bims-carter Biomed News
on CAR-T Therapies
Issue of 2025–10–19
53 papers selected by
Luca Bolliger, lxBio
  1. Special Issue "The Promising Future of CAR-Based Therapies: A Matter of Molecular Details".
  2. Allogeneic CAR-T cells in lupus: Bridging the gap for a new therapeutic era?
  3. Immunotherapy Strategies for Systemic Lupus Erythematosus: Focusing on CAR-T Cell Therapy.
  4. Allogeneic CAR-T cell therapy in autoimmune diseases.
  5. Microenvironmental regulation of solid tumour resistance to CAR T cell therapy.
  6. Under the Hood: Evidence-Based Review of Allogeneic Chimeric Antigen Receptor T Cells for Hematologic Malignancies.
  7. CAR-T in the Treatment of Solid Tumors-A Review of Current Research and Future Perspectives.
  8. Limitations of CAR-T-Cell Therapy in Hematologic Malignancies: Focusing on Antigen Escape and T-Cell Dysfunction.
  9. iPSC-derived T cells and macrophages: Manufacturing and next-generation application approaches.
  10. CRISPR-mediated generation of a tumor-associated antigen-deficient Raji platform to investigate antigen loss in CAR-T cell therapy.
  11. Envirotune-CAR-T: a hypoxia-responsive and glutamine-enhanced CAR-T cell therapy for overcoming tumor microenvironment-mediated suppression.
  12. Advancing Cancer Immunotherapy Using Lipid Nanoparticle-Based Approaches.
  13. HLA molecules: Another challenge for CAR T cell therapy.
  14. SPION-functionalized CAR-T cells: Overcoming key barriers in solid tumor therapy.
  15. A Novel Early Memory-Enriched Allogeneic NKG2D CAR-T Cell Therapy Based on CRISPR/Cas9 Technology for Solid Tumors.
  16. Advancing cell therapy manufacturing: an image-based solution for accurate confluency estimation.
  17. Recent advances in feeder-free NK cell expansion as a future direction of adoptive cell therapy.
  18. Translational Insights into NK Immunophenotyping: Comparative Surface Marker Analysis and Circulating Immune Cell Profiling in Cancer Immunotherapy.
  19. Cardiovascular Risk in Autoimmune Diseases: Mechanisms, Management, and Emerging Evidence.
  20. The role of NK cells in regulating tumorimmunity: current state, challenges and future strategies.
  21. Tumor-on-chip models of CAR-T cell therapy.
  22. Eliminating REMS for CAR T-Cell Therapies: An Opportunity to Improve Access.
  23. Challenges for Visual Inspection and Particle Control in Cell Therapy Products.
  24. Immunotherapy in Neuroblastoma: Mini-Review of Novel Directions and Challenges.
  25. Nanomedicine targeting the PD-1/PD-L1 axis in autoimmune diseases: breaking conventional barriers to restore immune tolerance.
  26. Optimizing post-transplantation cell therapies to enhance graft-versus-leukemia effects in hematological malignancies.
  27. CAR NK cell production from human cord blood NK progenitor cells is enhanced by stimulation of the IL-15 receptor.
  28. A tumor-on-a-chip for in vitro study of CAR-T cell immunotherapy in solid tumors.
  29. Tracking Inflammation in CAR-T Therapy: The Emerging Role of Serum Amyloid A (SAA).
  30. Novel treatments for myasthenia gravis.
  31. The Evolving Role of Hematopoietic Stem Cell Transplantation in Philadelphia-like Acute Lymphoblastic Leukemia: From High-Risk Standard to Precision Strategies.
  32. Perspectives on the FDA platform technology designation program for the approval of gene therapies: a Swiss multi-stakeholder exploratory interview study.
  33. Amniotic Treatments for the Treatment of Knee OA: Do They Work and Are They Safe?
  34. Revolutionizing pediatric gene and cell therapy: The hope for lipid-based nanoparticles in blood disorders.
  35. Overcoming Immune Therapy Resistance in Cancer Through Innate Immune Reprogramming.
  36. Inborn errors of immunity with atopic phenotypes: what we know so far.
  37. Intein-based modular chimeric antigen receptor platform for specific CD19/CD20 co-targeting.
  38. Experiences of Patients and Family Caregivers After Chimeric Antigen Receptor T-Cell Therapy: A Qualitative Study.
  39. Analysis of single-cell TCR repertoires and gene expression from multi-modal scRNA-seq data.
  40. Biological Nanotherapeutics Derived From Human Umbilical Cord Mesenchymal Stem Cells: Mechanisms and Translational Potential in Multisystem Therapies for Regeneration and Oncology.
  41. Enhanced FOS expression improves tumor clearance and resists exhaustion in NR4A3-deficient CAR T cells under chronic antigen exposure.
  42. From Biological Waste to Therapeutic Resources: A Comprehensive Review of Stem Cell Sources, Characterization, and Biomedical Potentials.
  43. Gamma Delta T Cells in the Tumour Microenvironment: A Double-Edged Sword.
  44. T-Cell Engagers in Acute Myeloid Leukemia: Molecular Targets, Structure, and Therapeutic Challenges.
  45. Cell-based treatments of lung diseases: overview and outlook.
  46. A Conceptual Review of Gut, Skin, and Oral Microbiota in Autoimmune Bullous Diseases: From Dysbiosis to Therapeutic Potential.
  47. Glucose-Enhanced Cryopreservation of hCAR-T Cells: Improved Recovery and Reduced Apoptosis.
  48. Reprogramming natural killer cells in the tumor microenvironment: Challenges and therapeuticopportunities.
  49. Conformation of HLA-E/peptide complex guides interaction with two novel HLA-E receptors: Stabilin 1 and 2.
  50. Pharmaceutical access in Brazil: challenges and opportunities.
  51. Utilization of Stem Cells in Medicine: A Narrative Review.
  52. How should we choose optimal salvage treatments following BCMA-directed CAR T-cell therapy?
  53. Umbilical cord blood-derived cytotoxic T lymphocytes target melanoma via HLA-A2-restricted tumour antigens.
  1. Int J Mol Sci. 2025 Oct 01. pii: 9587. [Epub ahead of print]26(19):
    Special Issue "The Promising Future of CAR-Based Therapies: A Matter of Molecular Details".
    Fabio Nicolini, Orsola Montini, Matteo Zurlo, Sarah Tettamanti, Massimiliano Mazza.
      In the rapidly advancing field of cancer immunotherapy, Chimeric Antigen Receptor (CAR)-T cell therapy is redefining treatment paradigms and offering renewed hope to patients with hematologic malignancies [...].
    DOI:  https://doi.org/10.3390/ijms26199587
  2. Med. 2025 Oct 10. pii: S2666-6340(25)00205-3. [Epub ahead of print]6(10): 100778
    Allogeneic CAR-T cells in lupus: Bridging the gap for a new therapeutic era?
    Giorgio Orofino, Raffaella Greco.
      Encouraging clinical responses to CAR-T cell therapy in autoimmune diseases have sparked interest in expanding this approach. Wang and colleagues1 reported early evidence that allogeneic anti-CD19 CAR-T cells may be a feasible and effective off-the-shelf treatment for systemic lupus erythematosus, supporting broader investigation of allogeneic CAR-T cell strategies across autoimmune conditions.
    DOI:  https://doi.org/10.1016/j.medj.2025.100778
  3. Immunol Invest. 2025 Oct 16. 1-27
    Immunotherapy Strategies for Systemic Lupus Erythematosus: Focusing on CAR-T Cell Therapy.
    Miao Tu, Wan Liu, Yujiao Wei, Kunyu Cao, Xiaoping Du, Jiyu Ju.
       INTRODUCTION: Systemic Lupus Erythematosus (SLE) is an incurable autoimmune disease. The remarkable success of Chimeric Antigen Receptor T-cell (CAR-T) therapy in oncology has prompted its investigation for autoimmune conditions, particularly SLE.
    METHODS: This review synthesizes current evidence, primarily from the last five years, to elucidate the pathological basis, mechanisms, advancements, and future directions of CAR-T therapy for SLE.
    RESULTS: Evidence indicates that CAR-T therapy, which targets pathogenic B cells or restores immune tolerance, is a promising intervention for SLE. Preclinical and early clinical data suggest it can effectively mitigate symptoms and may induce sustained, drug-free remission, representing a shift from chronic management.
    DISCUSSION: CAR-T cell therapy represents a transformative potential for SLE treatment. Future efforts should focus on target optimization, safety enhancement, and validation of long-term efficacy in larger clinical trials.
    Keywords:  CAAR-T cells; CAR-T cells; CAR-Tregs; Systemic lupus erythematosus
    DOI:  https://doi.org/10.1080/08820139.2025.2574351
  4. Immunotherapy. 2025 Oct 14. 1-15
    Allogeneic CAR-T cell therapy in autoimmune diseases.
    Yuanyuan Ma, Juliang Qin, Mingyao Liu, Bing Du.
      Emerging evidence demonstrates the potential efficacy of chimeric antigen receptor (CAR) T cells in autoimmune diseases. Currently, this therapy relies primarily on patient-derived autologous CAR-T cells. However, the application of autologous CAR-T cells is hindered by several limitations, such as high costs, time-consuming, and vulnerability to failure during the manufacturing process. Allogeneic CAR-T cells are genetically engineered T cells derived from healthy donors that hold great promise for expanding the accessibility of CAR-T cell therapy and may overcome the limitations of autologous CAR-T cells. Recent studies with small sample sizes have suggested the potential of allogeneic CAR-T cells in autoimmune diseases. These results have motivated researchers and physicians to further investigate the application of allogeneic CAR-T cells. In this review, we discuss the development of allogeneic CAR-T cells, current studies on CAR-T cell therapy for autoimmune diseases, and potential toxicities of allogeneic CAR-T cells. In addition, we discuss current challenges and future directions for implementing this therapy in clinical practice.
    Keywords:  Allogeneic CAR-T; Autoimmune disease; CRS; GVHD; HVGR; ICANS; Lymphodepleting chemotherapy
    DOI:  https://doi.org/10.1080/1750743X.2025.2572963
  5. Nat Rev Immunol. 2025 Oct 14.
    Microenvironmental regulation of solid tumour resistance to CAR T cell therapy.
    Zachary L Lamplugh, Nils Wellhausen, Carl H June, Yi Fan.
      Chimeric antigen receptor (CAR) T cell therapy holds significant promise for the treatment of cancer; however, its efficacy in solid tumours is substantially hindered by the immunosuppressive tumour microenvironment (TME). Solid tumours can resist immunotherapy by impairing T cell trafficking, function and persistence. One of the initial obstacles that CAR T cells encounter is the abnormal tumour vasculature, which restricts efficient T cell infiltration, further compounded by a dense extracellular matrix. CAR T cells that do infiltrate the tumours are outnumbered by immunosuppressive cells such as regulatory T cells, myeloid-derived suppressor cells and tumour-associated macrophages. Additionally, tumour cells can contribute to CAR T cell resistance by upregulating immune checkpoint molecules, such as PDL1 and CTLA4, and engage in metabolic competition. In this Review, we discuss how cellular and non-cellular components of the TME impair CAR T cell therapy and consider potential strategies to improve CAR T cell therapies for solid tumours, either by reprogramming the TME or by engineering CAR T cells to resist the immunosuppressive effects of the TME.
    DOI:  https://doi.org/10.1038/s41577-025-01229-3
  6. Transplant Cell Ther. 2025 Oct 09. pii: S2666-6367(25)01477-0. [Epub ahead of print]
    Under the Hood: Evidence-Based Review of Allogeneic Chimeric Antigen Receptor T Cells for Hematologic Malignancies.
    Asfand Yar Cheema, Hossam M Ali, Bibi Maryam, Muhammad Faisal Aslam, Praveena S Thiagarajan, Daniyal Shahid, Mishaal Munir, Ali Najam, Shahzad Raza, Faiz Anwer.
      Chimeric Antigen Receptor T cell (CAR-T) therapy has transformed the treatment of hematological malignancies. Autologous CAR-T therapies have shown remarkable efficacy but face multiple challenges, including the need to collect autologous T cell lymphocytes, logistical complexity, prolonged manufacturing time, inadequate quantity due to the collection of already exhausted cells from heavily treated patients, T cell quality not meeting the FDA specifications, and high costs, thereby limiting their widespread use. Allogeneic CAR-T (allo-CAR-T) therapy offers a promising alternative and several advantages, including immediate availability as an off-the-shelf product, standardized production that meets pre-defined quality standards, and potentially reduced costs. However, allo-CAR-T therapies encounter significant challenges, particularly the risk of graft-versus-host disease (GvHD), a clinically observed complication unless mitigating steps are taken, and host immune-mediated rejection, which can compromise their safety and effectiveness. Alternative approaches focus on gene-editing techniques and cell source modifications to maintain the efficacy of allo-CAR-Ts in hematologic malignancies while minimizing complications. Techniques such as CRISPR/Cas9-mediated disruption of TCR and HLA genes, the use of γδ T cells, and the overexpression of immunomodulatory proteins like CD47 offer promising strategies for creating safer and more effective CAR-T cell therapies. However, further research and clinical validation are necessary to optimize these approaches and minimize the risk of adverse immune reactions in patients. This review summarizes current advancements in gene editing, the use of CRISPR-Cas9 technology, innovations in lymphodepletion regimens, and strategies for overcoming graft rejection. We also dive into currently approved therapies, ongoing clinical trials, and future directions.
    Keywords:  Allogeneic; CAR T; CRISPR; Chimeric Antigen Receptor T cell; Hematologic Malignancy; Immunotherapy
    DOI:  https://doi.org/10.1016/j.jtct.2025.09.044
  7. Int J Mol Sci. 2025 Sep 28. pii: 9486. [Epub ahead of print]26(19):
    CAR-T in the Treatment of Solid Tumors-A Review of Current Research and Future Perspectives.
    Natalia Picheta, Julia Piekarz, Karolina Daniłowska, Katarzyna Szklener, Sławomir Mańdziuk.
      The aim of this narrative review is to present the current state of knowledge regarding the use of chimeric antigen receptor T-cell (CAR-T) therapy in solid tumors. Phase I clinical trials and side effects are discussed. The review is based on an analysis of available scientific publications, primarily phase I trials, Food and Drug Administration (FDA) reports, and PubMed, Scopus, and Google Scholar sources. It includes clinical trials and review articles from 2016 to 2025. Accumulated data indicate promising efficacy of CAR-T therapy in the treatment of certain solid tumors, particularly those of the gastrointestinal tract, although clinical responses were often limited to disease stabilization. The therapy was generally well tolerated, with a low incidence of serious adverse events. Efficacy was found to depend on factors such as the type of target antigen, the presence of conditioning therapy, and the ability to overcome the immunosuppressive tumor microenvironment. CAR-T therapy remains experimental outside of hematological malignancies, but further development, refinement of receptor design, and the search for better molecular targets may make it an effective treatment option for solid tumors as well. Current studies are in early phase and require confirmation in larger-scale randomized trials.
    Keywords:  CAR-T; CAR-T limitations; chimeric antigen receptor T-cells; solid tumors CAR-T
    DOI:  https://doi.org/10.3390/ijms26199486
  8. Int J Mol Sci. 2025 Oct 03. pii: 9669. [Epub ahead of print]26(19):
    Limitations of CAR-T-Cell Therapy in Hematologic Malignancies: Focusing on Antigen Escape and T-Cell Dysfunction.
    Yanyu Lin, Shuqi Luo, Jianhui Wei, Shujin Lin, Dawei Wang, Xiangqian Zhao, Zexin Feng, Yangkun Shen, Qi Chen.
      Chimeric antigen receptor T (CAR-T)-cell therapy has revolutionized the treatment of hematological malignancies, yet long-term efficacy remains constrained by antigen escape and T-cell dysfunction. Recent advances have rapidly elucidated the molecular underpinnings of antigen escape mechanisms and intrinsic T-cell dysfunction, revealing novel vulnerabilities in current CAR-T paradigms. In this review, we discuss the limitations of CAR-T-cell therapy in hematological malignancies, particularly regarding antigen escape mechanisms and T-cell dysfunction. It is noteworthy that in recent years, multi-targeted CAR-T and engineered CAR-T cells have demonstrated promising clinical efficacy in overcoming drug resistance and relapse in hematological malignancies. Here, we also discuss emerging approaches to enhance the efficacy of CAR-T-cell therapy, including advanced CAR-T-cell engineering techniques, the identification of novel therapeutic targets, and the development of multi-targeted CAR-T-cell strategies.
    Keywords:  CAR-T; T-cell dysfunction; antigen escape; hematologic malignancies
    DOI:  https://doi.org/10.3390/ijms26199669
  9. Adv Drug Deliv Rev. 2025 Oct 13. pii: S0169-409X(25)00198-X. [Epub ahead of print] 115713
    iPSC-derived T cells and macrophages: Manufacturing and next-generation application approaches.
    Débora Basílio-Queirós, Isabelle Rivière, Sjoukje J C van der Stegen, Nico Lachmann.
      Chimeric antigen receptor (CAR) technology has transformed the immunotherapy field with significant success in the treatment of hematological diseases. Nonetheless, challenges in scalability, donor variability as well as in the treatment of solid tumors warrants innovative solutions. Induced pluripotent stem cell (iPSC) technology has revolutionized the filed as an emerging renewable source for CAR-based therapies, facilitating the development of off-the-shelf immune cells products. This review focuses on the recent developments of iPSC-derived CAR-T cells and CAR-macrophages, including differentiation protocols, gene engineering strategies and mitigation of Graft-versus-Host Disease (GvHD), as well as alternatives for histocompatibility constraints. Additionally, we will discuss how iPSC-derivation enhances accessibility of low-frequency immune cell populations including MR1-restricted αβT, γδT, Natural Killer T (NKT) and Microglial cells. Despite great progress achieved, the limited but continuously growing clinical experience and manufacturing challenges, warrant further exploration. Advancements in manufacturing scalability and genetic engineering position iPSC-based therapies at the forefront of clinical strategies to address unmet clinical needs in cancer treatment.
    Keywords:  Cancer; Cell manufacturing; Chimeric antigen receptors; Immunotherapy; Macrophages; T cells; iPSC
    DOI:  https://doi.org/10.1016/j.addr.2025.115713
  10. Front Genome Ed. 2025 ;7 1649993
    CRISPR-mediated generation of a tumor-associated antigen-deficient Raji platform to investigate antigen loss in CAR-T cell therapy.
    Aditya Ramdas Iyer, Mehwish Nafiz, Pragya Gupta, Arvinden Vr, Vinodh Saravanakumar, Mohammad Sufyan Ansari, Md Shakir, Tanveer Ahmad, Sivaprakash Ramalingam.
      Tumor-associated antigen (TAA) loss remains a significant mechanism of resistance to chimeric antigen receptor (CAR) T cell therapy, leading to relapse in patients with B-cell malignancies and representing a major clinical challenge. Recent clinical data suggest that CD19 antigen loss triggers relapse in more than 40% of patients undergoing CD19 CAR-T cell therapy. To rigorously validate antigen loss, robust in vitro models that mimic the dynamic process of antigen escape are essential. However, the current absence of these models hampers our ability to fully evaluate and optimize treatment strategies. To model this clinically relevant phenomenon, we generated single (sKO), double (dKO), and triple (tKO) knockout Raji lymphoma cell lines targeting CD19, CD20, and CD22 using CRISPR/Cas9 genome editing. Initially, we established a dual-reporter cell line expressing the fluorescent marker mCherry and the bioluminescent marker Luciferase, enabling a uniform luminescence background across all the knockout cell lines before performing the CRISPR/Cas9 editing. The loss of individual or combinatorial TAAs was validated at the genomic, transcript, and protein levels. Functional co-culture assays with antigen-specific CAR-T cells showed that antigen-deficient Raji cells resisted CAR-T cell-mediated killing, closely mimicking clinical relapse. The triple knockout (tKO) model, in particular, provided a superior system compared to commonly used K562 models, as it retains the same lymphoma background while eliminating the crucial antigenic targets, thus better simulating resistance to CAR-T cell therapy. These antigen-loss models serve as valuable tools for studying mechanisms of CAR-T cell resistance and evaluating next-generation, multi-targeting CAR-T cell therapies.
    Keywords:  B-cell malignancies; CAR-T cell therapy; CRISPR/Cas9; antigen escape; antigen loss
    DOI:  https://doi.org/10.3389/fgeed.2025.1649993
  11. J Immunother Cancer. 2025 Oct 13. pii: e012321. [Epub ahead of print]13(10):
    Envirotune-CAR-T: a hypoxia-responsive and glutamine-enhanced CAR-T cell therapy for overcoming tumor microenvironment-mediated suppression.
    Wenying Li, Jiannan Chen, Jiayi Li, Shuai Wang, Zhengliang Chen, Lianfeng Zhao, Yaoyao Zhao, Lili Gu, Jiaqi Liu, Yan Zhang, Xinhao Yang, Tianyu Chen, Zhigang Guo.
       BACKGROUND: Chimeric antigen receptor (CAR)-T cell therapy has demonstrated remarkable success in hematologic malignancies; however, its efficacy in solid tumors remains limited. A major barrier is the immunosuppressive tumor microenvironment (TME), which is characterized by hypoxia and nutrient deprivation, leading to impaired CAR-T cell proliferation, persistence, and cytotoxic function. To address these barriers, we designed a dual-regulatory CAR-T strategy that integrates hypoxia-responsive control with metabolic enhancement to improve therapeutic efficacy in solid tumors.
    METHODS: To overcome these barriers, we developed a next-generation CAR-T platform with dual adaptations targeting the metabolic and transcriptional constraints of the TME. Specifically, we engineered hypoxia-responsive regulatory elements derived from VEGF to drive sustained CAR expression under hypoxic conditions. Concurrently, we overexpressed the glutamine transporter SLC38A2 to enhance glutamine uptake and metabolic fitness in nutrient-deprived environments.
    RESULTS: Compared with conventional CAR-T cells, our engineered CAR-T cells exhibited superior antitumor activity under hypoxia and nutrient stress, with enhanced proliferation, elevated memory phenotype, and reduced exhaustion markers. Mechanistically, quantitative PCR demonstrated upregulation of glutamine metabolic and glycolytic pathways, while Seahorse assays confirmed enhanced oxidative phosphorylation and glycolysis. SLC38A2 knockout reversed these enhancements, highlighting its role in sustaining CAR-T metabolic fitness.
    CONCLUSION: Our findings establish SLC38A2 as a critical metabolic regulator that enhances CAR-T antitumor efficacy, providing a promising strategy to improve the durability and efficacy of CAR-T cell therapies in TME.
    Keywords:  Chimeric antigen receptor - CAR; Immunotherapy; Memory; Solid tumor; Tumor microenvironment - TME
    DOI:  https://doi.org/10.1136/jitc-2025-012321
  12. Int J Nanomedicine. 2025 ;20 12283-12305
    Advancing Cancer Immunotherapy Using Lipid Nanoparticle-Based Approaches.
    Pedro Henrique Dias Moura Prazeres, Gabriel Henrique Costa da Silva, Gabriel Vieira Azevedo, Natalia Jordana Alves da Silva, Pedro Augusto Carvalho Costa, Walison Nunes Da Silva, Anderson Oliveira Lobo, Pedro Pires Goulart Guimaraes.
      Cancer immunotherapy, including adoptive cell therapies, cancer vaccines, and cytokine-based therapies, have revolutionized targeted approaches in the treatment of different tumors. However, the broader application of immunotherapies, such as for engineered T cells expressing a chimeric antigen receptor (CAR-T cells), remains limited by challenges in production, systemic toxicity, and inefficient delivery, especially in solid tumors. Recent advances in nucleic acid delivery technologies, notably ionizable lipid nanoparticles (LNP), offer promising solutions to overcome these barriers. LNPs have shown potential in delivering messenger RNA (mRNA), and DNA for the generation of CAR-T cells, cancer vaccines, bispecific antibodies, and cytokine-based immunotherapies. The clinical success of LNP-based platforms in mRNA COVID-19 vaccines and interference RNA therapies for genetic disorders further validates their effectiveness in gene delivery, highlighting LNPs as versatile carriers for therapeutic nucleic acids. Furthermore, LNPs can be optimized for off-the-shelf formulations, enabling personalized treatments targeting specific patient needs. In this review, we highlight the role of LNP platforms in advancing mRNA and DNA delivery for cancer immunotherapy. We explore their potential to improve CAR-T cell production, advance cancer vaccines, and support the development of bispecific antibody- and cytokine-based therapies, ultimately paving the way for more effective, scalable, and accessible immunotherapeutic strategies.
    Keywords:  CAR-T cells; adoptive cell therapy; cancer immunotherapy; cancer vaccines; gene delivery; lipid nanoparticles
    DOI:  https://doi.org/10.2147/IJN.S541061
  13. Curr Res Transl Med. 2025 Oct 10. pii: S2452-3186(25)00056-X. [Epub ahead of print]73(4): 103547
    HLA molecules: Another challenge for CAR T cell therapy.
    Ikram Salih, Meryem Fakhkhari, Hicham Berrougui, Abdelouahed Khalil, Karim Benabdellah, Erden Atilla, Khalid Sadki.
      CAR-T cell therapy marks a groundbreaking advancement in the treatment of hematological malignancies, demonstrating significant potential to induce durable remissions. However, several limitations hinder its effectiveness, including antigen loss, immune evasion, and hostile tumor microenvironment. The interplay between CAR-T cell therapy and HLA molecules, particularly HLA-DR and HLA-G, emphasises critical challenges to achieving sustained therapeutic success. Monocytes with low or negative HLA-DR expression and high HLA-G presence contribute to immune evasion and reduced CAR-T cell effectiveness. Additionally, genetic variations in HLA influence susceptibility to hematological malignancies and disease progression. Therapeutic strategies to regulate HLA expression and function are crucial to overcome these obstacles. Approaches such as blocking HLA-G, enhancing HLA-DR expression, and optimising HLA profiles in patients by gene editing can improve outcomes of CAR-T cell therapy. Continued research on HLA-mediated immune modulation will improve these strategies and advance CAR-T cell therapy.
    Keywords:  CAR-T cell therapy; HLA molecules; HLA regulation; Hematological malignancies; Immune evasion
    DOI:  https://doi.org/10.1016/j.retram.2025.103547
  14. Biochem Biophys Res Commun. 2025 Oct 07. pii: S0006-291X(25)01486-X. [Epub ahead of print]788 152770
    SPION-functionalized CAR-T cells: Overcoming key barriers in solid tumor therapy.
    Lucas R Carnell, Christoph Alexiou, Christina Janko.
      Chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable success in the treatment of hematological malignancies, but its efficacy in solid tumors remains limited. Major barriers include heterogenous antigen expression, poor tumor infiltration, and a strongly immunosuppressive tumor microenvironment. In addition, systemic administration of potent CAR-T cells frequently causes severe toxicities such as cytokine release syndrome (CRS) and neurotoxicity. Superparamagnetic iron oxide nanoparticles (SPIONs) have emerged as multifunctional tools to address these challenges. They enable magnetic field-guided accumulation of CAR-T cells at tumor sites, potentially overcoming infiltration barriers and reducing systemic exposure. Simultaneously, their magnetic properties allow non-invasive tracking by magnetic resonance imaging (MRI). This review summarizes recent advances in SPION-functionalized CAR-T cells, highlighting their potential to enhance solid tumor therapy by improving targeting, reducing systemic toxicity, and enabling real-time imaging.
    Keywords:  Adoptive cell therapy; Chimeric antigen receptor (CAR); Magnetic cell targeting; Nanomedicine; Superparamagnetic iron oxide nanoparticles
    DOI:  https://doi.org/10.1016/j.bbrc.2025.152770
  15. Cancers (Basel). 2025 Sep 30. pii: 3186. [Epub ahead of print]17(19):
    A Novel Early Memory-Enriched Allogeneic NKG2D CAR-T Cell Therapy Based on CRISPR/Cas9 Technology for Solid Tumors.
    Cristina Aparicio, Mónica Queipo, Marina Belver, Francisco Espeso, Julia Serna-Pérez, Lucía Enríquez-Rodríguez, Carlos Acebal, Álvaro Martín-Muñoz, Antonio Valeri, Alejandra Leivas, Paula Río, Daniel J Powell, Rosa Lobo-Valentín, David Arrabal, Joaquín Martínez-López, Ana Sánchez, Miguel Á de la Fuente, Margarita González-Vallinas.
      Background/Objectives: Chimeric Antigen Receptor (CAR)-T cell therapy has demonstrated impressive clinical results against hematological malignancies. However, currently commercialized CAR-T therapies are designed for autologous use, which entails some disadvantages, including high costs, manufacturing delays, complex standardization, and frequent production failures due to patient T cell dysfunction. Moreover, their CARs target one specific antigen, increasing the probability of antigen-negative tumor relapses. To overcome these limitations, we developed a novel NKG2D CAR-T cell therapy for allogeneic use with broad target specificity, as this CAR targets eight different ligands commonly upregulated in both solid and hematological tumors. Additionally, the manufacturing process was optimized to improve the phenotypic characteristics of the final product. Methods: Multiplex CRISPR/Cas9 technology was applied to eliminate the expression of TCR and HLA class I complexes in healthy donor T cells to reduce the risk of graft-versus-host disease and immune rejection, respectively, as well as lentiviral transduction for introducing the second-generation NKG2D-CAR. Moreover, we sought to optimize this manufacturing process by comparing the effect of different culture interleukin supplementations (IL-2, IL-7/IL-15 or IL-7/IL-15/IL-21) on the phenotypic and functional characteristics of the product obtained. Results: Our results showed that the novel CAR-T cells effectively targeted cervicouterine and colorectal cancer cells, and that those manufactured with IL-7/IL-15/IL-21 supplementation showed the most suitable characteristics among the conditions tested, considering genetic modification efficiency, cell proliferation, antitumor activity and proportion of the stem cell memory T cell subset, which is associated with enhanced in vivo CAR-T cell survival, expansion and long-term persistence. Conclusions: In summary, this new prototype of NKG2D CAR-T cell therapy for allogeneic use represents a promising universal treatment for a wide range of tumor types.
    Keywords:  CRISPR; NKG2D; T cells; T-cell memory; allogeneic; cancer immunotherapy; chimeric antigen receptor (CAR); interleukins; off the shelf; solid tumors
    DOI:  https://doi.org/10.3390/cancers17193186
  16. Front Bioeng Biotechnol. 2025 ;13 1651144
    Advancing cell therapy manufacturing: an image-based solution for accurate confluency estimation.
    John Mason, Martin Kraft, Jakob Hueckels, Hao Wei, Konstantinos Spetsieris.
      Cell therapies represent a transformative approach for treating diseases resistant to conventional therapies, yet their development and manufacturing face significant hurdles within the biopharmaceutical sector. A critical parameter in the production of these therapies is cell confluency, which serves as both an indicator of biomass in adherent cultures and a determinant of product quality. However, existing methods for measuring confluency are often inadequate for the large-scale cultivation systems used in industry, and current software solutions lack comprehensive automation capabilities necessary for a manufacturing environment. This article introduces a novel image-based software application designed for accurate cell confluency estimation, integrated with a high-throughput microscopy system. Utilizing a machine-learning model for pixel classification, the application facilitates efficient image and metadata processing in a cloud environment, delivering results through an interactive web interface. By incorporating methods from process analytical technologies, manufacturing data digitalization, and data science, this platform enables automated image acquisition, storage, analysis, and reporting in near-real time. The proposed solution aims to streamline the manufacturing process of cell therapeutics, ultimately enhancing the reliability and speed of delivering these innovative treatments to patients.
    Keywords:  PAT; cell culture; cell therapy; data science; imaging; manufacturing
    DOI:  https://doi.org/10.3389/fbioe.2025.1651144
  17. Front Immunol. 2025 ;16 1675353
    Recent advances in feeder-free NK cell expansion as a future direction of adoptive cell therapy.
    Jimin Lee, Munsik Kim, Hanbin Jeong, Ilkoo Noh, Jeehun Park.
      Adoptive cell therapy has progressed rapidly following the success of CAR-T therapy, with NK cells emerging as strong candidates for next-generation treatments. NK cells naturally recognize abnormal cells without genetic modification and do not cause graft-versus-host disease, making them suitable for mass production from donor blood. Traditional NK cell expansion often relies on cancer-derived feeder cells, posing safety and quality concerns. This review examines both feeder cell-based and feeder-free NK cell culture methods. We analyze the limitations of feeder-based approaches and categorize feeder-free strategies, including cytokine combinations, antibody stimulation, blood components, nanoparticles, and hydrogels. Among these, nanoparticle-based methods show strong potential for enabling safe, scalable, and standardized NK cell expansion without the risks associated with feeder cells. In this paper, we review recent advancements in NK cell culture techniques and propose the potential of nanoparticle technology in developing feeder-free NK cell culture methods.
    Keywords:  NK cell expansion; adoptive cell therapy; allogenic cell therapy; feeder-free; nanoparticle
    DOI:  https://doi.org/10.3389/fimmu.2025.1675353
  18. Int J Mol Sci. 2025 Sep 30. pii: 9547. [Epub ahead of print]26(19):
    Translational Insights into NK Immunophenotyping: Comparative Surface Marker Analysis and Circulating Immune Cell Profiling in Cancer Immunotherapy.
    Kirill K Tsyplenkov, Arina A Belousova, Marina V Zinovyeva, Irina V Alekseenko, Victor V Pleshkan.
      Cells of the innate immune system, particularly natural killer (NK) cells, serve as the first line of defense against tumor development and play a critical role in antitumor immunity. Characterizing the immune cell pool and its functional state is essential for understanding immunotherapy mechanisms and identifying key cellular players. However, defining NK cell populations in mice, the primary model for cancer immunotherapy, is challenging due to strain-specific marker variability and the absence of a universal NK cell marker, such as human CD56. This study evaluates surface markers of NK and other peripheral blood immune cells in both humans and mice, associating these markers with specific functional profiles. Bioinformatic approaches are employed to visualize these markers, enabling rapid immunoprofiling. We explore the translational relevance of these markers in assessing immunotherapy efficacy, including their gene associations, ligand interactions, and interspecies variations. Markers compatible with rapid flow-cytometry-based detection are prioritized to streamline experimental workflows. We propose a standardized immunoprofiling strategy for monitoring systemic immune status and evaluating the effectiveness of immunotherapy in preclinical and clinical settings. This approach facilitates the design of preclinical studies that aim to identify predictive biomarkers for immunotherapy outcomes by monitoring immune status.
    Keywords:  NK cells; cancer immunotherapy; circulating immune cell profiling; immune monitoring; liquid biopsy; mouse models; surface markers; translational research
    DOI:  https://doi.org/10.3390/ijms26199547
  19. Cureus. 2025 Sep;17(9): e91897
    Cardiovascular Risk in Autoimmune Diseases: Mechanisms, Management, and Emerging Evidence.
    Maheen Bhangwar Baloch, Chris Alphonse, Nehal Baldev, Genesis Marie Nin-Arroyo, Rohith Keezhath, Anahita Behara, Swati Khurana, Stephanie Nwokeji, Bashir Imam, Yozahandy A Abarca-Pineda.
      Cardiovascular disease is a leading cause of morbidity and mortality among patients with autoimmune disorders. Chronic inflammatory conditions such as rheumatoid arthritis, systemic lupus erythematosus, psoriasis, and inflammatory bowel disease are associated with accelerated atherosclerosis and other vascular complications. Persistent inflammation, dysregulated cytokine networks, and autoantibody-mediated pathways contribute to endothelial dysfunction, pro-thrombotic states, and metabolic disturbances. In addition to traditional risk factors, disease-specific elements such as chronic glucocorticoid exposure and altered lipid profiles influence overall risk. Management strategies emphasize the control of systemic inflammation alongside standard cardiovascular prevention measures. Biologic therapies targeting tumor necrosis factor, interleukin-6, and other inflammatory mediators may attenuate cardiovascular risk by slowing plaque progression. Lifestyle interventions and pharmacologic measures (e.g., statins and antihypertensives) are crucial to mitigate coexisting risks. Emerging evidence from recent cohort studies and clinical trials suggests that these targeted treatments can improve cardiovascular outcomes in autoimmune populations. Advanced vascular imaging and novel biomarkers now allow the earlier detection of subclinical atherosclerosis. Ongoing research into genetic predisposition, the gut microbiome, and new immune pathways offers deeper insight into risk mechanisms. By integrating current pathophysiologic understanding with evolving clinical data, these insights inform strategies for optimizing long-term cardiovascular health in patients with autoimmune disease.
    Keywords:  atherosclerosis; autoimmune diseases; cardiovascular risk; chronic inflammation; endothelial dysfunction; il-17 inhibitors; lifestyle intervention; methotrexate; risk stratification; tnf-α inhibitors
    DOI:  https://doi.org/10.7759/cureus.91897
  20. Cancer Cell Int. 2025 Oct 17. 25(1): 360
    The role of NK cells in regulating tumorimmunity: current state, challenges and future strategies.
    Weixiong Zhu, Chuanlei Fan, Yongqing Zhao, Wancheng Li, Jubao Niu, Shi Dong, Zengxi Yang, Wence Zhou.
      Natural killer (NK) cells are lymphocytes of the innate immune system. Their multifaceted cytotoxic mechanisms, coupled with their capacity to modulate immunity through cytokine secretion, underscore their pivotal role in orchestrating the immune microenvironment within tumors. This comprehensive review aims to elucidate the biological properties of NK cells, shedding light on their intricate involvement in tumor immunity. Furthermore, this review provides a comprehensive summary of the crosstalk between NK cell and other cells, and therapeutic strategies that target both T cells and NK cells, thereby offering potential avenues for therapeutic interventions. Finally, we have summarized the current status, advantages, and limitations of CAR-NK cell therapy, providing a reference for future CAR-NK cell engineering designs.
    Keywords:  CAR-NK cell therapy; Cancer immunotherapy; NK cell; T cell; Tumor immune microenvironment
    DOI:  https://doi.org/10.1186/s12935-025-03980-y
  21. Nat Biotechnol. 2025 Oct 17.
    Tumor-on-chip models of CAR-T cell therapy.
    Gordana Vunjak-Novakovic.
      
    DOI:  https://doi.org/10.1038/s41587-025-02819-1
  22. Cancers (Basel). 2025 Oct 02. pii: 3216. [Epub ahead of print]17(19):
    Eliminating REMS for CAR T-Cell Therapies: An Opportunity to Improve Access.
    Angel Luis Orosco-Ttamina, Cecilia Arana Yi, Mazie Tsang, Talal Hilal, Allison Rosenthal, Javier Munoz.
      Autologous Chimeric antigen receptor (CAR) T-cell therapies have demonstrated substantial efficacy in patients with relapsed or refractory hematologic malignancies; however, their implementation has been constrained by regulatory barriers. Risk Evaluation and Mitigation Strategies (REMS), mandated by the U.S. Food and Drug Administration (FDA), were initially implemented to mitigate risks associated with cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and other treatment-related toxicities. On 27 June 2025, the FDA removed REMS requirements for all approved B-cell maturation antigen (BCMA) and CD19-directed autologous CAR T-cell therapies, citing that current product labeling sufficiently communicates safety information. Key regulatory changes include the elimination of site certification and tocilizumab stocking requirements, a reduction in the recommended post-infusion proximity period from four weeks to two weeks, increased flexibility regarding monitoring locations, and a shortened driving restriction from eight weeks to two weeks. This review examines the rationale for the REMS requirements for CAR T-cell therapies, synthesizes contemporary safety data from clinical trials and real-world practice, and explores the implications of this regulatory shift for access to care, particularly in rural and underserved populations. The removal of REMS requirements may facilitate broader implementation of CAR T-cell therapies and alleviate logistical and institutional barriers, offering the potential to expand access while preserving patient safety.
    Keywords:  CAR T-cell therapies; REMS; access to care; health equity; patient safety
    DOI:  https://doi.org/10.3390/cancers17193216
  23. PDA J Pharm Sci Technol. 2025 Oct 16. pii: pdajpst.2025-000021.1. [Epub ahead of print]
    Challenges for Visual Inspection and Particle Control in Cell Therapy Products.
    Roman Mathaes, Antonio Burazer, Satish K Singh, John G Shabushnig, Atanas Koulov.
      Cell therapy products represent a transformative class of advanced medicinal products with unique manufacturing and quality control challenges. Unlike conventional parenteral products, cell therapies consist of living cells-typically delivered as turbid, non-filterable suspensions-which inherently complicates the control and detection of visible (VP) and subvisible particles (SvP). This review outlines the distinctive risks associated with particle generation in autologous and allogeneic cell therapies and highlights limitations of existing pharmacopeial methods for particle testing.We identify three major sources of particles in cell therapy products: the manufacturing process with often several manual manipulation steps, the single use manufacturing components, and the container closure systems. The complexity of the process is compounded by small batch sizes, short shelf-life, and complex formulations, and thus traditional sampling and visual inspection approaches have limitations in their utility. Therefore, cell therapy products often require tailored inspection strategies and supplemental process simulations.We review the current global regulatory requirements (USP <790>, Ph. Eur. 2.9.20, JP 6.06), contrast US and EU definitions for particle types, and discusses practical gaps in harmonization. We further evaluate emerging technologies like flow imaging microscopy for SvP characterization and propose optimized visual inspection strategies tailored for turbid cell suspensions. However, preventative or preemptive control, rather than end-stage inspection, is recommended as the most effective strategy. This requires systematic risk assessment, raw material control, process simulations, and supplier collaboration.The authors advocate for the development of cell therapy-specific inspection standards and call for regulatory alignment to support consistent global development and patient access.
    Keywords:  Advanced therapy medicinal products (ATMPs); Cell therapy; Flow imaging microscopy; Particulate contamination; Regulatory guidance; Subvisible particles; Visible particles; Visual inspection
    DOI:  https://doi.org/10.5731/pdajpst.2025-000021.1
  24. J Pediatr Hematol Oncol. 2025 Oct 13.
    Immunotherapy in Neuroblastoma: Mini-Review of Novel Directions and Challenges.
    Marwa Kabil, Mohamed Fawzy.
      Neuroblastoma (NB) is the most frequent pediatric extracranial solid tumor that derives from neural crest cells, driven by aberrant expression and regulation of developmental proteins. The core regulatory circuitry driving NB consists of normal human proteins that are expressed in embryonic development but largely turned off postnatally in normal tissues. The adaptive immune system is thought to be unable to target these oncofetal antigens because high-affinity self-reactive T cells are deleted during thymopoiesis. Current treatment standard in patients with HR-NB consists of an intense treatment protocol with induction chemotherapy, surgical tumor resection, consolidation therapy with autologous bone marrow transplantation, followed by retinoid as differentiating therapy, significantly increasing survival rates to about 50%. Immunotherapy further improved survival rates that included monoclonal antibody (Anti-GD2 MoAb/Dinutuximab) and cytokines (ie, IL-2 and GM-CSF, [33-37]). CAR T cells are made from autologous T cells that engineered genetically to express a CAR. In vitro engineering methods have been developed to create antigen-specific T cells without the need for isolation from tumor tissues. Leukapheresis is used to separate unspecific T cells from the patient's peripheral blood, then genetically modified with a tumor-specific recognition construct (eg, tumor-specific TCR, CAR), expanded, and enriched in culture in the presence of cytokines under good manufacturing practice (GMP) conditions, and transduced with a vector. This allowed them to produce a CAR that targets a tumor-specific antigen. Following preparatory chemotherapy, the CAR T cell product is administered into the patient.
    Keywords:  CAR; NB; T cell; immunotherapy
    DOI:  https://doi.org/10.1097/MPH.0000000000003133
  25. J Nanobiotechnology. 2025 Oct 11. 23(1): 664
    Nanomedicine targeting the PD-1/PD-L1 axis in autoimmune diseases: breaking conventional barriers to restore immune tolerance.
    Gang Xiang, Yuanxu Cui, Pan Wang, Yuantao Feng, Chengyuan Zhang, Jie Lou, Xing Zhou.
      Autoimmune diseases (ADs) arise from the breakdown of self-tolerance, leading to pathogenic immune responses against healthy tissues. The PD-1/PD-L1 immune checkpoint is pivotal for maintaining peripheral tolerance by suppressing autoreactive T cells, and its dysfunction drives the pathogenesis of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), and other ADs. Conventional approaches-including monoclonal antibodies, soluble PD-L1 fusion proteins, small-molecule or RNA regulators, and cell- or gene-based therapies-have shown promise. However, their broader application is constrained by systemic immunosuppression, off-target effects, infection and malignancy risks, and manufacturing complexities. Nanomedicine offers transformative solutions by leveraging polymeric nanoparticles, liposomes or lipid nanoparticles, extracellular vesicles (EVs), and biomimetic cell-membrane coatings to deliver PD-1/PD-L1 agonists with high spatial and temporal precision. These nanocarrier platforms enable localized checkpoint activation, co-delivery of tolerogenic agents, and improved biodistribution with reduced systemic toxicity. Here, we systematically review the structural and signaling features of the PD-1/PD-L1 axis, outlines the limitations of conventional therapeutic modalities, and highlights how nanocarrier-based approaches overcome these barriers to restore immune homeostasis in ADs. By integrating mechanistic insights with advanced delivery technologies, this review outlines a roadmap for next-generation, precision-engineered interventions aimed at reestablishing immune tolerance and improving clinical outcomes in ADs.
    Keywords:  Autoimmune disease; Immune checkpoint; Immune tolerance; Nanomedicine; Nanoparticles; PD-1/PD-L1; Therapeutic delivery.
    DOI:  https://doi.org/10.1186/s12951-025-03766-4
  26. Curr Opin Immunol. 2025 Oct 10. pii: S0952-7915(25)00151-7. [Epub ahead of print]97 102675
    Optimizing post-transplantation cell therapies to enhance graft-versus-leukemia effects in hematological malignancies.
    Simone A Minnie, Melissa M Berrien-Elliott, Melody Smith, Melinda A Biernacki, Marie Bleakley.
      Allogeneic hematopoietic cell transplantation (HCT) can cure patients with high-risk hematologic malignancies. Donor T and natural killer (NK) cells contribute to graft-versus-leukemia (GVL) effects that provide relapse protection. Post-HCT relapses often represent inadequate GVL, but alloreactive lymphocytes that confer GVL may also cause graft-versus-host-disease (GVHD). Here, we review recent developments to selectively augment GVL while minimizing GVHD. Insights into the unique mechanisms of post-HCT T cell dysfunction highlight interventions to enhance GVL-mediating T cells. Early clinical data suggest that adoptive transfer of engineered donor T cells, expressing either transgenic T cell receptors specific for minor histocompatibility antigens presented exclusively on recipient hematopoietic cells or chimeric antigen receptors binding surface proteins on malignant cells, can mitigate post-HCT relapse. NK cells, key GVL mediators after haploidentical HCT, can be induced into a highly functional memory-like state and administered to HCT recipients to enhance GVL. These innovations promise much-needed improvements in post-HCT outcomes.
    DOI:  https://doi.org/10.1016/j.coi.2025.102675
  27. Cancer Immunol Immunother. 2025 Oct 13. 74(11): 338
    CAR NK cell production from human cord blood NK progenitor cells is enhanced by stimulation of the IL-15 receptor.
    Yosuke Kogue, Shunya Ikeda, Yuto Maehara, Ryuhei Kawamoto, Makiko Suga, Shuhei Kida, Kumi Shibata, Kazuhito Tsutsumi, Hiraku Murakami, Emiko Mizuta, Yo Mizutani, Yuta Yamaguchi, Daisuke Okuzaki, Naoki Hosen.
      Cord blood (CB)-derived chimeric antigen receptor (CAR) natural killer (NK) cells have demonstrated significant antitumor efficacy. We recently reported that CB-derived CAR NK cells predominantly originate from CD7+CD56-CD34-HLA-DR-Lin- NK cell precursors in CB. Here, we demonstrate that stimulating the interleukin (IL)-15 receptor on these NK precursors enhances the production of CAR NK cells from CB cells. In CB CD56-CD34-HLA-DR-Lin- cells, the IL-15 receptor was exclusively expressed on CD7+ NK cell precursors. Using K562 feeder cells that express not only 4-1BB ligand and membrane-bound (mb) IL-21 but also mbIL-15 significantly increased the production of mature NK cells from the purified NK cell precursors or T cell-depleted CB cells. The in vitro and in vivo antitumor effects of CAR NK cells generated using K562 feeder cells that express mbIL-15 were comparable to those of CAR NK cells produced using K562 feeder cells that do not express mbIL-15. These results suggest that K562 feeder cells expressing 4-1BBL, mbIL-21, and mbIL-15 can increase the production of CAR NK cells from CB cells while maintaining their cytotoxic potential. This method could also be useful for expanding NK cells from CB for any type of adoptive NK cell therapy with or without CAR transduction.
    Keywords:  Adoptive cell therapy; CAR NK cell; Cord blood; IL-15; NK cell; Progenitor cell
    DOI:  https://doi.org/10.1007/s00262-025-04191-0
  28. Nat Biotechnol. 2025 Oct 17.
    A tumor-on-a-chip for in vitro study of CAR-T cell immunotherapy in solid tumors.
    Haijiao Liu, Estela Noguera-Ortega, Xuanqi Dong, Won Dong Lee, Jeehan Chang, Sezin Aday Aydin, Yumei Li, Yonghee Shin, Xinyi Shi, Maria Liousia, Marina C Martinez, Joshua J Brotman, Soyeon Kim, Zeyu Chen, Anni Wang, Zirui Ou, Jungwook Paek, Ju Young Park, Aidi Liu, Haonan Hu, Zebin Xiao, Dora Maria Racca, Se-Jeong Kim, G Scott Worthen, Wei Guo, Ellen Puré, Taewook Kang, Joshua D Rabinowitz, E John Wherry, Edmund K Moon, Steven M Albelda, Dan Dongeun Huh.
      Our limited understanding of cancer-immune interactions remains a critical barrier to advancing chimeric antigen receptor (CAR)-T cell therapy for solid malignancies. Here, we present a microengineered system that enables vascularization of human tumor explants and their controlled perfusion with immune cells to model the activity of CAR-T cells in the tumor microenvironment. Using vascularized human lung adenocarcinoma tumors, we first demonstrate the ability of our tumor-on-a-chip system to simulate, visualize and interrogate CAR-T cell function. We then test a chemokine-directed CAR-T cell engineering strategy in a model of malignant pleural mesothelioma and validate our findings in a matching in vivo mouse model. Finally, we describe a potential therapeutic target that can be pharmacologically modulated to increase the efficacy of CAR-T cells in lung adenocarcinoma, for which we present biomarkers identified by global metabolomics analysis. Our microphysiological system provides promising in vitro technology to advance the development of adoptive cell therapies for cancer and other diseases.
    DOI:  https://doi.org/10.1038/s41587-025-02845-z
  29. Cancers (Basel). 2025 Sep 30. pii: 3184. [Epub ahead of print]17(19):
    Tracking Inflammation in CAR-T Therapy: The Emerging Role of Serum Amyloid A (SAA).
    Ilaria Pansini, Eugenio Galli, Alessandro Corrente, Marcello Viscovo, Silvia Baroni, Nicola Piccirillo, Patrizia Chiusolo, Federica Sorà, Simona Sica.
      Background: Chimeric antigen receptor (CAR) T-cell therapy has revolutionized treatment of relapsed/refractory large B-cell lymphoma (LBCL), but its administration is often complicated by cytokine release syndrome (CRS). Interleukin-6 (IL-6) is widely used to monitor CRS, though its clinical value diminishes after tocilizumab administration. We aimed to evaluate serum amyloid A (SAA), a dynamic acute-phase reactant, as a treatment-independent biomarker of inflammation and toxicity in CAR-T recipients. Methods: This retrospective study included 43 adults with LBCL treated with axicabtagene ciloleucel. SAA and other inflammatory markers were assessed from lymphodepletion through day +11 post-infusion. CRS and ICANS were graded per ASTCT criteria. Statistical analyses included Mann-Whitney U tests, Spearman's correlation, and ROC curve analysis to evaluate predictive performance. Results: SAA levels peaked at day +4 and normalized by day +11, displaying wave-like kinetics. Levels were significantly higher in patients with any-grade CRS at early timepoints but showed no association with ICANS. SAA correlated strongly with CRP, suPAR, sST2, fibrinogen, ferritin, procalcitonin, and IL-6. Compared to IL-6, SAA was more predictive of CRS at day +2 and +4, and unaffected by tocilizumab. Baseline SAA also correlated with the mEASIX score, suggesting linkage to endothelial stress. Non-responders at 3-month PET had higher baseline SAA than responders (196.0 vs. 17.7 mg/L, p = 0.036), with ROC analysis yielding an AUC of 0.74 and an optimal threshold of 79.8 mg/L. Conclusions: SAA is a robust and dynamic marker of systemic inflammation, with potential utility in both toxicity monitoring and response prediction in the CAR-T setting. Its independence from IL-6 modulation positions it as a promising biomarker for future integration into clinical algorithms.
    Keywords:  CAR-T cell therapy; acute-phase proteins (APPs); inflammatory biomarkers; serum amyloid A (SAA)
    DOI:  https://doi.org/10.3390/cancers17193184
  30. Int Rev Neurobiol. 2025 ;pii: S0074-7742(25)00094-7. [Epub ahead of print]183 133-160
    Novel treatments for myasthenia gravis.
    Pushpa Narayanaswami, Ryan Verity, John Vissing.
      Advances in immunology over the last several years have provided insights into the pathophysiology of autoimmune diseases such as generalized myasthenia gravis (gMG). This has translated into the development of effective, rapidly acting, and targeted novel immune therapies. The two categories of new therapies available at present include the complement C5 inhibitors and the neonatal Fc receptor (FcRn) antagonists. The place of these drugs in the algorithm of MG treatment continues to evolve. Simultaneously, drug development proceeds, with other complement inhibitors, new B cell inhibitor therapy, chimeric antigen therapies and immune tolerizing therapies are in the pipeline. The treatment of gMG will continue to evolve; treatments for subgroups of patients including MuSK- ab+, seronegative and thymoma-associated MG are important areas for future development.
    Keywords:  Complement inhibitors; FcRn antagonists; Myasthenia gravis; Pathophysiology; Targeted treatment
    DOI:  https://doi.org/10.1016/bs.irn.2025.08.001
  31. Cancers (Basel). 2025 Oct 05. pii: 3237. [Epub ahead of print]17(19):
    The Evolving Role of Hematopoietic Stem Cell Transplantation in Philadelphia-like Acute Lymphoblastic Leukemia: From High-Risk Standard to Precision Strategies.
    Matteo Molica, Claudia Simio, Laura De Fazio, Caterina Alati, Marco Rossi, Massimo Martino.
       BACKGROUND: Philadelphia-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk subtype of B-cell ALL characterized by a gene expression profile similar to BCR::ABL1-positive leukemia, but lacking the BCR::ABL1 fusion gene. It is frequently associated with kinase-activating alterations, such as CRLF2 rearrangements, JAK-STAT pathway mutations, and ABL-class fusions. Patients with Ph-like ALL typically experience poor outcomes with conventional chemotherapy, underscoring the need for intensified and targeted therapeutic approaches.
    METHODS: This review summarizes current evidence regarding the role of hematopoietic stem cell transplantation (HSCT) in patients with Ph-like ALL. We analyzed retrospective cohort studies, registry data, and ongoing clinical trials, focusing on transplant indications, molecular risk stratification, measurable residual disease (MRD) status, timing of transplant, and post-transplant strategies.
    RESULTS: Retrospective data suggest that HSCT in first complete remission (CR1) may improve survival in patients with high-risk molecular lesions or MRD positivity at the end of induction. However, the lack of prospective data specific to Ph-like ALL limits definitive conclusions. Post-transplant relapse remains a challenge, and novel strategies, including the use of tyrosine kinase inhibitors or JAK inhibitors as post-HSCT maintenance therapy, are being explored. Emerging immunotherapies, such as chimeric antigen receptor (CAR) T cells, may reshape the therapeutic landscape and potentially alter the indications for transplantation.
    CONCLUSIONS: HSCT remains a crucial therapeutic option for selected patients with Ph-like ALL, particularly those with poor molecular risk features or persistent MRD. However, further prospective studies are needed to evaluate the indication for HSCT in CR1 and the potential integration of transplantation with targeted and immunotherapeutic strategies. Personalized treatment approaches based on genomic profiling and MRD assessment are essential to improve outcomes in this high-risk subset.
    Keywords:  CAR-T cell therapy; JAK-STAT pathway; Philadelphia-like ALL; genomic profiling; hematopoietic stem cell transplantation; high-risk leukemia; measurable residual disease; tyrosine kinase inhibitors
    DOI:  https://doi.org/10.3390/cancers17193237
  32. Orphanet J Rare Dis. 2025 Oct 14. 20(1): 514
    Perspectives on the FDA platform technology designation program for the approval of gene therapies: a Swiss multi-stakeholder exploratory interview study.
    Yi Han, Kelly E Ormond.
       BACKGROUND: The U.S. Food and Drug Administration (FDA)'s platform technology designation program aims to streamline the development and approval process for advanced therapy medicinal products and is anticipated to be particularly beneficial for the development of gene therapies for rare and ultra-rare diseases. This is an exploratory interview study of Swiss-based perspectives, including insights from stakeholders in industry, academia, regulation, and reimbursement. The objective of our study is to document Swiss professionals' views on the US platform designation program and to assess the acceptability and feasibility of a similar program in Europe.
    RESULTS: Participants identified benefits such as reduced redundancy in pre-clinical testing, standardization of manufacturing, and increased predictability of regulatory requirements. Concerns were raised about clinical assessment, commercialization strategies, and global regulatory alignment. Though participants anticipate it to increase innovation in the rare disease area, some raised the possibility that technologies may stagnate around a platform, or that designations may quickly become obsolete due to the speed of technological development.
    CONCLUSIONS: The introduction of the platform technology designation program in the US is a step towards increasing treatment options for ultra-rare diseases. While there is potential for platform designation to enable development in this area, its success will depend on addressing the outlined challenges.
    Keywords:  Advanced therapy medicinal products (ATMP); Drug development; Gene therapy; Pharmaceutical regulation; Platform technology; Rare disease therapy
    DOI:  https://doi.org/10.1186/s13023-025-04038-y
  33. Clin Sports Med. 2025 Oct;pii: S0278-5919(24)00160-1. [Epub ahead of print]44(4): 687-697
    Amniotic Treatments for the Treatment of Knee OA: Do They Work and Are They Safe?
    Shane A Shapiro, Jennifer R Arthurs, Caelen J Williams, Yusuf N Mufti, Jared P Sachs.
      Perinatal orthobiologics, or birth-associated products for musculoskeletal pathologies are autologous or allogeneic therapeutics sourced from biomaterials donated and recovered from healthy individuals during or around the birthing process. As popularity related to stem cell therapy for knee osteoarthritis (OA) has grown, perinatals are often purported to be a type of stem cell therapy for operative and nonoperative use. Though several such products have already been trialed in humans for knee OA, these products will require premarket authorization in the form of a biologics license application (BLA). We review the nomenclature, basic science and clinical research for perinatal orthobiologics to date.
    Keywords:  Amniotic medicine; Cartilage regeneration; Mesenchymal stem cell; Orthobiologics; Perinatal; Umbilical cord blood; Wharton’s jelly
    DOI:  https://doi.org/10.1016/j.csm.2024.12.005
  34. Curr Res Transl Med. 2025 Oct 03. pii: S2452-3186(25)00054-6. [Epub ahead of print]73(4): 103545
    Revolutionizing pediatric gene and cell therapy: The hope for lipid-based nanoparticles in blood disorders.
    Fatemeh Zahedipour, Tahereh Mohammadian Gol, Silas Wisser, Anjana Ramesh, Guillermo Ureña-Bailén, Mahmoud Reza Jaafari, Markus Mezger.
      The rapidly advancing field of lipid-based nanoparticles (LNPs) as delivery systems for nucleic acids has the potential to revolutionize treatment strategies. LNPs have demonstrated exceptional versatility in delivering genetic material and therapeutic agents to target cells. In gene and cell therapy, LNPs could serve as efficient carriers for introducing genetic materials into the cells, addressing inherited genetic disorders at their root. Their minimal toxicity and immune response make them particularly suitable for pediatric applications. Additionally, the scalability and cost-effectiveness of LNP production offer practical advantages over methods such as viral vectors and electroporation (EP), improving accessibility to advanced therapies for children worldwide. In 2018, the first FDA-approved LNP-based siRNA therapy (Patisiran/ Onpattro®) for treating hereditary amyloidosis brought attention to the feasibility of LNPs for gene therapy. Eventually, authorization and approval of the mRNA-LNP vaccines against COVID-19 (Comirnaty® of BioNTech/Pfizer and SpikeVax® of Moderna) was another milestone for the development of LNP-based nucleic acid therapies. Later, LNPs were applied successfully for the delivery of pDNA, mRNA and siRNA in many types of genetic disorders and cancers. This innovative approach offers a brighter future for pediatric healthcare, where children can look forward to healthier and more fulfilling lives. This review paper provides an overview of the applications of LNPs in gene and cell therapies with a special focus on their pre-clinical application in primary cells, including natural killer cells, T cells, and hematopoietic stem cells, highlighting LNPs' efficacy, safety profile, and potential for transforming the landscape of pediatric healthcare in the future.
    Keywords:  Blood disorders; Cell therapy; Gene editing; Gene therapy; LNP; Pediatric
    DOI:  https://doi.org/10.1016/j.retram.2025.103545
  35. Int J Mol Sci. 2025 Sep 30. pii: 9554. [Epub ahead of print]26(19):
    Overcoming Immune Therapy Resistance in Cancer Through Innate Immune Reprogramming.
    Giada Mandracci, Nardine Soliman, Nadia El Khawanky.
      Overcoming immune resistance remains the critical barrier to durable immunotherapy responses. Tumors with non-inflamed, "cold" microenvironments exclude cytotoxic lymphocytes and evade checkpoint blockade. Innate nucleic acid-sensing pathways-including TLRs, RIG-I-like RNA sensors, and the cGAS-STING DNA-sensing axis-can recondition this hostile landscape by licensing dendritic cells, restoring antigen presentation, and recruiting effector T and NK cells. In this review, we synthesize mechanistic insights into how these receptors function across tumor and immune compartments and evaluate recent translational advances spanning small-molecule and nucleic acid agonists, engineered delivery systems, and clinical trials. We highlight challenges that have limited clinical impact, including pathway silencing, systemic toxicity, and lack of predictive biomarkers, while emphasizing emerging solutions such as tumor-intrinsic targeting, CAR-T/NK engineering, and biomarker-guided patient selection. By integrating innate activation into rational combination regimens, innate immune reprogramming offers a blueprint to convert resistant disease into one susceptible to durable immune control.
    Keywords:  MDA5; RIG-I; STING pathway; TLRs; cancer immunotherapy; dendritic cells; immune therapy resistance; innate immunity; nucleic acid sensing; pattern recognition receptors; tumor microenvironment
    DOI:  https://doi.org/10.3390/ijms26199554
  36. Expert Rev Clin Immunol. 2025 Oct 13.
    Inborn errors of immunity with atopic phenotypes: what we know so far.
    Ivan Taietti, Francesca Cenzato, Ilaria Brambilla, Gian Luigi Marseglia, Amelia Licari, Riccardo Castagnoli.
       INTRODUCTION: Inborn errors of immunity with atopic phenotypes (IEIwA) represent a growing and complex subset of monogenic disorders that manifest primarily through severe and multifaceted allergic symptoms. These conditions bridge the fields of immunodeficiency and atopy, posing significant diagnostic and therapeutic challenges.
    AREAS COVERED: A literature search was performed via the online database PubMed, including all publication years 2021-2024, with the objective of identifying the most recent advancements in the field of IEIwA. This review provides an updated synthesis of the immunogenetic mechanisms underlying IEIwA, categorizing them by pathophysiological pathways, including impaired T cell receptor signaling, cytokine dysregulation, T cell repertoire restrictions, regulatory T cell dysfunction, metabolic abnormalities, and skin barrier defects. Advances in genomic technologies, especially whole exome/genome sequencing, have refined the classification and recognition of these disorders. Moreover, the review highlights red flags that may aid in differentiating monogenic IEIwA from multifactorial allergic conditions. Emerging targeted therapies, such as monoclonal antibodies and small molecules, offer new avenues for precision medicine, though curative treatments like hematopoietic stem cell transplantation remain essential for many conditions.
    EXPERT OPINION: This review underscores the need for heightened awareness, early recognition, and tailored management strategies to improve outcomes in patients with IEIwA.
    Keywords:  Allergy; Atopy; Immune dysregulation; Inborn Errors of Immunity; Inborn errors of immunity with atopic phenotypes; Primary Atopic Disorders; Primary Immunodeficiencies; Severe Atopic Diseases
    DOI:  https://doi.org/10.1080/1744666X.2025.2575361
  37. Mol Oncol. 2025 Oct 13.
    Intein-based modular chimeric antigen receptor platform for specific CD19/CD20 co-targeting.
    Pablo Gonzalez-Garcia, Noelia Moares, Wenjie Yi-He, Rosa Luna-Espejo, Ricardo Fernandez-Cisnal, Javier Ocaña-Cuesta, Juan P Muñoz-Miranda, Antonio Gabucio, Cecilia M Fernandez-Ponce, Francisco Garcia-Cozar.
      Development of chimeric antigen receptor T-cell therapy has revolutionized the treatment of B-cell malignancies, although challenges such as antigen escape and tumor heterogeneity often decrease treatment success. Modular CARs targeting multiple antigens have been proposed as an interesting solution to address these challenges by reducing the likelihood of tumor cells evading treatment through the loss of a single antigen. In this study, we present a new modular CAR platform, termed CARtein, which takes advantage of intein interactions to jointly target CD19 and CD20 antigens. We demonstrate that the CARtein system, which features a universal CAR signaling backbone that covalently binds to specific scFv-intein recognition partners, generates fully active CARs. Functionality was validated using Raji cells and K562 cells expressing CD19 and/or CD20, observing significant T cell activation through NFAT and NFκB promoter activity and CD69 upregulation. Overall, our study lays the foundation for the establishment of a new way to target multiple antigens through a universal and inert CAR backbone with highly specific activation.
    Keywords:  acute lymphoblastic leukemia (ALL); chimeric antigen receptor (CAR); immunotherapy; intein; modular CAR; non‐Hodgkin's lymphoma (NHL)
    DOI:  https://doi.org/10.1002/1878-0261.70146
  38. Semin Oncol Nurs. 2025 Oct;pii: S0749-2081(25)00144-5. [Epub ahead of print]41(5): 151951
    Experiences of Patients and Family Caregivers After Chimeric Antigen Receptor T-Cell Therapy: A Qualitative Study.
    Britt Snoek, Wendy H Oldenmenger, Susanne M van Hooft, Pim G N J Mutsaers.
       OBJECTIVES: This study aimed to explore the experiences and counseling needs of family caregivers and patients with relapsed or refractory B-cell lymphoma after CAR T-cell therapy.
    METHODS: A qualitative descriptive design was used. Twelve interviews were conducted with patients individually or together with their family caregiver between December 2021 and March 2022. The interviews were transcribed verbatim, coded and a qualitative thematic analysis was carried out.
    RESULTS: Five themes that influenced experiences and counseling needs after CAR T-cell therapy were identified: (1) emotional impact, (2) impact on daily life, (3) individual coping strategies, (4) social support, and (5) professional care. Most patients experienced fear of disease progression and infections. Others experienced CAR T-cell therapy as easier than previous treatment with chemotherapy followed by an autologous stem cell transplant. Both patients and family caregivers emphasized the importance of their support system and clear information about the treatment. Some family caregivers found the treatment pathway more challenging than patients, especially when neurological side-effects occurred.
    CONCLUSION: Patients need personalized counseling before, during, and after treatment. Our study helps to identify important themes to consider during (after)care, where nurses play a crucial role. Family caregivers are important and may experience treatment differently. Therefore, they may need different counseling. Early identification of personal coping strategies can be a starting point for improving care.
    IMPLICATIONS FOR NURSING PRACTICE: CAR T-cell therapy can be a complex pathway and has a unique profile of toxicity. Family caregivers play an important role. Both can experience an impact on emotional well-being, daily life and social functioning. Hematology nurses should be aware of the potential impact of CAR T-cell therapy with the consideration that every person has different coping strategies and keep in mind that each person has different coping strategies and may need different counseling.
    Keywords:  CAR T-cell therapy; Counseling needs; Family caregiver; Hematological malignancies; Patient-reported outcomes; Quality of life
    DOI:  https://doi.org/10.1016/j.soncn.2025.151951
  39. Methods Cell Biol. 2025 ;pii: S0091-679X(25)00088-3. [Epub ahead of print]199 191-220
    Analysis of single-cell TCR repertoires and gene expression from multi-modal scRNA-seq data.
    Christina Plattner, Gregor Sturm, Dietmar Rieder.
      Single-cell RNA and T-cell receptor (TCR) sequencing are powerful tools for dissecting T-cell diversity and function with unprecedented resolution. Analyzing transcripts and TCR sequences expressed by individual T-cells, enables comprehensive characterization of T-cell repertoires, antigen specificity and clonal dynamics which is fundamental in understanding the adaptive immune responses in various physiological and pathological conditions, including cancer, autoimmune diseases, and infectious diseases. To perform integrative analyses of multi-modal data from single-cell RNA and TCR sequencing experiments specialized bioinformatic tools are required. Here we exemplify the application of Scirpy, a versatile Python package specifically designed for single-cell TCR sequencing analysis, which streamlines the processing and analysis of TCR sequencing data. Scirpy offers a user-friendly framework for tasks like repertoire characterization, visualization, and clonotype identification. Moreover, Scirpy integrates seamlessly with other single-cell analysis tools from the scverse ecosystem, enabling comprehensive multi-modal data integration and downstream analyses.
    Keywords:  Multi-modal scRNA-seq; Scirpy; T-cell diversity; T-cell receptor sequencing; clonotypes; immune repertoire characterization; single-cell RNA sequencing
    DOI:  https://doi.org/10.1016/bs.mcb.2025.03.007
  40. Int J Nanomedicine. 2025 ;20 12117-12175
    Biological Nanotherapeutics Derived From Human Umbilical Cord Mesenchymal Stem Cells: Mechanisms and Translational Potential in Multisystem Therapies for Regeneration and Oncology.
    Ruirui Zhang, Zhipeng Xu, Shijie Xu, Rong Li, Hui Qian.
      Extracellular vesicles derived from human umbilical cord mesenchymal stem cells (hucMSCs-EVs) represent a promising cell-free therapeutic strategy in regenerative medicine and oncology. These vesicles exhibit low immunogenicity, are non-invasively sourced, and possess multiple regenerative properties. This review examines the biogenesis of EVs and distinctive features of hucMSCs-EVs compared to other MSC-derived EVs. We explore their molecular mechanisms and preclinical efficacy across multiple organ systems, including nervous, locomotor, respiratory, circulatory, digestive, urinary, reproductive, and hormonal. HucMSCs-EVs demonstrate a dual role: promoting tissue repair through immunomodulation, angiogenesis, and anti-apoptosis in regenerative contexts, while exerting microenvironment-dependent pro- or anti-tumor effects in oncology. Despite promising preclinical results, clinical translation requires overcoming challenges such as standardized production, delivery optimization, and safety evaluation. As multifunctional biological nanotherapeutics, hucMSCs-EVs show transformative potential for treating multisystem diseases. However, their universal applicability is constrained by heterogeneity, biodistribution limitations, and environment-dependent efficacy. Future work should focus on scalable manufacturing, targeted delivery strategies, and rigorous clinical trials to realize their full therapeutic potential.
    Keywords:  EVs; biogenesis; cancer therapy; extracellular vesicles; hucMSCs; human umbilical cord mesenchymal stem cells; multisystem therapeutics; regenerative medicine; translational challenges
    DOI:  https://doi.org/10.2147/IJN.S550390
  41. Sci Adv. 2025 Oct 17. 11(42): eadw3571
    Enhanced FOS expression improves tumor clearance and resists exhaustion in NR4A3-deficient CAR T cells under chronic antigen exposure.
    Peidi Yin, Jigui Yang, Yiyang Jiang, Linhong Han, Tianchen Xiong, Haofei Liu, Yiliang Fang, Wenchen Ruan, Jiayang Wu, Longjuan Chen, Leyong Tan, Yonglin Zuo, Xin Wu, Fangyuan Mao, Rui Huang, Xindong Liu, Xiu-Wu Bian.
      The dysfunction of chimeric antigen receptor (CAR) T cells in the tumor microenvironment is a major obstacle to their therapeutic efficacy against solid tumors. Through single-cell RNA sequencing analysis of tumor-infiltrating T cells from patients with glioma, NR4A family genes were identified as closely associated with T cell exhaustion and were coexpressed with dysfunctional genes HAVCR2 and TIGIT. Notably, CAR T cells with NR4A3 knockdown exhibited enhanced cytotoxic activity against tumors, leading to improved tumor clearance and prolonged survival in vivo. However, the promoted antiexhausted phenotype diminished with prolonged tumor burden. This decline in T cell function correlates with the compensatory down-regulation of FOS induced by chronic antigen exposure following NR4A3 knockdown. Overexpressing FOS alongside NR4A3 knockdown robustly boosted the antitumor responses of CAR T cells by skewing their phenotypes and transcriptional profiles away from exhaustion and toward increased effector function. These findings offer a promising strategy for the clinical modification of CAR T cell therapy.
    DOI:  https://doi.org/10.1126/sciadv.adw3571
  42. Stem Cell Rev Rep. 2025 Oct 15.
    From Biological Waste to Therapeutic Resources: A Comprehensive Review of Stem Cell Sources, Characterization, and Biomedical Potentials.
    Beatrice Camia, Manuela Monti.
      The concept of utilizing biological waste as a resource dates back centuries, with early practices in traditional medicine repurposing discarded tissues for healing purposes. In recent decades, advances in stem cell biology have revitalized this concept by identifying multipotent stem cells within various waste materials, including urine, adipose tissue, follicular fluid, umbilical cord blood, fetal annexes, menstrual blood, and dental pulp byproducts. These sources offer a minimally invasive, ethically sound, and cost-effective alternative to conventional stem cell harvesting methods. Stem cells derived from waste materials exhibit robust proliferative abilities and multilineage differentiation potential, positioning them as valuable tools for regenerative medicine, tissue engineering, and personalized therapeutic applications. Clinical studies highlight their promise. For example, mesenchymal stem cells from adipose tissue and umbilical cord blood have shown safety and some effectiveness in early trials. These studies report improvements of up to 30-40% in recovery scores for osteoarthritis and ischemic heart disease, as well as a 20-35% decrease in inflammatory markers for autoimmune disorders. Cord blood stem cell transplants have shown 70-90% survival rates in children with blood cancers. This underscores the clinical potential of waste-derived stem cells. However, regulatory issues limit broader use. Agencies like the U.S. Food and Drug Administration and the European Medicines Agency classify many processing methods, especially enzymatic digestion, as "more-than-minimal manipulation." This triggers strict requirements for Good Manufacturing Practice, clinical validation, and safety checks. These rules protect donors, ensure consistency, and check long-term safety. However, they also slow down clinical adoption. This review describes the history and recent advances in recycling biological waste to obtain stem cells, operating within the theoretical framework that positions waste-derived materials as viable sources for regenerative medicine. It highlights how these developments are transforming biomedical research and clinical care.
    Keywords:  ATMP regulation; Biological waste; Extracellular vesicles; GMP manufacturing; Mesenchymal stem cell; Multilineage differentiation; Regenerative medicine
    DOI:  https://doi.org/10.1007/s12015-025-10989-3
  43. Immunology. 2025 Oct 14.
    Gamma Delta T Cells in the Tumour Microenvironment: A Double-Edged Sword.
    Mohammad Javad Hayati, Javad Yaghmoorian Khojini, Fatemeh Khara, Arezoo Heydari, Nasim Vousooghi, Seyed Mohammad Sadra Abootorabi, Maryam Barkhordar, Mohammad Javad Mousavi.
      Gamma delta (γδ) T cells represent a distinct group of lymphocytes capable of functioning in both pro-tumorigenic and anti-tumorigenic capacities inside the tumour microenvironment (TME). Their unique ability for MHC-independent recognition of stress-induced antigens enables swift immunosurveillance, positioning them as a double-edged sword in cancer immunosurveillance. This review critically investigates this dichotomy, analysing their potent tumour-suppressive roles, which are primarily driven by subsets like Vγ9Vδ2 T cells through cytotoxic mechanisms such as perforin and granzyme release and the secretion of pro-inflammatory cytokines like interferon-gamma (IFN-γ). Conversely, we explore their tumour-promoting functions, wherein subsets such as IL-17-producing Vδ1 T cells can foster an immunosuppressive milieu, angiogenesis, and immune evasion. The function of γδ T cells is extensively examined, emphasising how the TME critically dictates this functional polarisation. This duality presents both a significant challenge and a promising opportunity for cancer immunotherapy. Future investigations and emerging therapeutic strategies are discussed, including the use of adoptive cell therapies with CAR-γδ T cells and combination approaches with immune checkpoint inhibitors, which aim to overcome the TME's suppressive barriers. A deeper understanding of the molecular switches that govern γδ T cell function is paramount for devising effective next-generation therapies that can exploit their full anti-cancer potential.
    Keywords:  Vγ9Vδ2 T cells; cancer immunotherapy; gamma delta (γδ) T cells; immune evasion; regulatory T cells; tumour microenvironment
    DOI:  https://doi.org/10.1111/imm.70035
  44. Cancers (Basel). 2025 Oct 07. pii: 3246. [Epub ahead of print]17(19):
    T-Cell Engagers in Acute Myeloid Leukemia: Molecular Targets, Structure, and Therapeutic Challenges.
    Hunter Daws, Kate Gallinero, Amanda Singh, Sanela Bilic.
      The treatment of acute myeloid leukemia (AML) remains challenging, largely due to high relapse rates following standard therapies. T-cell engagers (TCEs) offer a promising immunotherapeutic approach by redirecting T cells to recognize and kill AML cells. These therapeutic proteins bind CD3 to T cells and a tumor-associated antigen to AML cells, facilitating targeted immune activation. While CD33 and CD123 are the most commonly targeted AML antigens, others such as CD135, CD38, and CLEC12A/CLL-1 are being evaluated in preclinical and clinical studies. In parallel, various TCE formats-including BiTEs, DuoBodies, DARTs, and DARPin-based constructs-have been developed to optimize pharmacokinetics, stability, and immune engagement. Despite the growing number of TCEs entering clinical evaluation, none have advanced beyond early Phase (I/II) trials, primarily due to the lack of optimal target antigens and challenges in balancing antileukemic activity with the risks of immune-related toxicities such as cytokine release syndrome (CRS). This review aims to summarize the current landscape of TCE development in AML, highlighting key targets, formats, and challenges.
    Keywords:  BiTE; CD123; CD33; DARPin; DART; DuoBody; T-cell engagers; TandAb; acute myeloid leukemia; cytokine release syndrome
    DOI:  https://doi.org/10.3390/cancers17193246
  45. Adv Drug Deliv Rev. 2025 Oct 11. pii: S0169-409X(25)00197-8. [Epub ahead of print]227 115712
    Cell-based treatments of lung diseases: overview and outlook.
    A M van der Does, L V Schledorn, R Olmer.
      Chronic lung diseases (CLD), including chronic obstructive pulmonary disease (COPD), pulmonary fibrosis and pulmonary hypertension, represent a significant health burden worldwide and their incidence is steadily increasing. Specifically, COPD and lung fibrosis lead to progressive tissue loss, particularly in the alveolar region, and can currently mainly be treated symptomatically, with some therapies slowing down progression. Regenerative cell therapy offers promising approaches to repair and restore permanently damaged lung tissue, focusing on different cell types such as epithelial, stromal, endothelial and pluripotent stem cells. Despite positive results in preclinical studies and initial clinical trials, large successes are lagging behind. This shows that there is still a considerable need for further research into e.g. optimal conditions, including cell sources and administration methods in humans. Challenges such as successful translation of beneficial strategies in animal models, safety risks of new strategies and the control of cell localization need to be addressed in more detail. Future research approaches should therefore support the identification of suitable cell types, the improvement of cell protection strategies and the development of predictable human models to enable the successful clinical application of regenerative cell therapy in CLD.
    Keywords:  Cell therapy; Chronic lung disease; Pluripotent stem cells;; Regeneration; Repair; Tissue
    DOI:  https://doi.org/10.1016/j.addr.2025.115712
  46. J Inflamm Res. 2025 ;18 13925-13943
    A Conceptual Review of Gut, Skin, and Oral Microbiota in Autoimmune Bullous Diseases: From Dysbiosis to Therapeutic Potential.
    Hanxiao Xu, Sizhe Li, Sihan Liu, Ya-Gang Zuo.
      Autoimmune bullous diseases (AIBDs), including pemphigus and bullous pemphigoid, are chronic inflammatory skin disorders characterized by dysregulated immune responses mediated by autoantibodies that target adhesion molecules in the skin and mucous membranes. Emerging evidence highlights the pivotal role of host microbiota dysbiosis in AIBDs pathogenesis, offering novel insights into disease mechanisms and therapeutic strategies. This review systematically synthesizes the current findings on gut, skin, and oral microbiota alterations in AIBDs, emphasizing their contributions via the gut-skin axis, microbial metabolites, and pathogen-host interactions. Key innovations include uncovering how specific pathogenic and commensal microbiota influence disease progression through intriguing skin inflammation and direct barrier impairment. Notably, while some microbiota changes overlap with other dermatoses, AIBDs exhibit distinct microbial signatures associated with their unique autoimmune mechanisms targeting adhesion molecules. Furthermore, we explore microbiota-targeted therapies, such as antibiotics, probiotics, and fecal microbiota transplantation, and demonstrate their potential to restore microbial homeostasis and improve clinical outcomes. By integrating multi-omics evidence and clinical data, this review bridges mechanistic insights with translational applications, proposing microbiota modulation as a promising adjunctive therapy for AIBDs. Our analysis identifies critical research gaps, including the need for longitudinal studies and personalized microbial interventions, positioning this review at the forefront of microbiome-inflammation-autoimmunity research.
    Keywords:  autoimmune bullous diseases; gut-skin axis; microbial metabolites; microbiota dysbiosis; microbiota-targeted therapies; skin inflammation
    DOI:  https://doi.org/10.2147/JIR.S551394
  47. Biomol Ther (Seoul). 2025 Oct 14.
    Glucose-Enhanced Cryopreservation of hCAR-T Cells: Improved Recovery and Reduced Apoptosis.
    Sang-Eun Jung, Youngchae Moon, Minji Lim, Hyungwoo Jeong, Hyungseok Seo.
      Human chimeric antigen receptor T (hCAR-T) cells are highly potent cellular therapeutics, but their clinical utility depends on stable long-term preservation due to high production costs and lengthy manufacturing processes. Cryopreservation is essential for ensuring the quality and logistics of these therapies. However, current commercial cryoprotectants such as CellBanker® are limited by high cost, undisclosed composition, and lack of flexibility for optimization. This study aimed to evaluate defined sugar-based cryoprotectants-trehalose, sucrose, and glucose-as potential alternatives for hCAR-T cell preservation. hCAR-T cells were cryopreserved using various concentrations of the three sugars in combination with DMSO. Post-thaw evaluations included viability, recovery, apoptosis, proliferative capacity, and immunophenotypic analysis. At 18 h after thawing, glucose 50 mM significantly improved recovery (1.03 ± 0.29 vs. 1.59 ± 0.20×10⁶ cells) and reduced apoptosis (52.58 ± 7.31% vs. 39.50 ± 2.16%) compared with DMSO alone. These results were comparable to, and in some cases exceeded, those obtained with the commercial product CellBanker®. Moreover, glucose at 50 mM exhibited approximately 1.9-fold higher cell proliferation after three days of culture compared to CellBanker®, while preserving a stable CD4+/CD8+ ratio and central memory T cell (TCM) profile. These findings indicate that sugar-based cryoprotectants, particularly glucose at 50 mM, can support post-thaw survival and function of hCAR-T cells. Given their defined composition, lower cost, and comparable efficacy, sugar-based formulations represent promising alternatives to commercial cryopreservation agents for advanced cell therapies.
    Keywords:  Cryopreservation; Glucose; Human CAR-T cells; Sugar-based cryoprotectants
    DOI:  https://doi.org/10.4062/biomolther.2025.144
  48. Cytokine Growth Factor Rev. 2025 Oct 10. pii: S1359-6101(25)00135-2. [Epub ahead of print]86 71-82
    Reprogramming natural killer cells in the tumor microenvironment: Challenges and therapeuticopportunities.
    Wenxue Ma, Sheldon Morris, Catriona Jamieson.
      Natural killer (NK) cells are central effectors of innate immunity, traditionally viewed as rapid responders capable of recognizing and eliminating malignant or virus-infected cells without prior sensitization. Their combined capacity to mediate direct cytotoxicity and secret cytokines has established NK cells as attractive and powerful effectors in immunotherapeutic strategies, including CAR-NK cell therapies and cytokine-based stimulation. However, recent discoveries challenge the notion of NK cells as uniformly antitumor. In certain tumor microenvironments (TME), NK cells undergo functional reprogramming into regulatory or dysfunctional phenotypes that can suppress CD8⁺ T cell activities and contribute to resistance against immune checkpoint blockade (ICB). These suppressive tumor-associated NK cells (TANKs) may limit antitumor immunity through cytokine competition, immune editing, and modulation of dendritic cell (DC) function. This review critically examines the dual roles of NK cells in cancer immunity, highlighting both their cytotoxic potential and their emerging immunoregulatory functions. We discuss how cytokine signaling, spatial distribution, and tumor-induced plasticity shape NK cell behavior, and evaluate the therapeutic implications of these findings. By addressing a critical knowledge gap in NK cell biology and integrating mechanistic insights with clinical perspectives, this review provides a framework for leveraging or reprogramming NK cells to enhance cancer immunotherapy outcomes.
    Keywords:  Cancer immunotherapy; Cytokine signaling; Functional plasticity; Immune checkpoint blockade (ICB); Natural killer (NK) cells; Tumor microenvironment (TME)
    DOI:  https://doi.org/10.1016/j.cytogfr.2025.10.001
  49. PLoS One. 2025 ;20(10): e0334543
    Conformation of HLA-E/peptide complex guides interaction with two novel HLA-E receptors: Stabilin 1 and 2.
    Tom A W Schoufour, Linda Voogd, Kees L M C Franken, Tom H M Ottenhoff, Ruud H M Wijdeven, Simone A Joosten.
      Human leukocyte antigen E (HLA-E) communicates cellular health to natural killer (NK) cells through presentation of peptides derived from the leader sequence of classical major histocompatibility complex class I (MHC-I), inhibiting NK cell activation and lysis of healthy cells. Besides this canonical role, HLA-E can also present peptides from pathogens such as Mycobacterium tuberculosis (Mtb) to T cells and can inhibit phagocytosis by engaging with LILRB1/2. To identify additional HLA-E binding surface molecules, we utilized a CRISPR/Cas9 activation screen with HLA-E tetramers, which identified Stabilin (STAB)1 and STAB2 as novel interactors. This interaction depended on the nature of the peptide/HLA-E complex, whereby high affinity peptides did not permit the interaction while low affinity peptides did. Functionally, expression of STAB1 or STAB2 on THP-1 monocytes increased phagocytic uptake of HLA-E coated microbeads. These results provide the first evidence of an interaction between Stabilin receptors and specific HLA-E conformations.
    DOI:  https://doi.org/10.1371/journal.pone.0334543
  50. Global Health. 2025 Oct 14. 21(1): 57
    Pharmaceutical access in Brazil: challenges and opportunities.
    Cristina M Ruas, Ronaldo Portela, Francisco de Assis Acurcio, Juliana Alvares-Teodoro, Augusto Afonso Guerra Júnior, Aaron S Kesselheim.
       BACKGROUND: Brazil faces challenges in ensuring equitable access to prescription drugs for its population. Socioeconomic disparities contribute to health inequalities, impacting access to health care services, including medicines. Brazil's Unified Health System aims to provide universal health care coverage, but only 30·5% of people obtain all of their prescribed medications through public channels free of charge. The objective is to characterize the Brazilian pharmaceutical market to better understand the underlying factors affecting medicine accessibility.
    METHODS: We conducted a literature review to assess the current state of the pharmaceutical market and prescription drug access in Brazil.
    FINDINGS: The Brazilian pharmaceutical market is extensive but highly concentrated, characterized by low investment in original research and development (R&D) and a heavy reliance on imported active pharmaceutical ingredients. Challenges include vulnerability to economic and external factors. Additionally, high medicine prices, prioritization of production of expensive new medicines over those for prevalent diseases, and shortages contribute to inequalities in access. Regulatory issues, underfunding of health care, and legal discrepancies exacerbate these challenges but also present opportunities for reform.
    INTERPRETATION: The policymakers should prioritize enhancing R&D investment, reducing dependency on international markets, strengthening regulatory frameworks, and improving health care system efficiency to ensure reliable access to essential medicines.
    Keywords:  Drug costs; Health care financing; Health inequalities; Health systems; Pharmaceutical industry
    DOI:  https://doi.org/10.1186/s12992-025-01141-4
  51. Int J Mol Sci. 2025 Oct 03. pii: 9659. [Epub ahead of print]26(19):
    Utilization of Stem Cells in Medicine: A Narrative Review.
    Banu Ismail Mendi, Rahim Hirani, Alyssa Sayegh, Mariah Hassan, Lauren Fleshner, Banu Farabi, Mehmet Fatih Atak, Bijan Safai.
      Regenerative medicine holds significant promise for addressing diseases and irreversible damage that are challenging to treat with conventional methods, making it a prominent research focus in modern medicine. Research on stem cells, a key area within regenerative medicine due to their self-renewal capabilities, is expanding, positioning them as a novel therapeutic option. Stem cells, utilized in various treatments, are categorized based on their differentiation potential and the source tissue. The term 'stem cell' encompasses a broad spectrum of cells, which can be derived from embryonic tissues, adult tissues, or generated by reprogramming differentiated cells. These cells, applied across numerous medical disciplines including cardiovascular, neurological, and hematological disorders, as well as wound healing, demonstrate varying therapeutic applications based on their differentiation capacities, each presenting unique advantages and limitations. Nevertheless, the existing literature lacks a comprehensive synthesis examining stem cell therapy and its cellular subtypes across different medical specialties. This review addresses this lacuna by collectively categorizing contemporary stem cell research according to medical specialty and stem cell classification, offering an exhaustive analysis of their respective benefits and constraints, thereby elucidating multifaceted perspectives on the clinical implementation of this therapeutic modality.
    Keywords:  cell therapy; embryonic tissue; pluripotency; regenerative medicine; stem cells
    DOI:  https://doi.org/10.3390/ijms26199659
  52. Immunotherapy. 2025 Oct 17. 1-14
    How should we choose optimal salvage treatments following BCMA-directed CAR T-cell therapy?
    Arvind Suresh, Darren Pan, Jodi Lipof, Anupama Kumar, Shagun Arora, Peter Sayre, Jeffrey Wolf, Thomas Martin, Ajai Chari, Alfred Chung.
      B-cell maturation antigen (BCMA) directed chimeric antigen receptor T-cell therapy (CAR-T) has transformed the treatment of relapsed/refractory multiple myeloma (RRMM), yet relapse is still common for most patients. A variety of different salvage treatment strategies have been studied in the last several years to address several resistance mechanisms that lead to relapse after BCMA CAR-T. To date, there are no clear guidelines regarding treatment sequencing strategies for salvage therapy. This review will investigate the current landscape of available salvage therapies and data supporting their use, as well as possible treatment sequencing strategies to maximize clinical outcomes in this difficult-to-treat population.
    Keywords:  BCMA; GPRC5D; Multiple myeloma; chimeric antigen receptor T-cells (CAR T-cells); relapse; salvage therapy
    DOI:  https://doi.org/10.1080/1750743X.2025.2571392
  53. Clin Transl Med. 2025 Oct;15(10): e70444
    Umbilical cord blood-derived cytotoxic T lymphocytes target melanoma via HLA-A2-restricted tumour antigens.
    Jiaji Liang, Xiao Jiang, Xi He, Zhiqin Dong, Jinqiang Lu, Shuxian Jiang, Hengyu Du, Haoran Mao, Songtao Luo, Xifeng An, Hongwei Liu.
       BACKGROUND: Melanoma is recognized as a highly malignant cancer with a generally poor prognosis, underscoring the critical need for effective therapeutic strategies. Adoptive cell therapy has emerged as a promising modality to improve treatment outcomes in melanoma. For endogenous cell therapy (ECT), peripheral blood (PB) has traditionally served as the primary cell source. However, the potential of umbilical cord blood (UCB) as an alternative source for ECT remains unclear. Furthermore, the repertoire of TCRs remains limited. These deficiencies impede the optimization and broader application of ECT for melanoma, highlighting the necessity for focused investigations to resolve these issues.
    METHODS: To evaluate the effects of HLA-A2 restricted antigen-specific CD8⁺ T cells on melanoma cells, the cytotoxic activity of CD8⁺ T cells derived from UCB and PB were conducted in vivo and in vitro assays. Single-cell RNA sequencing combined with TCR V(D)J sequencing was employed to characterize cellular composition and quantify the frequencies of specific TCR clonotypes. The generation probability and peripheral occurrence probability of antigen-specific CD8⁺ TCR sequences from UCB and PB were computed using the Simple Olga Sonia algorithm. Finally, molecular docking simulations were conducted to predict the binding affinity between isolated TCRs and pMHC.
    RESULTS: No significant differences were observed in the cytotoxic effects mediated by antigen-specific CD8⁺ T cells derived from UCB versus PB. Phenotypic analysis revealed that PB-derived antigen-specific CD8⁺ T cells were predominantly effector and proliferating cells, whereas those from UCB consisted largely of memory cells. TCR sequencing identified a greater diversity of antigen-specific TCR clonotypes in PB, meanwhile UCB-derived TCRs exhibited strong pMHC binding. Molecular docking simulations confirmed high binding affinity between pMHC and TCR clones isolated from both sources.
    CONCLUSIONS: Antigen-specific CD8⁺ T cells from UCB and PB display comparable cytotoxic efficacy against melanoma, albeit with distinct compositional profiles of antigen-specific CD8⁺ T cell subsets. Candidate TCRs can be effectively activated by the tumor-associated antigens MART1 and gp100. This activation promotes the expansion of the available TCR repertoires, thereby mitigating the previous constraint of a limited TCR library.
    KEY POINTS: Endogenous T-celltherapy for melanoma has used adult peripheral blood as the cell source andachieved certain results, but the cellular components of effector T cells werenot clear. At the same time, it was not clear whether umbilical cord bloodcould be used as a cell resource bank for endogenous T-cell therapy. This studydemonstrated that T cells from umbilical cord blood can be used as a cellresource bank for endogenous T-cell therapy. It further clarified that thereare different components of antigen-specific T cells in umbilical cord bloodand peripheral blood. Antigen-specific T cells from peripheral blood are mainlyproliferative T cells, while those from umbilical cord blood are mainlyeffector T cells and memory T cells. Finally, TCR sequencing was used to obtainTCRs that can target melanoma, expanding the corresponding TCR database.
    Keywords:  MART1; antigen‐specific TCR; cancer immunotherapy; gp100; melanoma; umbilical cord blood
    DOI:  https://doi.org/10.1002/ctm2.70444
This page is being maintained by Thomas Krichel. It was last updated on 2025‒10‒20 at 10:59.