0010-4825(25)01685-3. [Epub ahead of print]200 111331
    Computational design of CAR-scFv linker variants for enhanced CD20 binding against B-cell malignancies.
    Purva Khodke, Bajarang Vasant Kumbhar.
      Chimeric Antigen Receptor (CAR)-T cell therapy is a transformative immunotherapy that engineer's T cells to selectively target and eliminate cancer cells. While highly effective in hematological malignancies, challenges such as antigen escape, suboptimal antigen binding, and limited CAR-T cell persistence. Although current FDA-approved CAR-T therapies primarily target CD19 and BCMA, expanding CAR-T technology to target CD20, a key antigen in B-cell malignancies, remains critical. The membrane-proximal location of CD20 and its short extracellular epitopes pose unique binding challenges, potentially reducing CAR-T efficacy. To address this, we employed a molecular modeling strategy using Ofatumumab, a fully human monoclonal antibody, as the framework for engineering CAR-scFvs, focusing on their binding mode, stability, and affinity towards membrane-bound CD20. We investigated the structural and functional impact of incorporating different linker regions, specifically the Whitlow and G4S3 linkers, on scFv performance. Molecular dynamics (MD) simulations, free energy landscape analysis and dynamics cross-correlation matrix revealed that scFv-Whitlow maintains a stable dynamic framework with flexible, independently moving VH and VL domains, supporting functional robustness, while scFv-G4S3 showed dynamics with preserved structural integrity. Molecular docking and MD simulations identified the extracellular loop 2 (ECL2) of CD20 as a key interaction site. Notably, binding energy calculations indicated higher binding affinity of scFv-Whitlow (-37.12 kcal/mol) for CD20 compared to scFv-G4S3 (-27.97 kcal/mol), highlighting its superior interaction dynamics. These findings position scFv-Whitlow as a promising candidate for anti-CD20 CAR-T cell therapy and provide valuable insights for the rational design of next-generation CAR constructs targeting CD20.
    Keywords:  CAR-T cell therapy; CD20; G(4)S(3) linker; Lipid bilayer membrane; Ofatumumab; Turret epitope; Whitlow linker
    DOI:  https://doi.org/10.1016/j.compbiomed.2025.111331
  7. Front Immunol. 2025 ;16 1688995
    Metabolic reprogramming of CAR T cells: a new frontier in cancer immunotherapy.
    Tjaša Frlic, Mojca Pavlin.
      Chimeric Antigen Receptor (CAR) T cell therapy has revolutionized hematological cancer treatment, but its efficacy in solid tumors remains limited by the immunosuppressive and metabolically hostile tumor microenvironment (TME). CAR T cells' functional compromise, exhaustion, and poor persistence are critically linked to their suboptimal metabolic fitness. This review highlights a paradigm shift: immunometabolism and its intricate interplay with epigenetics profoundly regulate T cell fate and function, establishing their reprogramming as a cornerstone for optimizing CAR T cell efficacy in diverse malignancies. We explore the intricate relationship between T cell differentiation and metabolic states, emphasizing that modulating CAR T cell metabolism ex vivo during manufacturing can drive differentiation towards less exhausted, more persistent memory phenotypes, such as stem cell central memory (Tscm) and central memory (Tcm) cells, which correlate with superior anti-tumor responses. Our analysis demonstrates that metabolic inhibitors offer significant potential to reprogram CAR T cells. Agents targeting glycolysis or the PI3K/Akt/mTOR pathway promote a memory-like phenotype by favoring oxidative phosphorylation (OXPHOS). Further strategies utilizing glutamine antagonists, mitochondrial modulators, or enzyme manipulation (e.g., IDH2, ACAT1) can epigenetically reprogram cells, fostering memory and exhaustion resistance. Similarly, nutrient level optimization during ex vivo expansion directly sculpts CAR T cell metabolic profiles. With approaches like glucose restriction/galactose substitution, or specific amino acid modulation (e.g., L-arginine, asparagine), persistence of CAR T cells in patients can be improved. The judicious selection and engineering of cytokines (e.g., IL-7, IL-15, IL-21) during manufacturing also plays a vital role in fostering desired memory phenotypes. In conclusion, metabolic engineering, leveraging its impact on epigenetic regulation during CAR T cell manufacturing, is crucial for generating potent, persistent, and functionally resilient products. This approach holds immense promise for expanding the curative potential of CAR T cell therapy to a broader range of cancers, particularly challenging solid tumors.
    Keywords:  T cell differentiation; adoptive cell immunotherapy; chimeric antigen receptor (CAR); epigenetics; exhaustion; immunometabolism; metabolic modulation; persistence
    DOI:  https://doi.org/10.3389/fimmu.2025.1688995
  8. PLoS One. 2025 ;20(12): e0338210
    Mapping the experiences of adult cancer patients receiving chimeric antigen receptor T-cell (CAR-T) therapy: A scoping review protocol.
    Isabela Girleanu, Anne-Marie Brady, Vanessa Boland.
       INTRODUCTION: Chimeric antigen receptor T-cell (CAR T) therapy is an advancement in cancer treatments, particularly for patients with haematological malignancies who have exhausted conventional therapies like chemotherapy and stem cell transplant. CAR-T therapy involves genetically engineering a patient's own T-cells to attack cancer cells. The development of CAR-T therapy increased survival rates in 30% to 80% of patients. Due to its novelty, CAR-T therapy can present unforeseen challenges that prolong the experience of living with cancer and its treatment journey. While CAR-T cell therapies have the potential to be curative, these innovative treatments are often accompanied by a significant symptom burden, primarily cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity (ICANS).
    METHODS AND ANALYSIS: The Arksey and O'Malley framework and the population, concept and context (PCC) framework will guide the development of this scoping review. The population of this review is adults (18 years of age and older). The concept scoped is experiences of patients in the context of CAR-T therapy. CINAHL, Medline (EBSCO), PsycINFO, EMBASE and Web of Science will be searched, including grey literature. Screening and data extraction will be conducted by two independent researchers following the inclusion criteria and The Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) checklist. The protocol has been registered on Open Science Framework on 13th of May 2025.
    STUDY STATUS: Record screening is currently ongoing and it is estimated to be completed by 21st of July 2025. Data extraction is estimated to commence on 22nd of July 2025 and to be completed by 4th of August 2025. Results are to be expected on 15th of August 2025.
    DISSEMINATION OF FINDINGS: Findings will be disseminated to relevant healthcare services electronically, through oral or poster presentations, conferences, congresses and publications.
    DOI:  https://doi.org/10.1371/journal.pone.0338210
  9. Hematology Am Soc Hematol Educ Program. 2025 Dec 05. 2025(1): 1-14
    Gene transfer and genome editing of T cells for cancer immunotherapy: from allogeneic HSCT to TCR gene editing.
    Chiara Bonini.
      Adoptive T-cell therapy has emerged as a transformative modality in cancer immunotherapy, building upon foundational principles established in allogeneic hematopoietic stem cell transplantation. In this setting, while donor T cells mediate curative graft-versus-leukemia and graft-versus-infection effects, their alloreactivity poses significant risks. Gene transfer strategies-such as suicide gene insertion-have enabled the safer use of donor lymphocytes by allowing the selective elimination of T cells in case of adverse events. With this initial gene therapy approach, several lessons on the function, persistence, safety, and efficacy of engineered T cells were learned. More recently, advances in genome editing technologies have enabled precise manipulation of T-cell genomes and function, including disruption of endogenous T-cell receptors (TCRs) and insertion of tumor-specific receptors, such as chimeric antigen receptors and tumor-specific TCRs. Integration of T-cell manufacturing protocols optimized for persistence and resistance to immune suppression-largely facilitated by the possibility to simultaneously edit multiple genes (multiplex genome editing) in the same cells-has positioned engineered T cells as programmable and persistent therapeutics. Here, we briefly review key milestones, challenges, and innovations in T-cell gene engineering, from allogeneic hematopoietic stem cell transplantation to next-generation TCR-edited immunotherapies.
    DOI:  https://doi.org/10.1182/hematology.2025000681
  10. Front Biosci (Landmark Ed). 2025 Nov 27. 30(11): 41250
    Progress and Future Perspectives of Treg Cell Therapy.
    Kehua Fang, Jinbao Zong, Xiaotian Chang.
      The important immunoregulatory roles of regulatory T cells (Tregs) include fostering tolerance to infections, controlling immune surveillance, and curtailing autoimmunity. Years of research have not only generated abundant knowledge in the field of Treg biology but also enabled the initial application of Tregs in cell therapy. However, most data in this field are obtained from laboratory animals and in vitro experiments. This review provides an updated summary and the latest understanding of Treg-targeting cell therapy. We introduce the unique traits of Tregs, review animal experiments and clinical trials on Treg injections, discuss limitations of Treg applications, and consider future perspectives on Treg-based therapies. Overall, the safety and potential efficacy of Tregs will broaden the scope of cell-based treatments.
    Keywords:  Tregs (regulatory T cells); cell therapy; immunodeficiency; immunoregulation; immunotherapy
    DOI:  https://doi.org/10.31083/FBL41250
  11. Biomed Pharmacother. 2025 Nov 29. pii: S0753-3322(25)01013-3. [Epub ahead of print]193 118819
    Nanobody CAR-T cells in cancer: From molecular design to clinical translation.
    Alaa Rifaah Eisa, Fatemeh Tavassoli Razavi, Akram Hoseinzadeh, Dariush Haghmorad, Rasoul Baharlou.
      Chimeric antigen receptor (CAR)-T cell therapy has revolutionized the management of hematologic malignancies. This review provides an overview of nanobody-based CAR-T therapy, highlighting how structural advancements in single-domain antibody (VHH) design enhance tumor targeting, safety, and manufacturability. Traditional CARs utilizing single-chain variable fragments (ScFv) continue to encounter numerous issues, including misfolding, tonic signaling, immunogenicity, and the difficulty in identifying certain tumor epitopes. Nanobody-based CARs employing VHHs constitute a compact, small, and highly selective alternative for tumor targeting. This review analyzes the molecular architecture, functional advantages, and clinical utilizations of nanobody CAR-T cells. We describe the structural features, including solubility, chemical resistance, and modularity that facilitate the advanced development of bispecific, trivalent, and logic-gated CAR forms. Preclinical studies demonstrate significant cytotoxicity of cells in vitro, elevated cytokine release, and successful in vivo tumor regression in both hematologic malignancies and solid tumors. Early-phase clinical trials, particularly targeting approaches based on BCMA (B cell maturation antigen), have presented encouraging safety profiles, persistence, and antitumor activity. Although there has been so much advancement, there are several limitations, such as the challenge of tumor heterogeneity, immune evasion, and T cell exhaustion. Innovative approaches, such as off-the-shelf allogeneic CARs, armored CARs, combination therapy based on checkpoint blockade or vaccines, and synthetic biology circuits, have the capabilities for overcoming several challenges listed above. Overall, nanobody CAR-T cells represent a flexible and innovative platform, which has a likelihood of increasing specificity, safety, and accessibility, thus paving the way for their wider integration in precision oncology beyond hematologic cancers.
    Keywords:  Bispecific CAR; Hematologic malignancies; Nanobody CAR-T cells; Single-domain antibody (VHH); Solid tumors; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.biopha.2025.118819
  12. Discov Oncol. 2025 Dec 05.
    Advancing breast cancer treatment through dual targeting CAR T cell therapy.
    Mujibullah Sheikh, Dilip Madia, Umesh B Telrandhe, Harpritkaur Bagga, Arya Deshmukh.
      
    Keywords:  Breast cancer; Dual-targeting CAR-T-cell therapy; Tandem CAR constructs.; Tumor antigen heterogeneity; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s12672-025-04195-3
  13. Semin Hematol. 2025 Nov 10. pii: S0037-1963(25)00050-2. [Epub ahead of print]
    Harnessing single-domain antibodies for CAR-T and bispecific antibody development.
    Mooyoung Jung, Jeong Yeon Hwang, Hyunbo Shim.
      Emerging antibody-based therapeutic modalities such as CAR-Ts and bispecific antibodies have proven highly efficacious in treating diseases, including hematological malignancies. However, the complex molecular architectures of these novel agents present significant challenges in their design and production, for which binding moieties with small size and favorable physicochemical properties may offer a promising solution. Single domain antibodies (sdAbs), typically derived from the heavy chain antibodies of camelids and cartilaginous fishes but increasingly from synthetic and other sources as well, are small (12-15 kDa), well expressed, and exhibit favorable physicochemical properties, making them ideal targeting domains for these new modalities. In this article, we review the origins and characteristics of sdAbs, along with recent studies on CAR-T cell therapies and bispecific antibodies for hematological malignancies that incorporate sdAbs into their constructs, with emphasis on their structures, binding properties, and therapeutic efficacies. Together, these developments underscore the promise of sdAb-based CAR-Ts and bispecific antibodies as next-generation therapeutics, with the potential to expand treatment options and improve outcomes in hematological malignancies and beyond.
    Keywords:  Bispecific antibody; Chimeric antigen receptor; Nanobody; Single domain antibody
    DOI:  https://doi.org/10.1053/j.seminhematol.2025.11.001
  14. J Immunother Cancer. 2025 Dec 02. pii: e013518. [Epub ahead of print]13(12):
    Enabling access to genetically modified cell therapies through flexible approaches to manufacturing and cost recovery.
    Mark D Stewart, Christopher R Cabanski, Jeff D Allen, John E Connolly, Ben M Beneski, Boro Dropulić, Steven A Feldman, Lee A Fleisher, Patrick J Hanley, Kristen Hege, Natasha Kekre, Holly Fernandez Lynch, Crystal L Mackall.
      Genetically modified cell-based therapies hold transformative potential, particularly for patients with rare cancers and ultra-rare diseases. However, progress toward regulatory approval, reimbursement, and broad patient access is often constrained by misaligned regulatory, manufacturing, and financial frameworks that do not reflect the realities of treating small populations and low-throughput production models. Drawing on a collaborative white paper and public meeting convened by Friends of Cancer Research and the Parker Institute for Cancer Immunotherapy in May 2025, this commentary outlines three strategies to streamline regulatory pathways and enable timely, sustainable access: (1) flexible approaches to Chemistry, Manufacturing, and Controls requirements in small populations, (2) adaptable regulatory frameworks to support diverse manufacturing models, and (3) limited cost recovery mechanisms to bridge early access and development gaps. Recent regulatory and policy discussions have echoed these priorities, signaling an opportunity to align oversight with operational realities to advance innovation and access for patients in high-need settings.
    Keywords:  Chimeric antigen receptor - CAR; Gene therapy; Immunotherapy
    DOI:  https://doi.org/10.1136/jitc-2025-013518
  15. Lancet Haematol. 2025 Dec;pii: S2352-3026(25)00294-7. [Epub ahead of print]12(12): e978-e985
    Medical tourism for cellular therapy: a clinical perspective.
    Chan H L Esther, Eugene Bingwen Fan, Yu Yue Hew, L M Poon.
      Medical tourism in the field of cellular therapy has been increasing exponentially, especially in the past decade, due to multiple advances in the field. Our Viewpoint explores this growing field, with a specific focus on haematopoietic stem-cell transplantation (HSCT) and chimeric antigen receptor (CAR) T-cell therapy. We discuss the global status, regulatory challenges, and ethical considerations associated with medical tourism. We highlight benefits and drawbacks of medical tourism with regard to patient care and the impact on local health-care systems. We also address the crucial distinction between regulated, evidence-based cellular therapies and risky, unproven stem-cell tourism, which preys on vulnerable patients. We offer practical insights from our experience practicing in a regional cellular therapy hub and emphasise the importance of comprehensive patient support through a multidisciplinary team, telemedicine integration, and international collaboration to improve patient outcomes. Last, we provide perspective and suggestions on how medical tourism can be a catalyst for change within patients' countries of origin in order to improve global health-care equity.
    DOI:  https://doi.org/10.1016/S2352-3026(25)00294-7
  16. Cytokine Growth Factor Rev. 2025 Nov 08. pii: S1359-6101(25)00144-3. [Epub ahead of print]86 238-259
    The intersection of CAR-T immunotherapy with emerging technologies.
    Begüm Coşar, Pelin Kılıç, Özlem Darcansoy İşeri.
      Chimeric antigen receptor (CAR) T-cell (CAR-T) therapy is a transformative modality in cancer immunotherapy that employs genetically engineered T-cells to eliminate malignant cells selectively. Its efficacy and limitations are governed by cytokine- and growth factor-mediated signaling networks that shape T-cell activation, proliferation, differentiation, and persistence. This review traces the molecular evolution of CAR-T architecture across generations, highlighting how synthetic modulation of cytokine and co-stimulatory pathways enhances potency while reducing exhaustion and toxicity. We discuss strategies that incorporate cytokine engineering, metabolic reprogramming, and logic-gated activation to counteract the immunosuppressive tumor microenvironment. Recent technological advances-such as clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (CRISPR/Cas9)-based cytokine pathway editing, induced pluripotent stem cell (iPSC)-derived "off-the-shelf" CAR-T platforms, and extracellular vesicle (EV)-mediated cytokine delivery-are reshaping adoptive immunotherapy. Framing CAR-T development through the lens of cytokine and growth factor biology, we outline how integrating these pathways enables safer, more durable, and scalable next-generation therapies for hematologic and solid tumors.
    Keywords:  Chimeric antigen receptor (CAR) T-cell (CAR-T); Cytokine signaling; Growth factor pathways; Metabolic reprogramming; Next-generation engineered T-cells; Tumor microenvironment (TME)
    DOI:  https://doi.org/10.1016/j.cytogfr.2025.11.001
  17. Nat Rev Clin Oncol. 2025 Dec 01.
    The development of CAR T cells for patients with CNS malignancies.
    Zev A Binder, Stephen J Bagley, Jessica B Foster, Donald M O'Rourke.
      Chimeric antigen receptor (CAR) T cells have become standard-of-care therapies for patients with certain relapsed and/or refractory haematological malignancies over the past decade. However, this approach remains largely ineffective in patients with solid tumours, in part owing to limited CAR T cell persistence, the immunosuppressive tumour microenvironment of many solid tumours and limited trafficking of CAR T cells into tumours. Central nervous system (CNS) tumours, many of which are associated with a poor prognosis and require new treatment approaches, present additional challenges such as the presence of the blood-brain barrier as well as concerns over treatment-related neurotoxicities. Despite these difficulties, clinical trials involving both adult and paediatric patients with primary CNS tumours have provided signals of efficacy. In this Review, we discuss completed, ongoing and anticipated trials testing CAR T cells in patients with CNS tumours. We also highlight the most promising preclinical developments that might lead to novel clinical approaches in this area.
    DOI:  https://doi.org/10.1038/s41571-025-01102-1
  18. Front Immunol. 2025 ;16 1608768
    Efficacy and safety of chimeric antigen receptor T-cell in the treatment of hematologic malignancy: an umbrella review of systematic review and meta-analysis.
    Zhengyu Yu, Caixia Jing, Li Xie, Lang Min, Lingfeng Li, Zhongwang Wang, Ting Niu.
       Background: This umbrella review consolidates data from systematic reviews and meta-analyses on the efficacy and safety of Chimeric Antigen Receptor T-cell (CAR-T) therapy in hematologic malignancies. The aim is to assess CAR-T efficacy across different malignancies, identify key safety concerns, and provide clinical recommendations.
    Methods: We conducted a thorough search of PubMed, Embase, Web of Science, and the Cochrane Database of Systematic Reviews up to May 2024. Systematic reviews and meta-analyses evaluating CAR-T efficacy in hematologic malignancies were included. The AMSTAR tool was used to assess methodological quality, and the GRADE system was employed to evaluate the quality of evidence for each outcome.
    Results: A total of 105 meta-analyses met the inclusion criteria. CD19-targeted CAR-T therapies demonstrated superior efficacy in acute lymphoblastic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL), particularly in relapsed or refractory cases (high-quality). However, CAR-T monotherapy showed reduced efficacy in central nervous system lymphoma (CNSL) (middle-quality). Combination therapies, particularly CAR-T with HSCT, improved complete response rates but were associated with increased severe adverse events, such as CRS and neurotoxicity (high-quality). Axi-cel was found to carry a higher risk of ICANS and neutropenia compared to Tisa-ce (high-quality), likely due to its CD28 costimulatory domains, which enhance T-cell activation.
    Conclusions: CAR-T therapy demonstrates promising clinical outcomes in ALL and DLBCL, but significant safety concerns remain. Combining CAR-T with therapies such as HSCT improves efficacy but also heightens the risk of severe toxicities. Future research should focus on optimizing CAR-T constructs, refining preconditioning regimens, and identifying predictive biomarkers to personalize treatment and mitigate risks in vulnerable populations.
    Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024581782.
    Keywords:  CAR-T therapy; acute lymphoblastic leukemia; diffuse large B-cell lymphoma; meta-analyses; umbrella review
    DOI:  https://doi.org/10.3389/fimmu.2025.1608768
  19. Cancer Immunol Res. 2025 Dec 01. OF1-OF12
    The Pleiotropic Roles of Cytokines in Chimeric Antigen Receptor T-cell Therapy.
    Carli M Stewart, Elizabeth L Siegler, Saad S Kenderian.
      Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of cancer. However, the durable response to this therapy remains low, and there is a risk of moderate-to-severe toxicities following treatment that requires close monitoring. Over the past decade, we have learned that cytokines play an important role in mediating CAR T cell-associated toxicities and efficacy. As such, cytokine modulation has become a popular area of investigation to improve therapeutic responses. Although the relationship of many cytokines with CAR T-cell therapy has been investigated, several recent studies suggest paradoxical roles for cytokines such as IFNγ, IL2, IL4, and IL10 in CAR T-cell response and toxicity. In this review, we summarize the history of these cytokines in immunotherapies, detail the contexts in which these cytokines have been beneficial or harmful in the context of CAR T-cell therapy, and discuss factors that may be dictating their pleiotropy.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-25-0631
  20. Am J Clin Oncol. 2025 Dec 03.
    Optimizing Natural Killer Cellular Therapy in Acute Myeloid Leukemia.
    Binsah George, Manu Pandey, Jacob Herstein, Abhishek Maiti.
      Acute myeloid leukemia (AML) continues to pose a major hurdle in hematologic oncology, driven by its genetic complexity and tendency to resist standard therapies. Even with progress in treatment-such as high-dose chemotherapy and hematopoietic stem cell transplantation (HSCT)-outcomes remain unsatisfactory for many patients. In recent years, immunotherapy has emerged as an appealing strategy to improve survival by strengthening the body's own anti-leukemia defenses. Natural killer (NK) cells, a critical component of innate immunity, have shown strong potential for directly eliminating AML cells without prior antigen exposure. This review outlines the role of NK cells in AML immune surveillance, mechanisms by which their function becomes impaired in the disease, and the current therapeutic approaches harnessing NK cells in AML management. We also discuss key obstacles and opportunities, including strategies to boost NK cell activity, counter immune escape, and improve treatment durability. Continued investigation is essential to refine NK cell-based therapies and bring patient-tailored immunotherapeutic options into broader clinical use.
    Keywords:  acute myeloid leukemia; immunotherapy; natural killer cellular therapy
    DOI:  https://doi.org/10.1097/COC.0000000000001262
  21. Medicine (Baltimore). 2025 Nov 28. 104(48): e45475
    Nanozymes: An emerging perspective in tumor diagnosis and treatment since the 21st century.
    Qiong He, Xuejin Hu, Sanmao Liu.
       OBJECTIVE: This study aims to systematically explore the development pattern and influence of nanozyme technology in the field of oncology diagnosis and treatment through bibliometric analysis methods, while identifying which countries are the innovation drivers in this field.
    METHODS: On October 16, 2024, a search of the Web of Science Core Collection (WoSCC) was conducted to review and analyze the application of nanozymes in oncology. A total of 977 studies published from 2007 to 2024 were retrieved and examined.
    RESULTS: We found that global research interest and publication volume related to this topic continue to rise. China leads in international cooperation, publication volume, and citation frequency, highlighting its outstanding position in this field. The Chinese Academy of Sciences is the largest contributing institution in terms of publication volume. Notably, ACS Applied Materials & Interfaces and Advanced Healthcare Materials are the 2 most popular journals in this field. In authors, Yang, Piaoping leads with 25 articles, and Qu, Xiaogang is the most cited author. The keyword co-occurrence network reveals 3 hotspots: "nanozymes," "photodynamic therapy," and "peroxidase-like activity"; "cell-death," "strategies," "recent progress," and "catalyst" are identified as trend topics for future exploration.
    CONCLUSION: Nanozymes hold significant promise for cancer diagnostics and therapy, with China, the United States, and Singapore leading the way in innovative research within this domain. Moving forward, research efforts should focus on fostering global collaboration and interdisciplinary synergy, innovate in the development of new nanozyme materials like SAzymes to improve catalytic performance and safety, investigate the potential role of nanozymes in cancer immunotherapy, and expedite the progression of nanozyme technologies from experimental settings to clinical use.
    Keywords:  bibliometrics; biomaterials; cancer; data visualization; nanozymes
    DOI:  https://doi.org/10.1097/MD.0000000000045475
  22. Hum Gene Ther. 2025 Dec 01.
    Long-Term Follow-Up of Patients Receiving Cell and Gene Therapy Products.
    Laszlo Irinyi, Barbara Mintzes, Julia Warning, Laura Collie, Amanda Rush, Cameron J Turtle, Jennifer A Byrne.
      Cell and gene therapies present unique challenges for long-term follow-up as they may lead to adverse events that could emerge years after treatment. Long-term follow-up helps identify potential delayed adverse events, such as oncogenesis or immunogenicity, which might not manifest immediately after treatment. Current regulatory guidelines emphasize a risk-based approach, recommending follow-up durations based on the therapy's mechanism of action between 5 and 15 years. To facilitate long-term monitoring, regulatory authorities recommend the establishment of long-term follow-up protocols, often involving patient registries and supported by real-world data sources to systematically capture and track data from treated patients. These long-term follow-ups are instrumental in both post-approval safety studies and reimbursement decisions, where payers may link payments to treatment outcomes. As the field of cell and gene therapy evolves, regulatory frameworks continue to adapt, balancing the need for comprehensive long-term follow-up with the feasibility of implementation to ensure that therapies are adequately monitored, ensuring patient safety and therapeutic effectiveness over time. However, maintaining patient engagement over extended periods, ensuring high-quality data collection, and addressing privacy concerns present significant challenges. Innovative solutions such as decentralized data collection, digital health technologies, and data linkage with electronic health records aim to alleviate patient burden and improve data reliability.
    Keywords:  cell and gene therapy; clinical registries; efficacy; long-term follow-up; regulations; safety
    DOI:  https://doi.org/10.1177/10430342251403439
  23. Cell Mol Life Sci. 2025 Dec 02.
    A comparative review of single-cell atlases: mapping cellular diversity across species and tissues.
    Keyun Look, Pei En Goh, Long Chiau Ming, Shi Hui Law, Sang Loon Tan, Ee Wern Tan, Hooi Leng Ser, Bey Hing Goh.
      Single-cell sequencing (sc-seq) technologies have revolutionized biomedical research by enabling high-resolution analysis of cellular heterogeneity across multiple dimensions, including transcriptomics, epigenomics, and spatial profiling. These advances have led to the development of comprehensive single-cell atlases-reference maps of cell types and states across tissues and organisms, such as the Human Cell Atlas and Mouse Cell Atlas. These resources are foundational frameworks for investigating gene regulation, tissue architecture, and disease mechanisms. However, variations in biological focus, species representation, and dataset scale among available atlases necessitate a systematic comparative evaluation. This review provides an in-depth analysis of current single-cell atlases, assessing their scope, strengths, and limitations based on an updated framework derived from Hrovatin et al. We discuss the transformative role of sc-seq in oncology, immunology, and infectious disease research and highlight critical gaps in atlas development, including underrepresented species and tissue types. Finally, we propose key recommendations to guide future efforts in expanding, integrating, and standardizing single-cell atlas initiatives for enhanced translational impact.
    Keywords:  Cellular heterogeneity; Human cell atlas (HCA); Mouse cell atlas (MCA); Single-cell atlases; Single-cell sequencing (sc-seq)
    DOI:  https://doi.org/10.1007/s00018-025-05952-x
  24. J Nucl Med Technol. 2025 Dec 04. 53(Suppl 1): 125S-131S
    Advocacy in Theranostics: Expanding Access and Awareness Across Disciplines.
    Sarah R Gibbons, Sara L Johnson, Cybil J Nielsen.
      Theranostics, the combination of diagnostic and therapeutic nuclear medicine, has revolutionized the field by offering patient-specific, targeted treatment options. Although the concept dates back to the early use of radioiodine to treat thyroid disorders, modern theranostics encompasses a wide range of diseases and options and is becoming an integral component of precision medicine. Despite rapid advancement, significant barriers, such as geographic disparities, workforce shortages, regulatory burden, inadequate infrastructure, high costs, and low awareness, among providers and patients limit equitable patient access to theranostic services. Overcoming these barriers will require coordinated action among health care institutions, policymakers, educators, and professional societies to harmonize standards, support workforce expansion, and develop flexible, scalable models of care and training. By uniting stakeholder efforts, embracing innovation, and prioritizing equity, the field can fulfill the promise of theranostics and ensure that these therapies reach all patients.
    Keywords:  access; advocacy; interdisciplinary approach; theranostics; underserved
    DOI:  https://doi.org/10.2967/jnmt.125.271076
  25. J Exp Clin Cancer Res. 2025 Dec 03.
    Inducing ferroptosis to improve cancer therapy: a promising tool for enhancing immunotherapy.
    Matteo Caforio, Stefano Iacovelli, Franco Locatelli, Valentina Folgiero.
       BACKGROUND: The discovery of ferroptosis as a novel mechanism of cell death has opened the door to a new scenario in which it could be used to support current cancer therapy, particularly in cases of relapse. Several compounds have been developed aimed to inhibit or induce ferroptosis in cancer cells by acting on different signaling pathways caable of activating or repressing, respectively, this cell death mechanism.
    MAIN BODY: This review shows how treatmenting cancer cells with ferroptosis inducers results in improved efficacy of immunotherapy. Indeed, the advantage of affecting ferroptosis lies in the capacity of compounds to improve immune system compartments. The involvement of ferroptosis in cancer treatment is now emerging, demonstrating the high translational potential of this approach capable of carrying out an immune response against tumors, dendritic cells (DC), regulatory T cells (Treg), Natural Killer cells (NK) and tumor-associated macrophages (TAM) exert an interesting role. Some immune check-point inhibitors (ICIs) have been approved as cancer immunotherapy, because they target cytotoxic T lymphocyte-associated antigen 4 (CTLA4), programmed cell death protein 1 (PD-1) and its ligand PD-L1. For this reason, promising results have been achieved by combining ferroptosis inducers with ICIs. At the same time, combining Chimeric Antigen Receptor (CAR) T-cell therapy with ferroptosis inducers shows promising anti-tumor activity, particularly in solid tumors. This approach demonstrates how the modulation of ferroptosis may improve the efficacy of CAR T-cells treatment by promoting tumor cell death and enhancing immunogenicity.
    CONCLUSION: In conclusion the development of clinical trials aimed at testing the efficacy of ferroptosis induction in combination with current cancer therapy will be the definitive proof of the valid opportunity provided by this therapeutic approach.
    Keywords:  Cancer; Ferroptosis; Immunotherapy
    DOI:  https://doi.org/10.1186/s13046-025-03593-3
  26. Expert Opin Biol Ther. 2025 Dec 06.
    Natural killer cell therapies in cancer: innovations, challenges, and future directions.
    Alaa A A Aljabali, Omar Gammoh, Esam Qnais, Abdelrahim Alqudah, Yahia El-Tanani, Vijay Mishra, Yachana Mishra, Mohamed El-Tanani, Taher Hatahet.
       INTRODUCTION: Natural killer (NK) cells are innate immune effectors that can eliminate malignant cells without prior sensitization. By recognizing cellular stress signals and releasing inflammatory mediators, they contribute to immune surveillance and regulation. Their therapeutic potential lies in their ability to act across donor barriers with a reduced risk of graft-related complications; however, clinical translation remains challenging due to tumor immune evasion and limited persistence in suppressive environments.
    AREAS COVERED: This review summarizes the biological roles of NK cells in cancer immunity and examines recent therapeutic approaches that harness their cytotoxic and regulatory properties. We discuss barriers to clinical application, including immune suppression, antigen loss, and manufacturing limitations. In addition, we highlight emerging strategies, such as gene editing, rational combination therapies, and standardized clinical trial designs, aimed at improving therapeutic efficacy.
    EXPERT OPINION: NK cell-based therapies represent a promising avenue in cancer immunotherapy but require carefully designed solutions to overcome their inherent limitations. Advances in biomarker-guided patient selection, integration with existing treatment modalities, and international collaboration will be critical for translating NK cell biology into effective and durable clinical outcomes.
    Keywords:  CAR-NK; Cancer; Immunotherapy; Natural killer cells; gene editing; tumor microenvironment
    DOI:  https://doi.org/10.1080/14712598.2025.2601053
  27. Adv Drug Deliv Rev. 2025 Dec 02. pii: S0169-409X(25)00229-7. [Epub ahead of print] 115744
    GMP-compliant manufacturing of iPSC-derived therapeutic cell products: Technologies, applications, risks and limitations.
    Alexandra Haase, Arjang Ruhparwar, Ulrich Martin.
      The development of induced pluripotent stem cells (iPSCs) has transformed the field of regenerative medicine. However, to use iPSCs for therapeutic applications, iPSC-based products must be produced under Good Manufacturing Practice (GMP) conditions. This process involves reprogramming somatic cells, characterizing and banking iPSC lines, introducing therapeutic transgenes if necessary, and scaling up cell expansion and differentiation for clinical use. This review provides an overview of the relevant regulatory authorities and relevant regulations in the US, Europe, and Japan. It also discusses the current challenges and opportunities in producing GMP-compliant iPSCs. These challenges include the need for defined culture media, as well as developing all the required GMP-compliant processes, such as reprogramming, establishing iPSC clones, and manufacturing processes that lead to the final advanced therapy medicinal product (ATMP). For autologous products in particular, this can be complicated by cell line-specific variation of proliferation velocity and differentiation biases. The review also discusses attempts to develop automated closed systems. It emphasizes the importance of ensuring the sterility, identity, (epi)genetic integrity, and functionality of the final cell products to guarantee to ensure the safety and the efficacy of iPSC-based therapies. However, the need for reproducibility, rigorous quality control and safety requirements has resulted in high regulatory hurdles and extremely high costs, which often prevent the initiation of clinical trials. Overcoming these challenges will enable iPSCs to play an integral role in future medicine and offer new treatment options for various diseases.
    Keywords:  Banking; Differentiation; GMP; Gene editing; Good manufacturing practice; Pluripotent stem cells; Reprogramming
    DOI:  https://doi.org/10.1016/j.addr.2025.115744
  28. Intern Emerg Med. 2025 Dec 02.
    Narrative review on microbiota and sepsis: the host's betrayal?
    Matteo Guarino, Agostino Di Ciaula, Piero Portincasa, Roberto De Giorgio.
      Sepsis remains a leading cause of morbidity and mortality worldwide. Increasing evidence suggests that the gut microbiota, long considered a "less relevant" to human body health, it plays a crucial role in the pathophysiology of sepsis. Disruption of the host-microbe balance contributes to impaired barrier integrity, microbial translocation, and dysregulated immune responses. This perspective raises the possibility that dysbiosis is not merely a consequence of critical illness, rather an active driver of septic progression. This narrative review explores the relationship between sepsis and gut microbiome. PubMed, Scopus, and EMBASE were searched from inception to September 2025. Recent studies have highlighted the triangular interplay between the intestinal barrier, gut microbiota, and immune system. Altered microbial composition and increased permeability foster systemic inflammation and immune dysfunction. Biomarkers such as diamine oxidase and intestinal fatty acid-binding protein are emerging as promising indicators of gut injury. Experimental therapies (i.e., faecal microbiota transplantation, targeted probiotics, prebiotics, postbiotics, and personalized antibiotic regimens guided by microbial profiling) provide potential to modulate host-microbe interactions. Integration of microbiome analysis with multi-omics and advanced bioinformatics may enable stratification of septic patients by microbial signatures, paving the way for precision medicine approaches. Modulation of gut microbiota represents a novel therapeutic frontier in sepsis. Conceptualizing sepsis as a disease of disrupted host-microbe symbiosis may unravel new diagnostic and therapeutic strategies. Future research should aim at prioritizing high-quality trials, innovative designs, and equitable implementation to target microbiota to improve survival and recovery in patients with sepsis.
    Keywords:  Dysbiosis; Faecal microbiota transplantation; Gut barrier; Immune system; Sepsis
    DOI:  https://doi.org/10.1007/s11739-025-04215-8
  29. Front Med (Lausanne). 2025 ;12 1664648
    The status quo of the development of decentralized clinical trials.
    Xiaoliang Chen, Mingxuan Zhao, Na Lei, Lichun Dong, Qiang Lv, Jiashi Sun, Jianchang He, Xianglin Zhang.
      Decentralized clinical trials (DCTs) have emerged as a transformative model in new drug development, offering alternatives to traditional site-based trials through the integration of digital technologies and remote processes. This literature review examines the current landscape of DCTs by academic studies, policy reports, and regulatory guidance from major global regions. The review identifies and discusses the opportunities and challenges of DCTs, including scientific and operational innovation, equity and accessibility, governance and trust, and sustainability and infrastructure. A comparative analysis of regulatory frameworks and guidance issued by different regulatory authorities all around the world reveals both convergences and distinctions in how DCTs are approached, particularly in areas such as digital health technologies or patient-centered models. The U.S. emphasizes efficiency and technological integration; the EU prioritizes equity and patient engagement; while China focuses on rare diseases, reducing regional disparities, and maintains a more cautious regulatory approach. The review concludes by identifying the need for greater international coordination and harmonization to fully realize the potential of DCTs while addressing their inherent risks. Building on observed regional differences, it further examines the challenges associated with harmonization, the implications of fragmented governance across jurisdictions, and the lessons learned from pilot implementations. These insights aim to inform future efforts toward more cohesive and globally aligned DCT frameworks.
    Keywords:  DCTs; decentralized clinical trials; digital clinical trials; digital health technology; transformative model
    DOI:  https://doi.org/10.3389/fmed.2025.1664648
  30. Int J Toxicol. 2025 Dec 04. 10915818251399664
    Challenges and Opportunities of Cosmeceutical Regulations: A Global Perspective.
    Munish Thakur, Rajni Bala.
      The international cosmeceutical sector has experienced unprecedented expansion, compelling regulatory bodies to enhance and update systems to tackle consumer protection, product effectiveness, and ethical issues. This review critically evaluates and contrasts regulatory settings in key markets, such as the European Union, United States, Canada, Japan, China, India, and Brazil. The examination is concentrated on key features including product definitions, pre-market approval procedures, and ingredient regulation, labeling requirements, post-market surveillance, and integrating ethical and environmental considerations. The outcome shows significant advances in regulatory harmonization, especially in the area of ingredient safety and adverse event reporting; however, there are still considerable challenges. Pioneering among these are the lack of a standard definition for "cosmeceuticals," highly variable ingredient limitations, and uneven application practice across jurisdictions. The speedy growth of e-commerce and cross-border sales additionally complicates regulatory control, adding to the possibility of non-compliant or counterfeited products reaching consumers. The review also identifies a shortage of empirical evidence to document the actual impact of recent regulatory reforms in the real world, as well as on innovation and market access. The present study recommends the promotion of international harmonization of standards, enhancement of post-market surveillance, convergence of ethical and sustainability dimensions, and targeted support for small- and medium-sized enterprises. Henceforth, while important progress has been achieved, the future of the industry rests on creating nimble, science-informed, and internationally harmonized regulatory systems that can keep pace with changing technologies and consumers' and public health priorities, ensuring both consumer safety and industry innovation.
    Keywords:  challenges; cosmeceutical; cosmetics; ethical issues; global; regulations; sustainability
    DOI:  https://doi.org/10.1177/10915818251399664
  31. Cancer Heterog Plast. 2025 ;2(4):
    Navigating Solid Tumor Heterogeneity: The Promise and Challenges of Antibody-Drug Conjugates.
    Ashley A Duhon, Karen McLean.
      Antibody drug conjugates (ADCs) are changing the landscape of cancer therapy. These agents contain an antibody directed at a tumor cell surface antigen linked to a cytotoxic payload that is released following complex internalization and processing by the lysosome. To date, seven ADCs have been approved by the Federal Drug Administration for the treatment of solid tumors and an additional seven ADCs are approved in hematologic malignancies; because of the unique aspects of solid tumor therapy, this review will focus specifically on ADCs for solid malignancies. Review of the design of these solid tumor ADCs highlights the successful evolution of ADC treatment to date, including selection of antigen target, chemical linker features, and payload. In this review, we focus on how spatial and temporal intratumoral heterogeneity uniquely limits durable efficacy of ADC therapy. We consider strategies to overcome these hurdles, including improved characterization of clinical samples for optimal ADC selection, improvements in ADC design, and combinatorial therapy. These preclinical and clinical efforts seek to overcome the challenges of tumor heterogeneity to improve ADC options and outcomes in the treatment of solid tumor malignancies.
    Keywords:  antibody drug conjugate; combination therapy; drug development; payload; resistance; tumor heterogeneity; tumor microenvironment
    DOI:  https://doi.org/10.47248/chp2502040017
  32. ADMET DMPK. 2025 ;13(5): 2988
    Advancing through the blood-brain barrier: mechanisms, challenges and drug delivery strategies.
    Ronny Vargas, Noelia Martinez-Martinez, Catalina Lizano-Barrantes, Jorge Andrés Pacheco-Molina, Encarna García-Montoya, Pilar Pérez-Lozano, Josep Mª Suñé-Negre, Carlos Suñé, Marc Suñé-Pou.
       Background and purpose: The delivery of therapeutics to the central nervous system (CNS) remains a major challenge due to the restrictive nature of the blood-brain barrier (BBB), a key evolutionary feature that preserves brain homeostasis. This review seeks to synthesize current knowledge on BBB composition, physiology, and transport mechanisms, and critically analyses drug delivery strategies aimed at overcoming this barrier and enabling effective CNS therapies.
    Approach: We conducted a comprehensive narrative review integrating evidence on BBB anatomy, transport and permeability mechanisms, drug delivery optimization strategies, with a particular focus on nanotechnology-based systems, and preclinical evaluation models.
    Key results: We highlight how a deeper understanding of BBB architecture and dynamic regulation can inform rational design of targeted strategies. Drug delivery approaches are summarized and compared, with emphasis on the potential of nanotechnology-based platforms to enhance CNS drug delivery. Translational considerations, including scalability, reproducibility, and regulatory requirements, are critically addressed. Major challenges identified include receptor saturation, competition with endogenous ligands, disease-specific variability in BBB permeability, and the limited predictive value of current preclinical models. Emerging tools, such as organ-on-chip (for evaluation) and microfluidic mixing (for manufacturing nanomaterials), offer promising means to improve physiological relevance and accelerate translation.
    Conclusion: Progress in BBB research has laid the groundwork for innovative therapies, but significant hurdles remain. Advancing CNS drug delivery will require collaborative work refining transport-targeting mechanisms, developing standardized preclinical models, and integrating fundamental research, applied nanomedicine, and regulatory science to open new opportunities for treating neurological and psychiatric disorders and brain tumours.
    Keywords:  Brain delivery; central nervous system; lipid nanoparticles; targeted therapy
    DOI:  https://doi.org/10.5599/admet.2988
  33. JCO Oncol Pract. 2025 Dec 04. OP2500652
    Outpatient Administration of Bispecific Antibody Therapy for Hematologic Malignancies: A Practical Guide.
    Kian J Rahbari, Raul Del Toro Mijares, Kathryn Kennedy, Leslie Mader, Salyka Sengsayadeth, Reena V Jayani-Kosarzycki, James Jerkins, Andrew Jallouk, Tae Kon Kim, Shakthi Bhaskar, Vivek G Patel, Brittney Baer, Sarah Moseley, David Morgan, Bipin N Savani, Adetola Kassim, Muhamed Baljevic, Olalekan Oluwole, Bhagirathbhai Dholaria.
      Bispecific antibodies (BsAbs) are currently used to treat hematologic malignancies by cross-linking cytotoxic T cells with tumor cells and thus stimulating cellular immunity. Hyperactivation of T cells leads to dysregulated cytokine release, which causes the chief toxicities of BsAbs, cytokine release syndrome (CRS) and immune effector cell-mediated neurotoxicity syndrome (ICANS). On the basis of clinical trial experiences, standard practice is to hospitalize patients for intensive monitoring during periods when the risk of CRS and ICANS is highest. A strategy to safely administer these medications outpatient would improve patient access and reduce health care-associated costs. The lessons learned from outpatient administration of chimeric antigen receptor T cell therapy (CAR-T) may be applied to BsAbs given overlapping toxicity profiles. Outpatient delivery of BsAbs is feasible but requires a specialized multidisciplinary team, a robust infrastructure with well-defined standard procedures, and significant patient support and education. Emerging clinical practices, including prophylactic anti-inflammatory therapy and modified dosing schedules, further facilitate safe outpatient administration.
    DOI:  https://doi.org/10.1200/OP-25-00652
  34. Hematology Am Soc Hematol Educ Program. 2025 Dec 05. 2025(1): 450-457
    Donor selection, graft engineering, and dosing oh my!
    Amy Moskop, Julie-An Talano.
      Allogeneic hematopoietic cell transplantation is a potentially curative therapy for patients with both malignant and nonmalignant disorders. To select the optimal donor for allogeneic hematopoietic cell transplantation, the first step is to search for a matched sibling donor or a matched unrelated donor, both of which yield comparable outcomes in the current clinical landscape. Additional donor options include haploidentical donors, mismatched unrelated donors, and umbilical cord blood donors. Newer transplant approaches have refined the use of these donor sources to improve outcomes. Beyond human leukocyte antigen compatibility, several non-human leukocyte antigen factors influence optimal donor selection. These include donor age, the presence of donor-specific antibodies, cytomegalovirus status, and ABO blood type compatibility. Various graft engineering strategies have been developed. These include posttransplant cyclophosphamide, T-cell depletion techniques such as CD34+ selection, CD45RA depletion, and αβ T-cell depletion, T regulatory purification, and umbilical cord blood expansion. Optimizing the cell dose used in transplantation is also critical to improving outcomes. All of these strategies combined allow nearly every patient to find a donor with continued improvements in outcomes.
    DOI:  https://doi.org/10.1182/hematology.2025000736
  35. Health Sci Rep. 2025 Dec;8(12): e71571
    The Neurocognitive Impact of CAR T Cell Therapy in Hematological Cancers: A Systematic Review of Cognitive Function, Quality of Life, and Psychological Outcomes.
    Ashvath Arumugam Pillai, Megha Tiwari, Sanjana B Patil, Dhruv Gandhi, Aparna Nanda, Sukriti Chugh, Sumit Chauhan, Shivangi Jha, Gaurish Angawalkar, Siddharth Prabhakar Shinde, Sanjit Sah, Amogh Verma.
       Background: Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of hematological malignancies, offering durable remissions. However, concerns regarding its neurocognitive and psychological impact have emerged, particularly in patients experiencing immune effector cell-associated neurotoxicity syndrome (ICANS). Despite growing clinical use, the long-term effects on cognitive function, psychological well-being, and quality of life (QoL) remain unclear.
    Objective: This systematic review evaluates the neurocognitive, psychological, and QoL outcomes associated with CAR T-cell therapy.
    Methods: A systematic search of PubMed, Embase, and Scopus was conducted following PRISMA guidelines. Eligible studies included randomized controlled trials, cohort studies, and observational studies assessing cognitive function, psychological outcomes (anxiety, depression, PTSD), and QoL post-CAR T-cell therapy. Study quality was assessed using the Cochrane Risk of Bias Tool for RCTs and the Newcastle-Ottawa Scale for observational studies.
    Results: Eighteen studies met the inclusion criteria. Up to 44% of CAR T-cell recipients experienced cognitive impairments, particularly in memory, attention, and executive function. ICANS was reported in 25%-70% of patients, with severe ICANS in 10%-20%. Persistent cognitive deficits were observed beyond 12 months in a subset of patients, particularly those with severe ICANS. Psychological outcomes included anxiety and depression in 35% of patients, with PTSD reported in those experiencing severe neurotoxicity. While QoL improved over time, patients with prolonged neurotoxicity had delayed recovery. EEG-based biomarkers, including the EICANS Score, showed promise in predicting ICANS severity.
    Conclusions: CAR T-cell therapy is associated with neurocognitive and psychological sequelae, particularly in patients with severe ICANS. Long-term cognitive monitoring, standardized assessments, and targeted rehabilitation strategies are needed to optimize patient outcomes.
    Keywords:  CAR T‐cell therapy; ICANS; cognitive impairment; hematological malignancies; neurotoxicity; psychological outcomes; quality of life
    DOI:  https://doi.org/10.1002/hsr2.71571
  36. Health Sci Rep. 2025 Dec;8(12): e71564
    Dysbiosis and Therapeutic Modulation of the Gut Microbiota in Multiple Sclerosis: A Narrative Review.
    Mojtaba Memariani, Hamed Memariani.
       Background and Aims: Multiple sclerosis (MS) is a persistent autoimmune disease that affects the central nervous system. The etiology of MS is complex, involving a variety of genetic and environmental factors. Mounting evidence suggests that dysbiosis significantly impacts the progression of MS mainly through its direct effects upon the immune system. Given the vital connection between the gut microbiota and immune health, particularly in the context of autoimmune diseases, this review aims to summarize the existing knowledge regarding alterations in the gut microbiota among MS patients, with a focus on microbiota-based therapeutic approaches.
    Methods: A detailed literature review was carried out to gather contemporary evidence on dysbiosis of the gut microbiota in MS patients. Furthermore, studies dealing with the modification of gut microbiota for therapeutic applications in MS have been included.
    Results: A distinct variation in specific bacterial phyla, orders, families, and genera, as well as metabolites, was found in MS patients. Exploring therapeutic options such as antibiotics, probiotics, dietary interventions, fecal microbiota transplantation, phage therapy, and helminth therapy may present valuable opportunities for gut microbiota modification in MS treatment.
    Conclusion: Altering the gut microbiota in patients with MS may serve as a potentially effective treatment strategy. Nevertheless, future research should prioritize the standardization of these therapies. Finally, it is imperative that researchers concentrate on large-scale studies or trials to scrutinize the practical relevance of these therapeutic options.
    Keywords:  diet; dysbiosis; gut microbiota; multiple sclerosis; probiotics
    DOI:  https://doi.org/10.1002/hsr2.71564
  37. Soc Sci Med. 2025 Nov 27. pii: S0277-9536(25)01163-3. [Epub ahead of print]389 118832
    Bridging the digital divide in the pharmaceutical industry: A future research agenda.
    Mario Miozza, Salvatore M Lombardo, Marco Galvagno, Luca Magni.
      Digital transformation is reshaping the pharmaceutical industry, but adoption remains fragmented due to regulatory constraints, organizational inertia, and unequal digital capabilities. This study investigates how the digital divide influences the implementation of new technologies across the pharmaceutical value chain. We combined a systematic literature review of 70 peer-reviewed studies with topic modeling (Latent Dirichlet Allocation) to provide an integrated overview of challenges, opportunities, and future research directions. Our analysis identified 16 thematic clusters consolidated into five strategic domains: Advancing Drug Discovery, Reinventing Organizational Strategies, Optimizing Manufacturing, Strengthening Supply Chains, and Developing Patient-Centric Models. The results show that digital transformation is not only a technical matter but also a systemic process shaped by regulation, governance, and socio-economic conditions. While artificial intelligence, blockchain, digital twins, and other technologies hold potential to accelerate innovation and improve patient outcomes, their benefits are distributed unevenly. Large multinational firms, advanced laboratories, and well-resourced health systems are better positioned to adopt these tools, while small and medium enterprises, emerging economies, and marginalized patient groups often face barriers in infrastructure, expertise, and compliance. From these findings, we developed a structured research agenda to bridge the pharmaceutical digital divide. Priorities include clarifying regulatory and institutional frameworks for digital technologies, identifying the organizational capabilities and governance models required for systemic adoption, and addressing equity implications to ensure inclusive access across geographies, firms, and patient populations. This study contributes methodologically by integrating systematic review and topic modeling, conceptually by framing digital transformation through a value-chain and digital divide perspective, and practically by offering a roadmap for managers, policymakers, and scholars.
    Keywords:  Digital transformation; LDA (Latent dirichlet allocation); Pharmaceutical industry; Research agenda; Systematic literature review; Topic modeling
    DOI:  https://doi.org/10.1016/j.socscimed.2025.118832
  38. Regen Med. 2025 Dec 01. 1-18
    Reimbursement routes and past practices for advanced therapy medicinal products in the Netherlands.
    Jurriaan Gort, Christine C van Hattem, Floris Logman, Geert W J Frederix, Lotty Hooft, Lourens T Bloem, Renske M T Ten Ham.
       AIM: Achieving market access for advanced therapy medicinal products (ATMPs) requires navigating national reimbursement routes. This is said to be particularly challenging for academic developers and small- and medium-sized enterprises, increasingly involved in ATMP development. We aimed to identify reimbursement routes for ATMPs in the Netherlands and assess how ATMPs obtained reimbursement.
    METHODS: We conducted a scoping review of legal and policy documents and identified ATMPs, granted EU-wide marketing authorization (MA) or national hospital exemption (HE) between January 2008 and March 2024, and assessed how these obtained reimbursement.
    RESULTS: The Dutch reimbursement process involves two steps: (i) obtaining entitlement and (ii) obtaining funding. Of the 27 ATMPs, since 2018, 82% (n = 14/17) of MA-ATMPs were temporarily excluded from reimbursement as they were placed in 'the lock,' requiring health technology assessments and often negotiations to obtain entitlement. All MA-ATMPs that obtained entitlement obtained funding through an additional code for funding ('add-on'). In contrast, HE-ATMPs cannot be placed in the lock and, although possible, the identified HE-ATMP was reimbursed without an add-on.
    CONCLUSION: We constructed a roadmap of current reimbursement routes for ATMPs in the Netherlands and found that the MA-ATMPs followed a standard reimbursement route similar to non-ATMPs, whereas HE-ATMPs did not.
    Keywords:  Advanced therapy medicinal products; cell therapy; cell- and tissue-based therapy; gene therapy; health insurance; health technology assessment; market access; reimbursement
    DOI:  https://doi.org/10.1080/17460751.2025.2594314
  39. J Biopharm Stat. 2025 Dec 02. 1-12
    Estimands for long-term follow-up trials in gene therapy products.
    Shihua Wen, Patricia Anderson, Ran Duan, Oleksandr Sverdlov, Alan Y Chiang.
      Gene and genetically modified cell therapies offer incredible potential but may come with certain risks and unknowns of delayed adverse events due to unique characteristics of these products. Major regulatory agencies all require long-term follow-up (LTFU) trials, which can be as long as 15 years, to monitor potential delayed adverse events and the durability of effectiveness. Various innovative approaches have been proposed to reduce the operational burden of gene and genetically modified cell therapy LTFU trials. In this article, the authors aim to apply the ICH E9(R1) estimand framework in the context of such LTFU trials, which can be beneficial during the protocol development stage. A hypothetical LTFU study is used to illustrate the estimand considerations discussed in the current manuscript. Proper estimand specifications for a LTFU study of a gene or genetically modified cell therapy can help add clarity to the study design, data collection, and statistical analysis plan, and help ensure the study is robust, transparent, and capable of addressing the important research questions posed by these advanced therapies.
    Keywords:  Advanced therapy medicinal product; cell & gene therapies; long-term follow-up study, estimand
    DOI:  https://doi.org/10.1080/10543406.2025.2592619
  40. Mol Biol Rep. 2025 Dec 01. 53(1): 149
    Immunological mechanisms underlying the novel application of mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) in graft-versus-host disease (GvHD) therapy.
    Fatemeh Ahangari, Mina Alimohammadi, Seyed Mahmoud Hashemi.
      A serious side effect of allogeneic hematopoietic cell transplantation (HCT) is known as graft-versus-host disease (GvHD), in which the recipient's body is attacked by donor immune cells, leading to a high rate of morbidity and death. Although there are several therapies available for GvHD, their efficacy is limited, and they sometimes have serious adverse effects. Recently, one of the most interesting research in the field of cell therapy is the use of mesenchymal stromal cells (MSCs), which have been investigated in the treatment of HCT and its consequences such as GvHD, due to their potential in tissue repair and immunomodulatory activities. The potential negative consequences of direct cell transplantation are avoided by using MSC-EVs, which are micro vesicles packed with physiologically active materials like proteins, microRNAs, and other nucleic acids. One of the biggest advantages of MSC-EVs is their ability to dramatically alter immune cell responses in GvHD by delivering immunomodulatory chemicals and anti-inflammatory drugs to recipient cells. Some of the significant discoveries include encouraging the differentiation of pro-inflammatory macrophages into tissue-reparative macrophages, inhibiting the generation of inflammatory cytokines, and improving the function of regulatory T-cells. This study details the effects of MSC-EVs on the multiple alterations that occurred inside host cells as well as immunomodulation mediated by both T cells and antigen-presenting cells in terms of the immunopathology of GvHD and direct regenerative effects on damaged tissues.
    Keywords:  Exosomes; Extracellular vesicles; Graft-versus-host disease; Hematopoietic cell transplantation; Immune regulation; Mesenchymal stromal cells
    DOI:  https://doi.org/10.1007/s11033-025-11295-4
  41. J Drugs Dermatol. 2025 Dec 01. 24(12): e67-e69
    FDA Boxed Warnings: Should Package Inserts Include Levels of Evidence?
    Andrea Leung, Tina Bhutani, Nicholas Brownstone, John Koo.
      Many medications commonly used in dermatology come with package inserts that contain boxed warnings that are frequently not evidence-based. Boxed warnings are the most serious warnings that the US Food and Drug Administration (FDA) can issue for medications through various methods, like class labeling, despite the absence of factual, high-quality evidence. Currently, there are several medications labeled with these boxed warnings for which there is no evidence, and in many cases, there actually may exist refuting evidence. However, these warnings persist in the package inserts. This has led to much hesitancy in their use, contributing to the undertreatment, or even lack of treatment, of conditions for which these medications are efficacious. Furthermore, the negative physical and mental effects of the lack of effective treatment for patients with skin disorders are well-documented. The authors call for transparency regarding the evidence, or lack thereof, behind these boxed warnings on the part of the FDA.
    DOI:  https://doi.org/10.36849/JDD.9122
  42. Immunotargets Ther. 2025 ;14 1347-1372
    The Role of Intestinal Microbiota and Immune System Interactions in Autoimmune Diseases.
    Batuhan Yurtseven, Esra Aydemir, Furkan Ayaz.
       Background: The intricate interplay between the intestinal microbiota and the immune system has emerged as a central theme in understanding autoimmune disease pathogenesis. This review comprehensively explores the role of gut microbiota in shaping immune development, establishing immune tolerance, and contributing to both local and systemic immune regulation.
    Methods: This review synthesizes the modulatory effects of microbial metabolites (eg, short-chain fatty acids and indole derivatives) on regulatory T cells (Tregs) and inflammatory pathways. The concept of "dysbiosis" is examined from functional and compositional perspectives, linking microbial imbalances to autoimmune disorders (IBD, MS, RA, and T1D). Microbiota-targeted therapeutic interventions (probiotics, prebiotics, FMT) are also evaluated.
    Key Findings: The synthesis of the literature confirms that microbial metabolites have a direct impact on Treg differentiation and inflammatory pathways. Dysbiosis, through functional and compositional disruptions, is strongly associated with the pathogenesis of various autoimmune disorders, including Inflammatory Bowel Disease, Multiple Sclerosis, Rheumatoid Arthritis, and Type 1 Diabetes. Therapeutic interventions such as probiotics, prebiotics, and Fecal Microbiota Transplantation show promising potential in restoring microbial and immune homeostasis.
    Conclusion: This review highlights the role of the gut-immune axis in autoimmune diseases. Despite current challenges, such as individual variability and determining causality, future directions toward precision microbiota and immune modulation are promising. This study provides a robust foundation for researchers and clinicians seeking to understand and therapeutically target the gut-immune axis.
    Keywords:  Tregs; autoimmune diseases; dysbiosis; gut microbiota; immune system; regulatory T cells
    DOI:  https://doi.org/10.2147/ITT.S569016
  43. Acta Neurol Belg. 2025 Dec 04.
    CAR T-cell-associated acute myelopathy: a rare but critical neurologic toxicity to recognize.
    Céline Everard, Gilles Crochet, Alissa Silva Gomes, Arnaud Robert, Aurélien Gonze.
      Chimeric Antigen Receptor T-cell (CAR-T) therapy has significantly improved outcomes in hematologic malignancies but may lead to rare and severe neurological complications beyond immune effector cell-associated neurotoxicity syndrome (ICANS), such as acute myelopathy. We report the case of a 59-year-old woman treated with CD19-targeted CAR-T cells for relapsed lymphoma, who developed grade IV ICANS followed by a clinical presentation of myelitis attributed to CAR T-cell therapy after exclusion of alternative diagnoses. Aggressive immunosuppressive treatment and supportive care failed to achieve neurological recovery. The patient remained ventilator-dependent due to cervical spinal cord lesions and ultimately died following transition to palliative care. This case underscores the diagnostic challenges posed by this medical emergency in critically ill patients since numerous confounding factors may obscure early signs of spinal cord involvement in the ICU setting. Early neurologic evaluation and multidisciplinary management are critical. This case aims to raise awareness on this rare yet dramatic complication, in which prompt initiation of treatment may prevent long term sequelae.
    DOI:  https://doi.org/10.1007/s13760-025-02950-5
  44. AAPS J. 2025 Dec 05. 28(1): 28
    Improvements in Data Quality Can Boost Efficiency and Reduce Development Costs: A Pharmacometric CRO's Perspective.
    Amparo de la Peña, Jill Fiedler-Kelly, Rebecca L Humphrey, Jeff S Barrett.
      Drug development can take up to 15 years, costing as much as $11 billion USD, and relies heavily on high-quality data. The goal of this investigation of contract research organizations (CROs) was to assess the impact of data management activities (such as curation, quality assessment and integration) on model-informed drug development (MIDD) deliverables. A survey was sent to a diverse sample of CROs, to evaluate their baseline experience with assessing the data quality of sponsor-provided data and the time required to create analysis-ready datasets. It was distributed to 44 colleagues from 32 companies offering pharmacometrics services, including data management. The survey included 11 questions; 9 were multiple choice and 2 open-ended. Responses were gathered anonymously to ensure confidentiality and intellectual property protection and later shared with all participants. Of the 17 survey respondents, most develop data specifications and create analysis-ready datasets. The majority (65%) said the data they received from sponsors was rarely (< 10%) immediately usable due to improper formatting and quality issues like missing data and inconsistencies. Over 50% cited lack of definition/specifications as the primary reason. Assuming an average programming cost of $250/hour, cleaning client data takes CROs 3 to 24 h, costing between $750 and $6000 per dataset. Significant time is spent on rectifying poor-quality data. Automated data quality assessments can improve efficiency checks, though automation alone cannot resolve all quality issues. Better communication, collaboration, and systematic approaches to address data quality issues involving automation and AI are essential to further improve data quality.
    Keywords:  AI; CROs; data quality; model-informed drug development; pharmacometrics
    DOI:  https://doi.org/10.1208/s12248-025-01168-w
  45. Arch Pharm Res. 2025 Dec 05.
    Exploration of recent advancements of nanoparticle-based therapeutics emphasis on diabetic-related chronic wound management: a comprehensive review.
    Esraa M Elshazly, Mona G Arafa, Samia A Nour.
      The skin is frequently subjected to injuries and disorders encompassing both acute and chronic wounds. Chronic wounds, including diabetic wounds, pose significant clinical problems due to prolonged and ineffective healing processes. Traditional therapies are associated with many limitations. In this regard, nanoparticles (NPs)-based drug delivery systems have emerged as promising solutions for improving chronic wound healing and to overcome the drawbacks of conventional approaches. Furthermore, the functionalization of these NPs through surface modification can increase the overall therapeutic performance. Incorporating them into advanced dosage form maximizes the therapeutic impact. Although their therapeutic promise is high, clinical translation of nanoparticles is hindered by challenges such as manufacturing problems with scaling up production of lipid nanoparticles and the regulatory difficulties related to nanoparticle characterization, such as compliance with FDA criteria for size variation. The current review endeavored to explore the most recently developed nanotechnology-based therapeutic agents that are used in diabetic chronic wound healing, especially SLNs. It also discusses the various surface modification strategies that can enhance therapeutic effectiveness. Further, to maximize the overall efficacy of the drug delivery system and to improve wound healing outcomes, the incorporation of NPs into advanced dosage forms such as thermoresponsive gels has a huge impact. This review also serves as a database for the methodology of collecting the required data, screening, and selection in addition to the pathways from NPs preclinical studies to the stages of clinical approval; moreover, NPs manufacturing and scaling-up feasibility.
    Keywords:  Diabetic chronic wound healing; Nanoparticles; Preclinical and clinical studies; Regulatory approach; Scaling up feasibility; Solid lipid nanoparticles; Thermo-responsive gel
    DOI:  https://doi.org/10.1007/s12272-025-01585-7
  46. J Clin Exp Hematop. 2025 Nov 28.
    Advances and future perspectives in chimeric antigen receptor T-cell and bispecific antibody therapies for multiple myeloma.
    Tomotaka Suzuki, Shinsuke Iida.
      The advent of T-cell-redirecting therapies has considerably reshaped the treatment landscape for relapsed/refractory multiple myeloma (RRMM), particularly in patients with triple-class exposed or refractory disease. Chimeric antigen receptor (CAR) T-cell therapies and bispecific antibodies (BsAbs), which primarily target B-cell maturation antigen (BCMA), have shown remarkable efficacy in pivotal trials and real-world settings. More recently, G protein-coupled receptor class C group 5 member D-targeted agents have emerged as promising options, particularly for patients who relapse after undergoing BCMA-directed therapy. CAR T-cell therapies can induce deep and durable responses with the potential for long-term remission. However, their use is limited because of manufacturing delays, center certification requirements, and severe toxicity risks. BsAbs offer the advantage of being off-the-shelf, enabling immediate treatment initiation and generally manageable safety profiles, making them the preferred option for frail patients or those with rapidly progressing disease. Nevertheless, continuous dosing and cumulative immunosuppression remain a clinical challenge. Although no direct comparative trials exist between CAR T-cell therapies and BsAbs, each modality has distinct advantages and limitations. Treatment decisions should be individualized based on disease characteristics, patient conditions, and institutional capabilities. Future directions include integrating these agents into earlier lines of therapy, developing novel targets, and exploring multi-antigen strategies to overcome antigen escape. As this field rapidly evolves, real-world evidence and personalized treatment approaches will become critical for optimizing outcomes in patients with RRMM. This review provides an up-to-date summary of the current T-cell-redirecting therapies, including their clinical profiles and safety considerations.
    Keywords:  B-cell maturation antigen; T-cell-redirecting therapy; bispecific antibodies; chimeric antigen receptor; multiple myeloma
    DOI:  https://doi.org/10.3960/jslrt.25038
  47. Cureus. 2025 Oct;17(10): e95608
    When David Surrenders the Sling: The Misalignment of Science and Strategy in Biotech-Pharma Partnerships.
    Shaheen E Lakhan.
      Partnerships between small biotechnology companies and large pharmaceutical corporations are essential to translating early discoveries into global therapies. Yet many of these alliances falter, not because of scientific failure, but because of structural, cultural, and ethical misalignment. What begins as a collaboration of complementary strengths often devolves into an unequal relationship, where the agility and innovation of the biotech are absorbed by the slower machinery of pharma. The result is stalled progress, diluted science, and lost opportunities for patients. This editorial examines the growing divide between small, platform-driven biotechs and large pharmaceutical partners, particularly as the frontier of medicine expands into digital, data-driven, and multimodal therapeutics. It explores how governance asymmetry, conflicting time horizons, and the commandeering of scientific authorship erode trust and value. Drawing on firsthand experience across multiple global collaborations, I argue that the future of medicine demands a new model of partnership, one that protects scientific sovereignty while enabling strategic alignment. True collaboration must evolve from transactional handoffs to the shared creation of enduring platforms that unite biology, behavior, and technology.
    Keywords:  biotechnology; commercialization; digital therapeutics; innovation policy; partnerships; pharmaceutical industry; scientific integrity
    DOI:  https://doi.org/10.7759/cureus.95608
  48. Ann Pharm Fr. 2025 Nov 29. pii: S0003-4509(25)00188-9. [Epub ahead of print]
    Companion Diagnostic: An Overview of Regulatory Framework, Challenges, and Future Directions.
    Harshada Kadam, Amisha Vora, Sanjay Sharma.
      In the era of precision medicine, companion diagnostic (CDx) is a prominent tool that links the gaps between diagnostics and therapeutics based on biomarker identification, which helps to ensure which patients are more likely to benefit from specific treatment. Initially, the focus is on oncology treatment, but in recent years, the scope of CDx has been gradually expanded towards cardiology, neurology, infectious diseases, and rare disorders. This review highlights the co-development of CDx with analysis of the regulatory framework in the United States (US), Europe (EU), and Japan. Despite regulatory standards, there are still bottlenecks that exist due to variations in approval pathways, CDx classification, technology transfer, and economic issues that remain a major hurdle for clinical implementation. Integration of advanced technologies like Next Generation Sequencing (NGS) and liquid biopsy is reshaping the existing frameworks of CDx and helps to tackle existing issues. AI (Artificial Intelligence) in CDx further holds the potential to expedite biomarker discovery, which helps in designing clinical trial studies, improves patient access, and provides real-time monitoring of treatment response. In addition to this, AI-driven technologies can expedite the regulatory decision-making process by evaluating vast, complex data sets in a short period of time, which ultimately enhances the adaptability of CDx development. Overall, this combination of technologies focuses on the evolution of CDx across the regions to expand the precision medicine approach.
    Keywords:  AI in CDx; Biomarker identification; Companion diagnostic; Precision medicine; commercialization hurdles; technology transfer
    DOI:  https://doi.org/10.1016/j.pharma.2025.11.010
  49. RSC Adv. 2025 Nov 27. 15(55): 47128-47147
    Perovskite quantum dots in cancer diagnosis and therapy: from synthesis to biomedical applications.
    Mohammad Abushuhel, G PadmaPriya, Shaker Al-Hasnaawei, Subhashree Ray, Kattela Chennakesavulu, Renu Sharma, Ashish Singh Chauhan, Hadi Noorizadeh, Mosstafa Kazemi.
      Perovskite quantum dots (PQDs) have emerged as a new generation of semiconductor nanomaterials with outstanding potential in oncology. Their unique optoelectronic features-including high photoluminescence quantum yields, tunable emission, and efficient charge transport-position them as superior candidates compared to conventional quantum dots. This review presents an integrated overview of PQDs, starting from their synthesis methodologies and structural-optoelectronic characteristics to their biocompatibility and biomedical applications. Special attention is paid to surface modification strategies, such as silica encapsulation, polymer coatings, hybrid nanostructures, and biomimetic approaches, which enhance aqueous stability, mitigate toxicity, and enable targeted delivery. Furthermore, the applications of PQDs in cancer diagnostics and therapy are highlighted, covering fluorescence and multimodal imaging, biosensing of tumor biomarkers, and advanced therapeutic modalities including photodynamic, photothermal, and integrated theranostic platforms. This review is among the first to systematically link PQD synthesis and property engineering with practical oncological applications. By addressing current limitations while outlining biomedical opportunities, this work emphasizes the promise of PQDs as versatile tools for next-generation cancer diagnosis and therapy.
    DOI:  https://doi.org/10.1039/d5ra08157b
  50. EBioMedicine. 2025 Dec 03. pii: S2352-3964(25)00498-0. [Epub ahead of print]122 106054
    Superparamagnetic iron oxide nanoparticles in clinical applications: current status and future perspectives.
    Zhanhang Guo, Dongfang Liu, Haiyan Zhang, Wenbing Yu, Yan Li, Ning Gu.
      Iron oxide nanoparticles (IONPs) demonstrate substantial translational potential in precision medicine, leveraging their favourable biocompatibility and distinctive magnetic properties. This comprehensive review systematically analyses their established clinical applications including magnetic resonance imaging (MRI) contrast enhancement, oncological interventions, and iron deficiency therapies. It further examines the critical design parameters governing the performance, safety, and metabolic fate of IONPs from a clinical-translational perspective. It addresses pivotal challenges in their clinical application and translation, including synthetic reproducibility, scalable manufacturing, and long-term biosafety, while also reviewing recent promising advances aimed at overcoming these hurdles. Furthermore, the translational potential of emerging preclinical innovations, including magnetic particle imaging (MPI), stem cell tracking modalities, and novel oral iron supplementation approaches, was critically evaluated. When integrated with multimodal imaging platforms and personalized therapeutic regimens, these advancements would pave the way for IONPs to become transformative agents in next-generation precision medicine.
    Keywords:  Cancer therapy; Clinical translation; Iron deficiency therapy; Iron oxide nanoparticles; Magnetic resonance imaging
    DOI:  https://doi.org/10.1016/j.ebiom.2025.106054
  51. Pharmacoeconomics. 2025 Dec 03.
    Practical Considerations for Incorporating Equity More Explicitly in Australian Health Technology Assessment Processes.
    Anagha Killedar, Martin Howell, Kirsten Howard, Sarah Norris.
      Globally, advances in methods to examine equity alongside economic evaluations are being considered for application in health technology assessment (HTA) processes which inform decisions to publicly fund pharmaceuticals and medical services. In this practical application, we focus on the Australian context and explore how several of these methods might be used to incorporate equity more explicitly in HTA decisions. Specifically, we describe distributional cost-effectiveness analysis, extended cost-effectiveness analysis, equity weighting, multi-criteria decision analysis, mathematical programming and other quantitative approaches. We consider the feasibility and suitability of each method considering contextual factors, highlight challenges, describe current use in Australia and make recommendations for their application. We argue that there are opportunities to use aspects of several different methods in the Australian context which would illuminate how costs (including out of pocket costs) and benefits are distributed across the population, how normative concerns for equity influence the calculated social value of a new technology, how equity criteria complement other measures of value and how the technology impacts non-health outcomes. However, some of the stated requirements for the methods, such as using the same social groupings for all analyses, applying cost-effectiveness thresholds and the application of algorithms may restrict the usefulness of the evidence generated in a context where there are many priority populations of interest, several aspects of equity are considered important and there is a well-established deliberative approach to decision-making. We recommend that the equity implications of new health technologies should be universally evaluated. However, a tailored and transparent approach should be taken whereby specific equity analyses consider the context of the technology and the chosen methods are well justified.
    DOI:  https://doi.org/10.1007/s40273-025-01568-y
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