bims-carter Biomed News
on CAR-T Therapies
Issue of 2025–09–14
fifty-one papers selected by
Luca Bolliger, lxBio
  1. In vivo CAR-T cell therapy: New breakthroughs for cell-based tumor immunotherapy.
  2. Expanding Immunotherapy Beyond CAR T Cells: Engineering Diverse Immune Cells to Target Solid Tumors.
  3. Overcoming solid-tumor barriers: armored CAR-T cell therapy.
  4. Expanding the frontier of CAR therapy: comparative insights into CAR-T, CAR-NK, CAR-M, and CAR-DC approaches.
  5. Impact of Serum/Xeno-Free Medium and Cytokine Supplementation on CAR-T Cell Therapy Manufacturing in Stirred Tank Bioreactors.
  6. Touch of youth: Mechanosensing expands stem-like CAR-T cells.
  7. Health-Related Values Discussions With Patients Receiving Allogeneic and Autologous Stem Cell Transplant and Chimeric Antigen Receptor Therapy (CAR-T): Implementation of an Early Nurse Practitioner-Led Primary Palliative Care Intervention.
  8. Comparative efficacy and safety of PSCA CAR-engineered Vδ1 γδ T cells for immunotherapy of pancreatic cancer.
  9. Systematic engineering of TROP2-targeted CAR T-cell therapy overcomes resistance pathways in solid tumors.
  10. Case Report: Remission of a patient with complex combination of autoimmune diseases by anti-CD19 CAR-T cell therapy.
  11. Natural born Killers: Harnessing NK cells to treat cancer.
  12. Advancing CAR T-Cell Therapy in Solid Tumors: Current Landscape and Future Directions.
  13. Overcoming barriers to referral for CAR T-cell therapy in patients with non-Hodgkin aggressive B-cell lymphomas: A Delphi consensus.
  14. Sequential intrathoracic injection and intravenous infusion of BCMA CAR-T cells in a patient with relapsed/refractory primary plasma cell leukemia.
  15. Multiplex engineering using microRNA-mediated gene silencing in CAR T cells.
  16. Engineering of Humanized PSMA-Directed CAR T Cells for Potent and Specific Elimination of Prostate Cancer Cells.
  17. Adoptive cellular therapies in multiple myeloma.
  18. From the Lab to the Plate: How Gut Microbiome Science is Reshaping Our Diet.
  19. Exosomes in Disease Therapy: Plant-Derived Exosome-Like Nanoparticles Current Status, Challenges, and Future Prospects.
  20. Endothelial Injury Following CAR-T Cell Immunotherapy for Hematological Malignancies.
  21. Exploring research trends in cancer immunotherapy via single-cell technologies: a scientometric perspective.
  22. Stem Cell-Derived Exosomes: A Comprehensive Review of Biomedical Applications, Challenges, and Future Directions.
  23. siRNA Therapeutics for the Treatment of Hereditary Diseases and Other Conditions: A Review.
  24. Universities can do more to prepare the biomedical workforce for the cell-, tissue- and gene-manufacturing industry.
  25. Global Analysis of Regulatory Frameworks and Drug Safety Standards in the Drug Approval Process.
  26. Natural killer cell-based immunotherapies for colorectal cancer: Current strategies, challenges, and future perspectives.
  27. Single-cell RNA Sequencing In Pediatric Sepsis: γδ T Cell Exhibits A Differentiation To γδT17 Subtype Along With Significantly Enhanced Cell Communication With Neutrophils.
  28. Adoptive cellular therapies in non-Hodgkin lymphomas.
  29. Nutritional status, immunonutrition, and gut microbiome: a coming of age for immunotherapy?
  30. Novel Prognostic Scoring Systems for Severe CRS after Anti-CD19 CAR-T-Cells in Acute B-Lymphoblastic Leukemia.
  31. Extrafollicular and Other Non-Germinal Center B Cell Responses: An Evolutionary Perspective.
  32. Improved identification of tumor-specific TCRs from circulating lymphocytes using autologous colorectal tumor organoids.
  33. Cellular immunotherapies for central nervous system cancers.
  34. Modulation of T Cell Regulation by Interleukin-2 Agonists: Mechanisms and Clinical Implications.
  35. Bibliometric analysis of immune-related acute kidney injury induced by cancer immunotherapy (2000-2025).
  36. Emerging therapies for the treatment of systemic sclerosis.
  37. Metabolic control of innate-like T cells.
  38. Predicators and Outcomes of Cytomegalovirus Reactivation in Chimeric Antigen Receptor T-Cell Therapy: A Systematic Review.
  39. Microbiome-derived metabolites in cancer-associated anemia: An underexplored mechanistic link.
  40. Mapping leadership and communities in EU-funded research through network analysis.
  41. Sequencing Anti-CD19 Therapies in Diffuse Large B-Cell Lymphoma: From Mechanistic Insights to Clinical Strategies.
  42. Advances in Lipid-Based Nanomedicine: Pathway Specific siRNA Therapy and Optimizing Delivery for Hepatocellular Carcinoma.
  43. Making Advanced Therapies Affordable and Accessible: Two Strategic Approaches.
  44. A comprehensive review of systemic sclerosis-primary biliary cholangitis overlap: emerging evidence for a distinct clinical subtype.
  45. Gut microbiome and rheumatoid arthritis: Revisiting the gut-joint axis.
  46. Redox-Active Nanozymes in Metabolic Modulation for Precision Therapeutics.
  47. Regulatory T cell therapy in solid organ transplantation: clinical applications and laboratory monitoring strategies.
  48. Etiopathogenesis and Current Management of Oncogenic Pruritus - A Narrative Review.
  49. Clinical Efficacy of Stem Cell Therapy in Neurotraumatic and Neurodegenerative Conditions: A Comparative Review.
  50. Ethical and Legal Governance of Generative AI in Chinese Healthcare.
  51. MASCC/ISOO Clinical Practice Statement: dental evaluation and management prior to treatment for hematologic malignancies and CAR T-cell therapy.
  1. Hum Vaccin Immunother. 2025 Dec;21(1): 2558403
    In vivo CAR-T cell therapy: New breakthroughs for cell-based tumor immunotherapy.
    Yifan Huang, Rong Cao, Siyang Wang, Xinfeng Chen, Yu Ping, Yi Zhang.
      Chimeric antigen receptor (CAR)-T cell immunotherapy represents an evolutionary advance in the treatment of cancer, yet it faces challenges such as manufacturing complexity, high cost, and time-consuming process. In recent years, the strategy of in vivo CAR-T cell therapy is emerging as a promising approach to improve anti-tumor effectiveness and safety. Briefly, T cells are genetically modified to express CAR protein directly in the body by delivery of vectors. With the continuous optimization of gene delivery systems, gene editing technologies and CAR structures, advancements in in vivo CAR-T therapies have notably enhanced safety, effectiveness, and application in clinical settings. Here, we review the key platforms of in vivo gene delivery and the progress of in vivo CAR-T cell therapy for cancers. We discuss the challenges of in vivo CAR-T cell therapy, such as safety issues of gene delivery, the persistence and function of CAR-T cell, and the immunosuppressive microenvironment in solid tumors.
    Keywords:  In vivo CAR-T cells; cancer; ex vivo CAR-T cells; gene delivery
    DOI:  https://doi.org/10.1080/21645515.2025.2558403
  2. Cancers (Basel). 2025 Sep 05. pii: 2917. [Epub ahead of print]17(17):
    Expanding Immunotherapy Beyond CAR T Cells: Engineering Diverse Immune Cells to Target Solid Tumors.
    Tereza Andreou, Constantina Neophytou, Fotios Mpekris, Triantafyllos Stylianopoulos.
      Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of certain hematologic malignancies, yet its success in solid tumors has been limited by antigen heterogeneity, an immunosuppressive tumor microenvironment, and barriers to cell trafficking and persistence. To expand the reach of cellular immunotherapy, multiple immune cell types-γδ T cells, invariant NKT cells, virus-specific T cells, natural killer (ΝΚ) cells, and myeloid effectors such as macrophages and dendritic cells-are now being explored as alternative or complementary CAR platforms. Each lineage brings unique advantages, such as the innate cytotoxicity and safety profile of CAR NK cells, the tissue infiltration and microenvironment-modulating capacity of CAR macrophages, or the MHC-independent recognition offered by γδ T cells. Recent advances in pharmacological strategies, synthetic biology, and artificial intelligence provide additional opportunities to overcome barriers and optimize CAR design and manufacturing scale-up. Here, we review the state of the art in engineering diverse immune cells for solid tumor therapy, highlight safety considerations across autologous, allogeneic, and in vivo CAR cell therapy approaches, and provide our perspective on which platforms might best address current unmet clinical needs. Collectively, these developments lay the foundation for next-generation strategies to achieve durable immunotherapy responses in solid tumors.
    Keywords:  CAR NK cells; CAR dendritic cells; CAR macrophages; cancer; cell therapy; chimeric antigen receptor (CAR); immunotherapy
    DOI:  https://doi.org/10.3390/cancers17172917
  3. Trends Cancer. 2025 Sep 11. pii: S2405-8033(25)00207-9. [Epub ahead of print]
    Overcoming solid-tumor barriers: armored CAR-T cell therapy.
    Nayoung Kwon, Yvonne Y Chen.
      Chimeric antigen receptor (CAR)-T cell therapy has shown significant clinical benefit in hematologic malignancies but remains less effective in solid tumors due to multiple barriers, including limited tumor infiltration, immunosuppressive microenvironments, and heterogeneity or imperfect specificity in tumor-antigen expression. 'Armoring' CAR-T cells to express chemokine receptors, enzymes that degrade extracellular matrix components, proinflammatory cytokines, or factors that modulate immunosuppressive signals could empower CAR-T cells to overcome barriers associated with solid tumors. However, translating promising preclinical results into reliable clinical benefit for patients with solid tumors remains challenging. This review critically examines emerging CAR-T cell armoring approaches and highlights key translational hurdles and the need for innovations in human-relevant disease models, safety designs, and treatment strategies for effective translation.
    Keywords:  CAR-T cell therapy; armored CAR-T cells; cancer immunotherapy; chimeric antigen receptor (CAR); solid tumors
    DOI:  https://doi.org/10.1016/j.trecan.2025.08.009
  4. Ann Hematol. 2025 Sep 10.
    Expanding the frontier of CAR therapy: comparative insights into CAR-T, CAR-NK, CAR-M, and CAR-DC approaches.
    Yiling Zhang, Rong Hu, Xiaoling Xie, Yuhua Li.
      Chimeric antigen receptor (CAR) therapies have demonstrated remarkable clinical efficacy in hematological malignancies, validating their therapeutic potential. However, challenges such as therapeutic resistance and limited accessibility hinder their broader application. To overcome these limitations, alternative CAR-based cell therapies, including CAR-Natural Killer (CAR-NK), CAR-macrophage (CAR-M), and CAR-dendritic cell (CAR-DC) therapies, have been proposed. Compared with CAR-T, CAR-NK cells have a higher safety profile in terms of cytokine release syndrome (CRS) and neurotoxicity, while being naturally cytotoxic, making them a promising option. Despite these advantages, CAR-NK therapy is limited by issues such as insufficient tissue infiltration and low transduction efficiency. CAR-M cells, with their potent infiltration capabilities and ability to function as antigen-presenting cells, also hold promise but face challenges related to suboptimal viral transduction efficiency. CAR-DCs are emerging as a highly promising approach and are currently undergoing active investigation. This review summarizes the profiles, current clinical trials, and comparative advantages and limitations of CAR-T, CAR-NK, CAR-M, and CAR-DC therapies. Finally, we discuss the key challenges to be addressed and the future prospects of these evolving CAR-based cell therapies.
    Keywords:  CAR-DC; CAR-M; CAR-NK; CAR-T; Cellular immunotherapy; Hematological malignancies
    DOI:  https://doi.org/10.1007/s00277-025-06538-0
  5. Biotechnol J. 2025 Sep;20(9): e70114
    Impact of Serum/Xeno-Free Medium and Cytokine Supplementation on CAR-T Cell Therapy Manufacturing in Stirred Tank Bioreactors.
    Pedro Silva Couto, Dale J Stibbs, Pierre Springuel, Ursula Schultz, Manuel Effenberger, Stephen Goldrick, Sergio Navarro-Velázquez, Manel Juan, Laura Herbst, Bastian Nießing, Katrin Mestermann, Carmen Sanges, Michael Hudecek, Qasim A Rafiq.
      Chimeric antigen receptor T-cell (CAR-T) therapies have demonstrated clinical efficacy in treating haematological malignancies, resulting in multiple regulatory approvals. However, there is a need for robust manufacturing platforms and the use of GMP-aligned reagents to meet the clinical and commercial demands. This study investigates the impact of serum/xeno-free medium (SXFM) and cytokine supplementation on CAR-T cell production in static and agitated culture systems, using 24-well plate G-Rex vessels and 500 mL stirred tank bioreactors (STRs), respectively. Under static conditions, SXFM media supported CAR-T cell expansion with growth kinetics comparable to foetal bovine serum, FBS-based RPMI, irrespective of the cytokine supplementation (IL-2 or the combination of IL-7 and IL-15). In contrast, when the expansion was conducted using STRs, several differences were observed with SXFM. Particularly, when supplemented with IL-2 SXFM, it increased transduction efficiency, supporting accelerated proliferation relative to FBS-containing RPMI. Additionally, SXFM maintained a higher CD4:CD8 ratio at harvest, a feature associated with improved clinical outcomes. No significant differences were observed in the CAR-T cell populations' differentiation status or activation and exhaustion profiles across the conditions. These results suggest that SXFM enables CAR-T cell manufacturing in STRs, improving key quality attributes such as transduction efficiency, growth kinetics, and CD4:CD8 ratio compared to FBS-supplemented medium.
    Keywords:  ATMP; CAR‐T; GMP; biomanufacturing; serum free; stirred‐tank bioreactor; xeno‐free
    DOI:  https://doi.org/10.1002/biot.70114
  6. Immunity. 2025 Sep 09. pii: S1074-7613(25)00330-9. [Epub ahead of print]58(9): 2148-2151
    Touch of youth: Mechanosensing expands stem-like CAR-T cells.
    Zhengxu Ren, Chenqi Xu.
      In this issue of Immunity, Lv et al. develop a new CAR-T cell culture system that uses integrin mechanical signaling to boost CAR-T proliferation while preserving stemness, pointing out a new direction of CAR-T manufacturing.
    DOI:  https://doi.org/10.1016/j.immuni.2025.07.021
  7. J Hosp Palliat Nurs. 2025 Oct 01. 27(5): E248
    Health-Related Values Discussions With Patients Receiving Allogeneic and Autologous Stem Cell Transplant and Chimeric Antigen Receptor Therapy (CAR-T): Implementation of an Early Nurse Practitioner-Led Primary Palliative Care Intervention.
      
    DOI:  https://doi.org/10.1097/NJH.0000000000001171
  8. J Immunother Cancer. 2025 Sep 09. pii: e011890. [Epub ahead of print]13(9):
    Comparative efficacy and safety of PSCA CAR-engineered Vδ1 γδ T cells for immunotherapy of pancreatic cancer.
    Zhixin Li, Ningyuan Liu, Zahir Shah, Lewei Jin, Lei Tian, Xiaolei Sun, Jianying Zhang, Zhiyao Li, Michael A Caligiuri, Jianhua Yu.
       BACKGROUND: γδ T cells possess unique immunological features including tissue tropism, major histocompatibility complex-independent antigen recognition, and hybrid T/natural killer cell properties that make them promising candidates for cancer immunotherapy. However, the therapeutic potential of Vδ1 γδ T cells, particularly when engineered with chimeric antigen receptors (CARs), remains underexplored in solid tumors such as pancreatic cancer (PC), largely due to their low abundance in peripheral blood and challenges in ex vivo expansion. This study aims to directly compare the preclinical safety and efficacy among CAR-engineered Vδ1 γδ T cells, Vδ2 γδ T cells, and conventional αβ T cells.
    METHODS: We developed a CAR targeting prostate stem cell antigen (PSCA) and engineered it into human blood-derived Vδ1 γδ T cells. These PSCA CAR-Vδ1 T cells were evaluated for antitumor activity against PSCA-expressing pancreatic tumor cells using both in vitro cytotoxicity assays and in vivo xenograft mouse models. Comparative analyses were conducted using PSCA CAR-Vδ1 γδ T cells, PSCA CAR-Vδ2 γδ T cells, and PSCA CAR-αβ T cells. Safety assessments of these CAR-engineered T cell subsets were conducted to evaluate graft-versus-host disease (GvHD) and cytokine release syndrome (CRS), while exhaustion profiles were assessed using single-cell RNA sequencing.
    RESULTS: Our study demonstrated that PSCA CAR-Vδ1 γδ T cells, PSCA CAR-Vδ2 γδ T cells, and PSCA CAR-αβ T cells exhibited similar antitumor efficacy. However, PSCA CAR-Vδ1 T cells did not exhibit GvHD or CRS compared with CAR-αβ T cells. PSCA CAR-Vδ1 T cells also had lower scores for exhaustion when compared with PSCA CAR-Vδ2 T cells by single-cell transcriptomic analysis.
    CONCLUSION: PSCA CAR-Vδ1 γδ T cells represent a potent and safe therapeutic modality for PSCA+ PC, with efficacy comparable to other CAR T cell types and potential advantages in safety and persistence. These findings support further development of CAR-Vδ1 T cell immunotherapy for solid tumors.
    Keywords:  Adoptive cell therapy - ACT; Chimeric antigen receptor - CAR; Immunotherapy; Solid tumor; T cell
    DOI:  https://doi.org/10.1136/jitc-2025-011890
  9. Cancer Immunol Res. 2025 Sep 08.
    Systematic engineering of TROP2-targeted CAR T-cell therapy overcomes resistance pathways in solid tumors.
    Elliott J Brea, Simon Baldacci, Neil Savage, Francesco Facchinetti, Conor Hinchey, Sachiv Chakravarti, Alexis Mottram, Kenneth Ngo, Ha Vo, Brittaney A Leeper, Bishma Tuladhar, Suthakar Ganapathy, Elena V Ivanova, Aisha Saldanha, Marie-Anais Locquet, Abdulmajeed Salamah, Malcolm Holterhus, Evelyn B Mesler, Martina De Vizio, Carla Stornante, Marco Campisi, Navin R Mahadevan, Tran C Thai, Timothy J Haggerty, Zehua Li, Cui Nie, Changjing Deng, Xiaoxiao Wang, Louis L Liu, Thanh U Barbie, Prafulla C Gokhale, Cloud P Paweletz, Anusuya Ramasubramanian, Pasi A Janne, David A Barbie, Eric L Smith.
      Antibody-based therapies have revolutionized cancer treatment but have several limitations. These include: down-regulation of the target antigen; mutation of the target epitope; or in the case of antibody drug conjugates (ADCs), resistance to the chemotherapy warhead. Since TROP2-targeted therapy with ADCs yields responses in TROP2+ solid tumors but lacks the durability observed with other immunotherapy-based approaches, we developed novel TROP2-targeting chimeric antigen receptor (CAR) T cells as an alternative. We observe high potency of TROP2 directed CAR T against multiple solid tumor models. We demonstrate that CAR T cell therapy can preserve high potency in models of ADC resistance and can be further engineered to prevent cell therapy resistance; leveraging fully-human single domain (VH-only) binder discovery to rationally engineer dual epitope-binding based (biparatopic) CARs. This work highlights the potency of CAR T cell therapies and how rational engineering leveraging dual-VH targeting domains can overcome resistance pathways to current therapies. In future work, the CAR engineering approaches presented here can serve as a platform to be partnered with other strategies to address the suppressive tumor microenvironment. This work highlights the potency of CAR T cell therapies and how rational engineering leveraging dual-VH targeting domains can overcome resistance pathways to current therapies.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-25-0527
  10. Front Immunol. 2025 ;16 1645304
    Case Report: Remission of a patient with complex combination of autoimmune diseases by anti-CD19 CAR-T cell therapy.
    Xudong Liu, Wenxiang Zhu, Nan Su, Yanyi Ma, Fang Wang, Jingyi Xu, Heyang Zhang, Xiaomeng Luo, Yuetong Zhao, Jianxun Wang, Yuanyuan Shi, Yishuo Li, Pingting Yang.
      CAR-T cell therapy has been proven effective in various autoimmune diseases, with most studies utilizing lentiviral-transduced CAR-T cells. In recent years, retroviral vector-transduced CAR-T cells-characterized by a high positivity rate, stable cell lines, and lower plasmid requirements-have attracted increasing attention. This article presents a complex case of a patient with SLE combined with APS and TBIRS. For four years following the diagnosis, the patient underwent conventional steroid therapy and immunotherapy, which yielded unsatisfactory and relapse-prone results. After receiving anti-CD19 CAR-T cells transduced with a retroviral vector, the patient experienced an excellent postoperative recovery without any infusion-related adverse reactions. Post-treatment, the patient's creatinine, anti-dsDNA antibodies, albumin, and glycated hemoglobin levels returned to normal, eliminating the need for ongoing glucocorticoids or hypoglycemic agents. Although there are some available reports of CAR-T cells treating SLE, it is still very rare and significant for successfully treating such a complicated case, especially after proving the unavailability of traditional therapy. Furthermore, this is the first reported case of treating TBIRS syndrome with retroviral vector-transduced CAR-T therapy.
    Keywords:  anti-CD19 CAR-T; antiphospholipid syndrome; autoimmunity; systemic lupus erythematosus; type B insulin resistance syndrome
    DOI:  https://doi.org/10.3389/fimmu.2025.1645304
  11. Best Pract Res Clin Haematol. 2025 Sep;pii: S1521-6926(25)00035-0. [Epub ahead of print]38(3): 101630
    Natural born Killers: Harnessing NK cells to treat cancer.
    Kanchi Patell, Katherine Myers, Amr Mohamed, David Wald, J Eva Selfridge.
      Adoptive cellular therapy, or the collection and transfer of immune cells to patients, is emerging as a treatment option for many malignancies, especially hematologic malignancies, with a growing role in solid tumors and non-malignant conditions such as autoimmune diseases. The adoptive transfer of the innate immune cell natural killer (NK) cells is uniquely poised as a potential therapy alone or as an adjunct to other immune-targeted therapies for patients with cancer, with several advantages over other cell therapies such as T cells. We review key concepts in NK cells as a therapy for human disease and discuss key trials using NK cells in malignancy.
    DOI:  https://doi.org/10.1016/j.beha.2025.101630
  12. Cancers (Basel). 2025 Sep 03. pii: 2898. [Epub ahead of print]17(17):
    Advancing CAR T-Cell Therapy in Solid Tumors: Current Landscape and Future Directions.
    Saeed Rafii, Deborah Mukherji, Ashok Sebastian Komaranchath, Charbel Khalil, Faryal Iqbal, Siddig Ibrahim Abdelwahab, Amin Abyad, Ahmad Y Abuhelwa, Lakshmikanth Gandikota, Humaid O Al-Shamsi.
       BACKGROUND: Chimeric Antigen Receptor (CAR) T-cell therapy has transformed the treatment of hematological malignancies, yet its application in solid tumors remains constrained by unique biological and logistical barriers.
    OBJECTIVE: This review critically examines the evolving landscape of CAR T-cell therapy in solid malignancies, with a focus on antigen heterogeneity, the immunosuppressive tumor microenvironment, and risks of on-target, off-tumor toxicity.
    METHODS: We outline recent advances in CAR engineering, including co-stimulatory optimization, dual- and multi-antigen targeting, armored CARs, and gene-edited constructs designed to enhance persistence and anti-tumor activity. Clinical progress is highlighted by recent FDA approvals of genetically modified T-cell therapies in synovial sarcoma and melanoma, underscoring the potential for broader solid tumor application. Additionally, we synthesize early-phase clinical trial findings across multiple solid tumor types (e.g., lung, colorectal, ovarian, glioblastoma), and discuss innovative approaches such as regional delivery, checkpoint blockade combinations, and incorporation of chemokine receptors for improved tumor infiltration. The review also considers future strategies, including artificial intelligence-guided target discovery and rational trial design to overcome translational bottlenecks.
    CONCLUSIONS: With expanding clinical experience and continued technological innovation, CAR T-cell therapy is steadily transitioning from an experimental strategy to a therapeutic reality in solid tumors, poised to reshape the future of cancer immunotherapy.
    Keywords:  CAR T; T-cell receptor (TCR) therapy; allogenic CAR T; cellular therapy; gene-edited T cells; solid tumors
    DOI:  https://doi.org/10.3390/cancers17172898
  13. Cytotherapy. 2025 Jul 25. pii: S1465-3249(25)00788-1. [Epub ahead of print]
    Overcoming barriers to referral for CAR T-cell therapy in patients with non-Hodgkin aggressive B-cell lymphomas: A Delphi consensus.
    Stefano Luminari, Annalisa Chiappella, Alice Di Rocco, Luca Arcaini, Roberto Freilone, Marco Ladetto, Massimo Martino, Pellegrino Musto, Luigi Rigacci, Carlo Visco, Paolo Corradini, Pier Luigi Zinzani.
      Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of aggressive B-cell non-Hodgkin lymphoma, particularly in relapsed/refractory large B-cell lymphoma and mantle cell lymphoma. Despite its transformative potential, significant challenges persist in optimizing patient identification and referral pathways to ensure timely and equitable access. This expert consensus, developed through the Delphi methodology, analyzes key barriers to the referral process and proposes structured solutions to enhance collaboration between referring treatment centers (RTCs) and qualified treatment centers (QTCs). Our findings highlight the importance of early and timely identification of CAR T-eligible patients through standardized disease assessments and strategies to streamline patient access through structured collaboration between RTCs and QTCs that can help overcome patient-specific logistical challenges. Proposed solutions should be broadly applicable across different health care systems. Addressing these clinical and logistical barriers in the referral process will be crucial for maximizing the benefits of CAR T-cell therapy and expanding its accessibility to a broader patient population.
    Keywords:  CAR T-cell; barriers to referral; consensus; non-Hodgkin aggressive B-cell lymphomas
    DOI:  https://doi.org/10.1016/j.jcyt.2025.07.007
  14. Int J Hematol. 2025 Sep 10.
    Sequential intrathoracic injection and intravenous infusion of BCMA CAR-T cells in a patient with relapsed/refractory primary plasma cell leukemia.
    Wei Han, Shuyang Wang, Mingming Zhang, Shan Fu, Wenjun Wu, Houli Zhao, Ka Wai Wong, Sze Fai Yip, Jiazhen Cui, Alex H Chang, Guoqing Wei, He Huang, Yongxian Hu.
      Patients with primary plasma cell leukemia (pPCL), particularly those with extramedullary disease (EMD), face a poor prognosis even with chimeric antigen receptor (CAR)-T cell therapy. This case report describes a patient with relapsed/refractory pPCL and life-threatening malignant pleural effusion (PE) treated with intrapleural CAR-T cells targeting B-cell maturation antigens. CAR-T cell expansion within the PE was observed, along with a rapid reduction in leukemia cell count and PE volume. Subsequent lymphodepletion chemotherapy and intravenous CAR-T cell therapy induced complete remission with 9 months of progression-free survival. This case highlights the potential advantages of integrating local and systemic CAR-T cell therapy in managing complex EMD cases.
    Keywords:  BCMA CAR-T; Extramedullary disease; Intrathoracic injection; Primary plasma cell leukemia
    DOI:  https://doi.org/10.1007/s12185-025-04064-3
  15. Front Immunol. 2025 ;16 1647433
    Multiplex engineering using microRNA-mediated gene silencing in CAR T cells.
    Giulia Golinelli, John Scholler, Audrey Roussel-Gervais, Antonija Šakić, Sten Ilmjärv, Decheng Song, Khatuna Gabunia, Mei Ji, Ting J Fan, Aasha Gupta, Mansi Deshmukh, Abdulla Berjis, Riccardo Cuoghi Costantini, Kimberly Apodaca, Neil C Sheppard, Sven Kili, Massimo Dominici, Marco Alessandrini, Carl H June, Bruce L Levine.
       Background: Multiplex gene-edited chimeric antigen receptor (CAR) T-cell therapies face significant challenges, including potential oncogenic risks associated with double-strand DNA breaks. Targeted microRNAs (miRNAs) may provide a safer, functional, and tunable alternative for gene silencing without the need for DNA editing.
    Methods: As a proof of concept for multiplex gene silencing, we employed an optimized miRNA backbone and gene architecture to silence T-cell receptor (TCR) and major histocompatibility complex class I (MHC-I) in mesothelin-directed CAR (M5CAR) T cells. The efficacy of this approach was compared to CD3ζ and β2-microglobulin (β2M) CRISPR/Cas9 knockout (KO) cells. miRNA-expressing cassettes were incorporated into M5CAR lentiviral vectors, enabling combined gene silencing and CAR expression. Antitumor activity was evaluated using in vitro assays and in vivo pancreatic ductal adenocarcinoma models.
    Results: Silenced (S) M5CAR T cells retained antitumor functionality comparable to, and in some cases exceeding, that of KO cells. In vivo, S M5CAR T cells achieved tumor control with higher persistence and superior metastasis prevention. In vitro assays demonstrated enhanced resistance to alloreactive natural killer (NK) cells and peripheral blood mononuclear cells (PBMCs).
    Conclusions: Titratable multiplex gene silencing via targeted miRNAs offers an alternative to gene editing for CAR T cells, with potential advantages in potency, persistence, metastasis prevention, and immune evasion for allogeneic products. This strategy may overcome tumor-induced immunosuppression while avoiding the risks associated with DNA double-strand breaks.
    Keywords:  CAR T; CRISPR/Cas9; gene silencing; miRNAs; multiplexing; solid tumors
    DOI:  https://doi.org/10.3389/fimmu.2025.1647433
  16. Cells. 2025 Aug 28. pii: 1333. [Epub ahead of print]14(17):
    Engineering of Humanized PSMA-Directed CAR T Cells for Potent and Specific Elimination of Prostate Cancer Cells.
    Tobias D Deller, Jamal Alzubi, Laura Mosti, Marie Peschers, Christian Gratzke, Philipp Wolf, Toni Cathomen.
      Chimeric Antigen Receptor (CAR) T cell therapy has achieved high response rates in patients with relapsed or refractory hematologic malignancies. However, comparable efficacy in solid tumors remains limited, partly due to poor CAR T cell persistence and immune-mediated rejection. A major contributor, which has hampered the clinical efficacy of CAR T cells in clinical practice, is the immunogenicity of the murine-derived single-chain variable fragments (scFvs) commonly used in CAR constructs. Cell and humoral immune responses to the murine parts of CARs have been implicated in CAR T cell rejection. Here, we describe the generation and in vitro characterization of humanized CAR T cells targeting prostate-specific membrane antigen (PSMA) on prostate cancer cells, based on two distinct murine scFvs (A5 and D7). Humanization improved the germinality index and successfully preserved CAR surface expression. Functional assays demonstrated that humanized PSMA-CAR T cells retained antigen-specific binding, activation and cytotoxicity, differentiation, exhaustion and cytokine secretion profiles comparable to their murine counterparts. These results support the feasibility of humanization as a strategy to reduce immunogenicity without compromising CAR T cell capabilities, providing a foundation for further in vivo validation in solid tumor settings.
    Keywords:  CAR T cells; T cell activation; T cell differentiation; T cell exhaustion; humanization; immunogenicity; prostate cancer; prostate-specific membrane antigen
    DOI:  https://doi.org/10.3390/cells14171333
  17. Best Pract Res Clin Haematol. 2025 Sep;pii: S1521-6926(25)00043-X. [Epub ahead of print]38(3): 101638
    Adoptive cellular therapies in multiple myeloma.
    David Kegyes, Bogdan Borlea, Marc Damian, Adrian Bogdan Tigu, Madalina Nistor, Diana Cenariu, Raluca Munteanu, Diana Gulei, Angela Dascalescu, Ion Antohe, Alina Tanase, Evangelos Terpos, Hermann Einsele, Ciprian Tomuleasa.
      Plasma cell myeloma (multiple myeloma) is a blood cancer characterized by the clonal proliferation of plasma cells in the bone marrow. Treatment strategies evolve year by year, new drugs getting Food and Drug Administration (FDA)-approved each year. Chimeric antigen receptor (CAR) therapies are an advanced form of immunotherapy that engineer T cells to recognize and destroy cancer cells. In recent years, adoptive cellular therapies have been successfully used to treat relapsed or refractory patients. Now, growing evidence supports their effectiveness when used earlier in treatment, even as an alternative to autologous hematopoietic stem cell transplantation. Ongoing research is expanding CAR therapy to solid tumors and enhancing safety and efficacy through innovative designs and combination strategies. In this paper, we aim to highlight the brief history and the latest advancements in CAR T-cell and NK-cell therapies for plasma cell myeloma.
    Keywords:  CAR NK-Cells; CAR T-cells; Chimeric antigen receptor; Immunotherapy; Multiple myeloma
    DOI:  https://doi.org/10.1016/j.beha.2025.101638
  18. J Nutr. 2025 Sep 04. pii: S0022-3166(25)00538-3. [Epub ahead of print]
    From the Lab to the Plate: How Gut Microbiome Science is Reshaping Our Diet.
    Anne Hiol, Patrick Veiga.
      This review explores the century-long trajectory of gut microbiome research and its contribution to shaping our modern diet. It further highlights the transformative potential of current discoveries to revolutionize future dietary habits and nutritional practices. From the pioneering work of E. Metchnikoff in the early 20th century, which led to the widespread adoption of yoghurt in many Western countries, to the emergence of probiotics and prebiotics, the microbiota has become a key determinant in human health and nutrition. Current developments provide new perspectives on the future, such as next-generation probiotics and prebiotics, dietary recommendations adapted to the specific needs of the microbiota, and precision nutrition that considers individual microbiota variability.
    Keywords:  diet; fermented foods; gut microbiome; personalized nutrition; prebiotic; probiotic; yoghurt
    DOI:  https://doi.org/10.1016/j.tjnut.2025.08.032
  19. Int J Nanomedicine. 2025 ;20 10613-10644
    Exosomes in Disease Therapy: Plant-Derived Exosome-Like Nanoparticles Current Status, Challenges, and Future Prospects.
    YuYing Song, NaNa Feng, QingYa Yu, YuanYuan Li, MingKun Meng, Xing Yang, ZhiQiang Gan, Tong Xu, Ce Tang, Yi Zhang.
      Exosomes are nano-sized extracellular vesicles secreted by diverse cell types that mediate intercellular communication through the transfer of proteins, lipids, and nucleic acids. Their ability to cross biological barriers and carry bioactive cargo has led to increasing interest in their use as targeted delivery systems for drugs, genes, and immunomodulatory molecules. Recently, plant-derived exosome-like nanoparticles, PLNs obtained from edible plants and medicinal herbs have emerged as a novel, biocompatible alternative to mammalian exosomes. PLNs exhibit low immunogenicity, enhanced safety, and scalable production, making them ideal candidates for clinical translation. This review synthesizes a wide body of experimental data on the biogenesis, molecular composition, and biological activity of PLNs, and provides a comparative assessment of their therapeutic applications across oncology, immunotherapy, regenerative medicine, and gene therapy. Technological advances in PLN engineering, isolation, and manufacturing are discussed, along with key translational barriers such as stability, regulatory standards, and delivery specificity. This review also discusses the scientific implications of PLNs in advancing precision medicine and propose future directions for their integration into next-generation nanotherapeutics.
    Keywords:  drug delivery; exosomes; gene therapy; immunotherapy; plant-derived exosome-like nanoparticles
    DOI:  https://doi.org/10.2147/IJN.S540094
  20. Cancers (Basel). 2025 Sep 01. pii: 2876. [Epub ahead of print]17(17):
    Endothelial Injury Following CAR-T Cell Immunotherapy for Hematological Malignancies.
    Christos Demosthenous, Paschalis Evangelidis, Athanasios Gatsis, Ioannis Mitroulis, Sofia Vakalopoulou, Anna Vardi, Stefania Bountoura, Ioanna Sakellari, Eleni Gavriilaki.
      Chimeric antigen receptor-T (CAR-T) cell immunotherapy constitutes a cornerstone in the management of patients with relapsed/refractory B-cell lineage lymphoid malignancies. Toxicities such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and hematotoxicity (ICAHT) have been recognized in the post-infusion period. The initial interplay between CAR-T cells and tumor cells, followed by cytokine release and the bystander activation of the innate immunity cells, result in endothelial cell injury. In the current review, the ongoing research regarding endothelial injury in CAR-T cell recipients is summarized. Various markers of endothelial injury have been investigated in CAR-T cell recipients, including markers of complement activation, such as soluble C5b-9, endothelial dysfunction (angiopoietin-2, VCAM1, ICAM-1), inflammation, and thrombosis (von Willebrand antigen, ADAMTS13, thrombomodulin). The expression level of these endothelial injury markers has been identified as impaired in CAR-T cell recipients, not only when compared with healthy controls but also among patients with severe CRS/ICANS and those with mild toxicities or without toxicities. Furthermore, the Endothelial Activation and Stress Index (EASIX) and modified versions of this score, calculated in the pre- and early post-infusion period, seem to predict development of severe toxicities, ICAHT, and, thus, poor overall survival in CAR-T cell patients. More data concerning the role of these endothelial injury markers and clinical outcomes in CAR-T cell settings are essential.
    Keywords:  CAR-T; CRS; ICANS; complement; endothelium; lymphoma; myeloma
    DOI:  https://doi.org/10.3390/cancers17172876
  21. Front Immunol. 2025 ;16 1640224
    Exploring research trends in cancer immunotherapy via single-cell technologies: a scientometric perspective.
    Zhongxun Li, Qi Han, Zimu Huang, Sen Zhang, Huina Guo, Hongliang Liu, Xiaoya Guan, Hairong Li, Chunming Zhang.
       Introduction: Cancer immunotherapy has brought new therapeutic hopes for cancer patients, but it is complex in its mechanism of action, and there are significant individual differences, which restricts its wide use. As single-cell analysis technology develops rapidly, it provides an innovative research approach to investigate immunotherapy mechanisms, to identify potential biomarkers, and to optimize individualized treatment strategies.
    Methods: The Core Collection of Web of Science (WOSCC) was used to retrieve and obtain relevant literature related to "application of single cell sequencing in cancer immunotherapy" since the establishment of the WOSCC. A quantitative analysis and visualization of the related literature was conducted using tools such as Bibliometrix, Excel, CiteSpace, VOSviewer, and Scimago Graphica.
    Results: The total number of related literatures included was 4856, with an average annual growth rate of 25.14%. According to published articles, China and the United States lead the field. Frontiers in immunology, Nature Communications, Journal for Immunotherapy of Cancer, Scientific Reports, Frontiers in Oncology and Cancers have an important academic influence in this field. Research hotspots focus on tumor immune microenvironment and cellular heterogeneity. Research trends such as spatial transcriptomics, standardized processes, and T cell function are becoming increasingly popular.
    Conclusion: In tumor immunotherapy, single-cell sequencing is profoundly changing the research paradigm. It not only improves our understanding of the immune microenvironment and therapeutic heterogeneity, but also assists us in identifying accurate markers and formulating individualized treatment plans.
    Keywords:  bibliometrix; heterogeneity; immunotherapy; single-cell RNA sequencing; tumor immune microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1640224
  22. Int J Nanomedicine. 2025 ;20 10857-10905
    Stem Cell-Derived Exosomes: A Comprehensive Review of Biomedical Applications, Challenges, and Future Directions.
    Jingyi Zhang, Xingzhao Tian, Yi Li, Chunyan Fang, Fang Yang, Liang Dong, Yifeng Shen, Shiyun Pu, Junjun Li, Degui Chang, Lanjie Lei, Xujun Yu.
      Stem cell-derived exosomes (SC-Exos) represent an innovative therapeutic breakthrough that circumvents key limitations of direct stem cell transplantation, demonstrating significant therapeutic potential while offering distinct advantages including reduced ethical controversies, decreased immunogenicity responses, and minimized tumorigenicity risks. This review provides a systematic analysis of SC-Exos research, encompassing diverse aspects from fundamental biological mechanisms and isolation and characterization techniques to advanced engineering strategies and therapeutic applications. The review elucidates the biological foundations of exosomes, analyzes different SC-Exos types and their unique characteristics, and explores multiple functional optimization strategies to enhance SC-Exos performance. Comprehensive biomedical engineering applications of SC-Exos across diverse therapeutic domains are presented, covering tissue engineering, advanced drug delivery systems, and treatments for cardiovascular, neurological, oncological, immunological, inflammatory, reproductive, musculoskeletal, and dermatological diseases, as well as other emerging applications. Clinical translation status is evaluated through analysis of current trials, revealing favorable safety profiles and promising preliminary efficacy of SC-Exos across multiple therapeutic domains. Nevertheless, significant challenges remain in standardization of isolation and purification techniques, quality control measures, therapeutic heterogeneity, scalable production capabilities, and comprehensive biosafety evaluation protocols. Future research priorities include establishing unified isolation and purification standards, developing comprehensive functional evaluation systems, optimizing administration routes and dosing regimens, and conducting large-scale multicenter clinical trials. This review provides systematic guidance for advancing effective SC-Exos-based therapeutic solutions, ultimately facilitating their clinical translation and expanding applications across biomedical challenges.
    Keywords:  biomedical applications; biomedical engineering; clinical translation; extracellular vesicles; nanomedicine; stem cell-derived exosomes
    DOI:  https://doi.org/10.2147/IJN.S527137
  23. Int J Mol Sci. 2025 Sep 05. pii: 8651. [Epub ahead of print]26(17):
    siRNA Therapeutics for the Treatment of Hereditary Diseases and Other Conditions: A Review.
    Alexei Shevelev, Natalia Pozdniakova, Evgenii Generalov, Olga Tarasova.
      RNA-based drugs hold significant potential, offering promising new treatments for a wide range of diseases, especially those with a genetic basis. By leveraging RNA interference (RNAi) and other RNA-mediated mechanisms, these therapies can precisely modulate gene expression and address the root causes of genetic defects. RNA-based drugs hold significant potential for treating a range of diseases. However, the transition of these therapies from laboratory research to clinical applications has encountered hurdles. This review explores the composition and outcomes of clinical trials for various modified short RNA drugs. We detail their mechanisms of action, delivery systems-with a focus on lipid nanoparticles and N-acetylgalactosamine (GalNAc) conjugates-and clinical efficacy in treating conditions such as transthyretin (TTR) amyloidosis. Our analysis reveals that while several RNAi-based drugs have achieved clinical approval, a critical unmet need remains: advanced delivery systems capable of precisely targeting diverse tissues, particularly outside the liver. We also underscore the importance of rigorous target validation utilising sophisticated bioinformatics tools and in vitro/in vivo assays to minimise off-target effects and ensure robust therapeutic efficacy. This review proposes a novel framework for optimising RNA drug development, emphasising the crucial interplay between delivery strategies, target specificity, and understanding disease-specific target biology.
    Keywords:  GalNAc conjugates; LNPs; RNA interference; RNA therapy; gene therapy; siRNA
    DOI:  https://doi.org/10.3390/ijms26178651
  24. Cytotherapy. 2025 Aug 29. pii: S1465-3249(25)00811-4. [Epub ahead of print]
    Universities can do more to prepare the biomedical workforce for the cell-, tissue- and gene-manufacturing industry.
    Ashley How, Min Thu Ta, Duc Tuan Thanh Phan, Andy Tay.
       BACKGROUND AND AIMS: Precision medicine is poised to revolutionize the treatment of complex diseases, with cell, tissue and gene therapy products (CTGTP) emerging as a major driver of innovation. As industry demand for skilled professionals grows, academic institutions must adapt to equip graduates with the necessary expertise. This study examines the undergraduate curricula and internship programs of top English-speaking universities globally to assess their alignment with industry needs in the CTGTP sector.
    METHODS: We conducted a comparative analysis of undergraduate programs in biomedical sciences, bioengineering and life sciences, identifying CTGTP-related coursework and evaluating the depth of theoretical training offered. In addition, we mapped major biomedical companies to determine the availability of internship and research opportunities, highlighting discrepancies between academic preparation and workforce requirements.
    RESULTS: Our findings indicate that although some universities are trying to integrate CTGTP as a teaching component, many institutions offer limited coursework, leaving students to seek specialization through electives, special programs or postgraduate education.
    CONCLUSIONS: To address this bottleneck in skilled labor, we propose curriculum enhancements, stronger industry-academic partnerships and expanded practical training opportunities to better prepare graduates for careers in the cell, tissue and gene manufacturing industry.
    Keywords:  CAR-T; cell manufacturing; cell therapy; gene therapy; tissue engineering
    DOI:  https://doi.org/10.1016/j.jcyt.2025.08.004
  25. Curr Drug Saf. 2025 Sep 04.
    Global Analysis of Regulatory Frameworks and Drug Safety Standards in the Drug Approval Process.
    Virendra S Gomase, Rupali Sharma, Suchita P Dhamane.
      The drug approval and review process plays a crucial role in the pharmaceutical industry, aiming to ensure that newly marketed drugs are safe, effective, and of high quality. Regulatory authorities overseeing this process, tailored to geographically distinct needs, include the U.S. FDA, EMA, Japan's Pharmaceuticals and Medical Devices Agency (PMDA), China's National Medical Products Administration (NMPA), and India's Central Drugs Standard Control Organization (CDSCO). This analysis offers insight into the various drug approval processes employed by these authorities and examines the International Council for Harmonisation's ongoing efforts to establish a global consensus on drug regulation standards. It also compares regulatory pathways and highlights current harmonization initiatives. The focus is on analyzing operational aspects of drug regulation and identifying challenges arising from these regulations. The ultimate goal is to present a clear understanding of the intricacies and dynamics of the global drug approval process. Regulating the drug approval process is essential to ensure that new drugs are safe for public consumption, as the introduction of a new drug often faces numerous hurdles beyond safety and efficacy. The challenges highlighted include variations in regulations between authorities, the complexity of modern therapeutics, and the balance between safety and speed. This paper provides an overview of innovations in drug development, their impact on regulatory pathways, ongoing harmonization efforts, and potential obstacles that may arise during the regulatory process.
    Keywords:  Biologics; clinical trials; drug approval process; drug development; efficacy.; global regulatory authorities; regulatory frameworks; regulatory harmonization; regulatory practices; safety
    DOI:  https://doi.org/10.2174/0115748863392869250827042742
  26. World J Gastroenterol. 2025 Sep 14. 31(34): 110051
    Natural killer cell-based immunotherapies for colorectal cancer: Current strategies, challenges, and future perspectives.
    Xiao-Jun Zhang, Yan Yu, Jing-Yu Li, Yu-Zhu Yan, Sha-Sha Jiang, Yi Zhang, Qin Fei, Yi-Ran Zhang, Yong-Xin Zhao, Lei Guo, Jing Lv, He-Ping Zhao.
      Natural killer (NK) cells have emerged as promising therapeutic agents for treating colorectal cancer because of their innate ability to recognize and eliminate tumor cells without prior sensitization. In this review, NK cell-based immunotherapeutic approaches, including cytokine therapy, immune checkpoint inhibition, antibody-dependent cellular cytotoxicity, and adoptive cell transfer, are comprehensively examined, and their respective clinical potential and limitations are highlighted. We discuss critical challenges in NK cell expansion, genetic engineering (particularly chimeric antigen receptor-NK development), and tumor microenvironment-mediated immunosuppression. Furthermore, we explore innovative strategies such as combination therapies, nanotechnology-enhanced delivery, and personalized medicine approaches that aim to overcome the current barriers. The review concludes with future directions emphasizing the need for standardized manufacturing protocols, new strategies to improve NK cell persistence, and clinical validation of emerging technologies, positioning NK cell immunotherapy as a transformative modality for colorectal cancer treatment.
    Keywords:  Colorectal cancer; Immunosuppression; Immunotherapy; Natural killer cells; Tumor microenvironment
    DOI:  https://doi.org/10.3748/wjg.v31.i34.110051
  27. J Innate Immun. 2025 Sep 02. 1-17
    Single-cell RNA Sequencing In Pediatric Sepsis: γδ T Cell Exhibits A Differentiation To γδT17 Subtype Along With Significantly Enhanced Cell Communication With Neutrophils.
    Wen-Jie Zhou, Ting Feng, Yue-Li Mu, Zhuo-Xu He, Dong Liu, Mei-Xing Yu, Hong Li.
      Abnormal immune responses are common clinical features in septic patients. γδ T cells, as innate immune cells, play an important role in host defense, immune surveillance and homeostasis. However, the immune characteristics of γδ T cells in pediatric sepsis remains remain poorly understood. In this study, we analyzed single-cell RNA high-throughput sequencing data of peripheral blood mononuclear cells (PBMCs) from pediatric septic patients. It demonstrates that γδ T cells exhibit a proinflammatory state with heightened immune responsiveness to pathogens in pediatric sepsis, as confirmed by the results of flow cytometric analysis showing elevated Th1 cytokines secretion, increased activation, and a propensity to differentiate into IL-17-producing (γδT17) cells during disease progression. Pseudotime analysis identified seven key genes potentially regulating the differentiation of γδ T cells to γδT17 subtype. Furthermore, cell-cell communication analysis revealed enhanced RETN-CAP1 binding between neutrophils and γδ T cells in pediatric sepsis, suggesting that neutrophil-derived resistin may promote γδ T cell differentiation into the γδT17 subtype via CAP1 receptor binding. In conclusion, this study provides a single-cell study that analyzed the immune status of γδ T cells in pediatric sepsis, highlighting their pivotal roles in pathogen response, inflammation propagation, and immune regulation. The observed differentiation toward the γδT17 subtype may facilitate neutrophil recruitment in this life-threatening condition. Elucidating the molecular mechanisms of γδ T cells in pediatric sepsis could offer a new theoretical basis for novel therapeutics.
    DOI:  https://doi.org/10.1159/000547934
  28. Best Pract Res Clin Haematol. 2025 Sep;pii: S1521-6926(25)00042-8. [Epub ahead of print]38(3): 101637
    Adoptive cellular therapies in non-Hodgkin lymphomas.
    David Kegyes, Bogdan Borlea, Marc Damian, Adrian Bogdan Tigu, Madalina Nistor, Diana Cenariu, Raluca Munteanu, Diana Gulei, Angela Dascalescu, Ion Antohe, Alina Tanase, Anca Colita, Nazar Shokun, Tetiana Skrypets, Hermann Einsele, Massimo Federico, Ciprian Tomuleasa.
      Lymphomas are a group of malignant proliferations of B, T or NK-lymphoid cells at different stages of maturation. While they primarily occur in lymph nodes or lymphatic tissues, they can also involve bone marrow, blood, or other organs. Despite advances in treatment, many patients experience relapse, or develop refractory disease, prompting the development of new therapies. One of the most promising innovations is represented by chimeric antigen receptors (CAR) T-cell therapy, that works by genetically modifying a patient's T lymphocytes to better target and kill their cancer cells. Currently, all FDA-approved CAR T-cell therapies target CD19 (a surface protein expressed on B lymphocytes), however, ongoing research includes CAR-Ts that address novel targets or target multiple antigens. This study aims to provide a comprehensive overview on the clinical use and therapeutic efficacy of both approved and emerging CAR-Ts in the treatment of lymphoma.
    Keywords:  CAR NK-Cells; CAR T-cells; Chimeric antigen receptor; Immunotherapy; Lymphomas
    DOI:  https://doi.org/10.1016/j.beha.2025.101637
  29. Front Immunol. 2025 ;16 1612567
    Nutritional status, immunonutrition, and gut microbiome: a coming of age for immunotherapy?
    Elisa Mattavelli, Francesco Agustoni, Alice Tartara, Francesca De Simeis, Lorenzo Perrone, Riccardo Caccialanza, Paolo Pedrazzoli, Valentina Da Prat.
      In the last decades, immunotherapy has revolutionized cancer treatment. Despite its success, a significant number of patients fail to respond, and the underlying causes of ineffectiveness remain poorly understood. Factors such as nutritional status and body composition are emerging as key predictors of immunotherapy outcomes. In particular, poor nutritional status, sarcopenia, and low skeletal muscle mass are associated with poorer survival and immunotherapy response in several cancers. Conversely, certain parameters of body composition, such as adiposity, may have beneficial effects on immunotherapy efficacy. Nutritional status and body composition can be targeted through tailored nutritional support, making it a potential strategy to improve immunotherapy outcomes. Specific nutrients and modulation of the gut microbiota may further enhance immune functions, offering promising avenues for clinical improvement. Despite the promising potential of tailored nutritional support, clinical evidence remains limited, and further research is needed to establish optimal strategies to optimize immunotherapy response and effectiveness.
    Keywords:  body composition; gut microbiome; immunonutrition; immunotherapy; nutritional status; treatment response and efficacy
    DOI:  https://doi.org/10.3389/fimmu.2025.1612567
  30. Curr Med Sci. 2025 Sep 10.
    Novel Prognostic Scoring Systems for Severe CRS after Anti-CD19 CAR-T-Cells in Acute B-Lymphoblastic Leukemia.
    Sha Ke, Tai-Yuan Zhang, Zhuo-Lin Wu, Wei Xie, Lin Liu, Meng-Yi Du.
       OBJECTIVE: To develop a novel prognostic scoring system for severe cytokine release syndrome (CRS) in patients with B-cell acute lymphoblastic leukemia (B-ALL) treated with anti-CD19 chimeric antigen receptor (CAR)-T-cell therapy, aiming to optimize risk mitigation strategies and improve clinical management.
    METHODS: This single-center retrospective cohort study included 125 B-ALL patients who received anti-CD19 CAR-T-cell therapy from January 2017 to October 2023. These cases were selected from a cohort of over 500 treated patients on the basis of the availability of comprehensive baseline data, documented CRS grading, and at least 3 months of follow-up. Data on patient demographics, treatment history, laboratory parameters, CAR-T-cell characteristics, safety, and efficacy endpoints were collected. CRS severity was graded according to the 2019 ASTCT consensus criteria. Univariate and multivariate logistic regression analyses were conducted to identify factors associated with CRS severity, and a prognostic model was constructed.
    RESULTS: The overall incidence of CRS was 67.2%, with 13.6% having grade ≥ 3 (severe) CRS. Higher baseline and post-lymphodepletion minimal residual disease (MRD) levels and neutropenia on day 7 post-infusion were significantly associated with severe CRS. Inflammatory markers (CRP, ferritin, and IL-6) and coagulation dysfunction (APTT) on day 7 post-infusion were also predictive of CRS severity. The prognostic model incorporating these factors demonstrated robust discriminatory ability, with an area under the ROC curve of 0.875.
    CONCLUSION: This study developed a novel prognostic scoring system for severe CRS in Chinese B-ALL patients receiving anti-CD19 CAR-T-cell therapy. The model integrates clinical and laboratory parameters to facilitate early identification and management of severe CRS. Further validation in larger, prospective cohorts is warranted.
    Keywords:  B-cell acute lymphoblastic leukemia; Chimeric antigen receptor T-cell immunotherapy; Cytokine release syndrome; Predictive model
    DOI:  https://doi.org/10.1007/s11596-025-00109-0
  31. Immunol Rev. 2025 Sep;334(1): e70060
    Extrafollicular and Other Non-Germinal Center B Cell Responses: An Evolutionary Perspective.
    Emily M Flowers, Emily R Siniscalco, Stephanie C Eisenbarth.
      Classic models of humoral immunity focus on the role of germinal centers (GCs) in producing high affinity, class switched protective antibodies. However, antibodies can also be produced through a diverse range of GC-independent pathways. Such pathways are often labeled "extrafollicular", even when the localization of individual responses remains unknown, but in this review, we group them together under the broad umbrella of "nonGC responses". Experiments in mammals show that nonGC responses provide important humoral protection against infections and complement the eventual GC-derived antibody response. In this review, we explore the immunological foundations of nonGC and GC responses through an evolutionary lens and investigate the mechanisms of humoral immunity throughout vertebrate evolution. In animals that predate the evolution of GCs as they appear in mammals, B cell responses still occur at organized sites and with features also seen in mammals, including adjacent T cell and B cell regions, sites for antigen deposit, and B cell proliferation and mutation. Here we review the commonalities in nonGC responses across multiple genera, before and after the emergence of GCs. This comparison helps frame current efforts to mechanistically understand pathways for nonGC responses and the relative roles of GC- and nonGC-derived antibodies in humoral immunity.
    Keywords:  B cells; antibodies; evolution; extrafollicular; humoral immunity
    DOI:  https://doi.org/10.1111/imr.70060
  32. Cancer Lett. 2025 Sep 10. pii: S0304-3835(25)00606-8. [Epub ahead of print] 218036
    Improved identification of tumor-specific TCRs from circulating lymphocytes using autologous colorectal tumor organoids.
    Lisha Ma, Xiya Wang, Qianjing Zhang, Zhaoya Gao, Xiangwen Ji, Zhilang Li, Yixian Li, Pengchong Zhang, Xuan Che, Yun Sun, Yun Bai, Hongkui Deng.
      The identification of effective T cell receptors (TCRs) with specific reactivity against tumor cells is critical for the efficacy of TCR-engineered T cell therapy. However, different approaches for screening effective TCRs remain to be explored. We developed an optimized approach to identify effective TCRs based on an organoid culture system with patient-derived tumor cells in the presence of oxaliplatin and autologous dendritic cells. By coculturing the immunogenic debris of patient tumor cells from the organoid, we successfully enriched tumor-reactive CD4+ and CD8+ T cells, enhanced the activation and proliferation of T cells, and could facilitate the identification of tumor-reactive CD8+ T cells from patients with MHC I-downregulated tumors. We further used autologous tumor organoids to verify that candidate tumor-specific TCRs can elicit patient-specific tumor recognition and killing when expressed in allogeneic T cells. Our organoid-based tumor-reactive T cell enrichment system and TCR screening validation platform provide an empirical strategy for the isolation of tumor-reactive T cells and can advance the study of TCR-engineered T cell therapy.
    Keywords:  TCR identification; TCR-T therapy; immunogenic cell death; immunotherapy; tumor organoid
    DOI:  https://doi.org/10.1016/j.canlet.2025.218036
  33. Neurooncol Adv. 2025 Sep;7(Suppl 4): iv84-iv94
    Cellular immunotherapies for central nervous system cancers.
    Brian J Scott, Michelle Monje.
      Cellular Immunotherapies have transformed therapeutic options for individuals with hematologic malignancies over the past 10 years. There are several distinct types of cellular immunotherapies, each with potential applications to CNS cancers. Here, we review cancer cellular therapeutics for cancers of the brain and spinal cord, focusing on the preclinical and clinical studies that have been done in glioblastoma, diffuse intrinsic pontine glioma/diffuse midline glioma, medulloblastoma and lymphoma involving the central nervous system. Numerous potential therapeutic targets have been identified, and several early clinical trials have demonstrated safety and feasibility of administering CAR T and CAR NK cells for intracranial tumors. Addressing mechanisms of treatment failure, while safely and effectively studying the most promising therapies will advance the treatment landscape for these extremely challenging diseases.
    Keywords:  cellular immunotherapy; chimeric antigen receptor T cell; chimeric antigen receptor natural killer cell; diffuse intrinsic pontine glioma/diffuse midline glioma; glioblastoma
    DOI:  https://doi.org/10.1093/noajnl/vdaf120
  34. Crit Rev Immunol. 2025 ;45(5): 19-34
    Modulation of T Cell Regulation by Interleukin-2 Agonists: Mechanisms and Clinical Implications.
    Shreya S Sonak, Sharda Ishwarkar, Charu Nimbarte, Vijaykumar D Nimbarte.
      IL-2 agonists significantly modulate T cell regulation, impacting activation, proliferation, differentiation, and immune homeostasis. Interleukin-2 (IL-2) is crucial for T cell growth and function, binding to the IL-2 receptor to trigger signaling pathways that balance immune responses. IL-2 promotes the expansion of effector T cells and enhances regulatory T cells (Tregs), preventing autoimmune responses. This review examines the mechanisms of IL-2 agonists on T cell regulation, including their roles in cytotoxic T cells and Tregs proliferation, and immune homeostasis. Clinically, IL-2 agonists show promise in treating autoimmune diseases by boosting Treg function and in cancer immunotherapy by enhancing cytotoxic T cell activity. Optimizing IL-2 therapies to balance these effects is ongoing. IL-2 agonists are pivotal in modulating T cell responses with significant therapeutic potential for autoimmunity and cancer. Understanding IL-2 signaling is crucial for developing targeted treatments leveraging this cytokine's benefits.
    DOI:  https://doi.org/10.1615/CritRevImmunol.2025059823
  35. Naunyn Schmiedebergs Arch Pharmacol. 2025 Sep 08.
    Bibliometric analysis of immune-related acute kidney injury induced by cancer immunotherapy (2000-2025).
    Boxiang Zhang, Lucy Yue Lau, Yi Chen, Rongli Xie.
      Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy but are increasingly linked to immune-related kidney injury (irKI). This study presents the first bibliometric analysis of irKI research (2000-2025), aiming to identify key trends, mechanistic insights, and pharmacological risk factors. We analyzed 2,179 publications to understand the evolution of irKI research, focusing on areas like T cell-mediated tubular injury, immune system-driven inflammation, and changes in metabolism. Co-prescription of nonsteroidal anti-inflammatory drugs (NSAIDs) and proton pump inhibitors has been identified as a pharmacological risk factor. Biomarkers such as KIM-1 and CXCL9, as well as novel imaging modalities, have shown diagnostic promise but remain underutilized. We also observed a lack of nephrotoxicity profiling for newer therapies such as chimeric antigen receptor T cell (CAR-T). This study highlights gaps in research and collaboration, particularly the need for better understanding of pharmacological risk factors like NSAID and proton pump inhibitor co-prescription. Future research should focus on improving strategies for predicting, diagnosing, and managing irKI. The study also emphasizes immune-driven inflammation, T cell-mediated tubular injury, and metabolic reprogramming as key contributors to irKI pathogenesis. Additionally, underutilized biomarkers (e.g., KIM-1, CXCL9) and emerging imaging techniques offer opportunities for early detection and monitoring.
    Keywords:  Bibliometric analysis; Immune checkpoint inhibitors; Immune-related adverse events; Pharmacology; Tumor immunotherapy
    DOI:  https://doi.org/10.1007/s00210-025-04582-1
  36. Nat Rev Rheumatol. 2025 Sep 08.
    Emerging therapies for the treatment of systemic sclerosis.
    Jörg H W Distler, Masataka Kuwana, Shervin Assassi, Christopher P Denton.
      Systemic sclerosis (SSc) is an autoimmune disease in which fibrotic, vascular, autoimmune and fibrotic mechanisms synergize to promote disease progression. SSc is associated with high morbidity and mortality, primarily owing to fibrotic tissue remodelling and subsequent organ failure. Despite progress with the approval of novel therapies, mortality remains high; approximately half of the people diagnosed with SSc will succumb to disease. This statistic highlights the considerable need for novel, effective therapies. Indeed, SSc has become a disease with very active drug development. Numerous drugs with different modes of actions are currently evaluated in or are about to enter clinical trials in SSc. These clinical trials provide hope for effectively slowing or even halting the progression of fibrosis and thereby further improving outcomes for patients with SSc.
    DOI:  https://doi.org/10.1038/s41584-025-01294-x
  37. Nat Rev Immunol. 2025 Sep 08.
    Metabolic control of innate-like T cells.
    Thomas Riffelmacher, Mitchell Kronenberg.
      Immunometabolism, the intersection of cellular metabolism and immune function, has revolutionized our understanding of T cell biology. Changes in cellular metabolism help guide the development of thymocytes and the transition of T cells from naive to effector, memory and tissue-resident states. Innate-like T cells are a unique group of T cells with special characteristics. They respond rapidly, reside mainly in tissues and express T cell receptors with limited diversity that recognize non-peptide antigens. This group includes invariant natural killer T (iNKT) cells, mucosal-associated invariant T (MAIT) cells and some populations of γδ T cells. Different subsets of innate-like T cells rely on specific metabolic pathways that influence their differentiation and function and distinguish them from conventional CD4+ and CD8+ T cells. Although there are differences between innate-like T cell types, they share metabolic and functional features. In this Review, we highlight recent research in this emerging field. Understanding how metabolic programmes differ between innate-like T cells and other T cells may open opportunities for tailoring innate-like T cell responses and adoptive T cell therapies for use in cancer, metabolic and autoimmune diseases.
    DOI:  https://doi.org/10.1038/s41577-025-01219-5
  38. Clin Lymphoma Myeloma Leuk. 2025 Aug 16. pii: S2152-2650(25)00297-6. [Epub ahead of print]
    Predicators and Outcomes of Cytomegalovirus Reactivation in Chimeric Antigen Receptor T-Cell Therapy: A Systematic Review.
    Muhammad Atif Khan, Faiza Humayun Khan, Abat Khan, Aneela Majeed, Chelsea Gorsline, Nausheen Ahmed.
       INTRODUCTION: Cytomegalovirus (CMV) reactivation is a common complication in immunocompromised patients, but poorly defined in those undergoing chimeric antigen receptor T-cell (CAR-T) therapy. This systematic review investigates the predictors and outcomes of CMV reactivation in CAR-T recipients, focusing on survival, relapses, and nonrelapse mortality (NRM).
    METHODS: A systematic review was conducted following PRISMA 2020 guidelines to compare outcomes between CMV reactivation (R) and nonreactivation (NR) groups. A comprehensive search of PUBMED, EMBASE, and CENTRAL identified 172 studies, of which 4 met the inclusion criteria. Data was synthesized using descriptive statistical analysis to report frequencies and percentages.
    RESULTS: Among 462 CAR-T recipients, 114 (24.7%) experienced CMV reactivation, with a median onset of 20 days and 1.73% developing end-organ disease. Reactivation was more common among those receiving BCMA-targeted CAR-T (7% vs. 2.9%) and with prior allo-HSCT (35% vs. 7%). Severe CRS (11.4% vs. 8.6%) and ICANS (37.7% vs. 26.7%) were also more frequent in the reactivation group. Use of immunosuppressive therapy, including steroids (56% vs. 42.8%) and tocilizumab-anakinra (12% vs. 5%), was higher. Studies showed increased 1-year mortality and relapse in the reactivation group, with CMV reactivation independently predicting mortality (HR 2.3, 95% CI: 1.2-4.5, P = .02).
    CONCLUSION: CMV reactivation is a serious complication in CAR-T therapy, associated with higher mortality, relapse, and NRM. Key risk factors include BCMA-targeted CAR-T, prior allo-HSCT, and severe CRS/ICANS. Targeted monitoring and prophylactic strategies are crucial to improve outcomes.
    Keywords:  CART-T; CMV infection; Mortality; Relapse; Risk factors
    DOI:  https://doi.org/10.1016/j.clml.2025.08.014
  39. World J Gastrointest Pharmacol Ther. 2025 Sep 05. 16(3): 110305
    Microbiome-derived metabolites in cancer-associated anemia: An underexplored mechanistic link.
    Zhe Wang, Feng Wang.
      The review by Bangolo et al highlights the role of the gut microbiome in cancer-associated anemia (CAA). However, the impact of microbiome-derived metabolites is underexplored. In this letter, we focus on short-chain fatty acids, tryptophan metabolites, and polyamines as key mediators linking dysbiosis to impaired erythropoiesis and iron homeostasis. We also propose a research framework that integrates multi-omics analysis and gnotobiotic models. Finally, we discuss the clinical potential of metabolite-based diagnostics and microbiome-targeted therapies in managing CAA.
    Keywords:  Aryl hydrocarbon receptor; Cancer-associated anemia; Gut microbiota; Microbial metabolites; Short-chain fatty acids; Tryptophan
    DOI:  https://doi.org/10.4292/wjgpt.v16.i3.110305
  40. Open Res Eur. 2024 ;4 268
    Mapping leadership and communities in EU-funded research through network analysis.
    Fabio Morea, Alberto Soraci, Domenico De Stefano.
       Background: Horizon 2020 and Horizon Europe are flagship programs of the European Union aimed at supporting research and innovation, fostering collaboration among companies, academic institutions, and research organizations. Comprehensive data on projects, objectives, participants, funding details, and results of Horizon projects is available through the open access portal CORDIS (Community Research and Development Information Service). This paper introduces a novel methodology for utilizing CORDIS data to reveal collaborations, leadership roles, and their evolution over time.
    Methods: The methodology is based on network analysis. Data is downloaded from the CORDIS portal, enriched, segmented by year and transformed into weighted networks representing collaborations between organizations. Centrality measures are used to assess the influence of individual organizations, while community detection algorithms are used to identify stable collaborations. Temporal analysis tracks the evolution of these roles and communities over time. To ensure robust and reliable results, the methodology addresses challenges such as input-ordering bias and result variability, while the exploration of the solution space enhances the accuracy of identified collaboration patterns.
    Results: To illustrate the approach, the methodology is applied to a specific case: analyse the evolution of collaborations in hydrogen valleys, in the broader frame of "hydrogen energy" research and innovation projects funded by Horizon programmes.
    Conclusions: The proposed methodology effectively identifies influential organizations and tracks the stability of research collaborations. The insights gained are valuable for policy-makers and organizations seeking to foster innovation through sustained partnerships. This approach can be extended to other sectors, offering a framework for understanding the impact of EU research funding on collaboration and leadership dynamics.
    Keywords:  Community Detection; Horizon 2020; Horizon Europe; Hydrogen; Hydrogen Valley; Innovation; Network Analysis
    DOI:  https://doi.org/10.12688/openreseurope.18544.2
  41. Int J Mol Sci. 2025 Sep 05. pii: 8662. [Epub ahead of print]26(17):
    Sequencing Anti-CD19 Therapies in Diffuse Large B-Cell Lymphoma: From Mechanistic Insights to Clinical Strategies.
    Filomena Emanuela Laddaga, Mario Della Mura, Joana Sorino, Amanda Caruso, Stefano Martinotti, Giuseppe Ingravallo, Francesco Gaudio.
      CD19-targeted therapies, including monoclonal antibodies, antibody-drug conjugates, and chimeric antigen receptor (CAR) T-cell products, have significantly improved outcomes in relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). Despite their clinical efficacy, resistance and antigen modulation pose substantial challenges, especially in patients requiring sequential therapy. This review provides a comprehensive overview of CD19 biology and its relevance as a therapeutic target. We examine mechanisms of resistance such as antigen loss, epitope masking, and T-cell exhaustion, as well as the implications of tumor microenvironmental immunosuppression. Future efforts should prioritize the integration of real-time diagnostics, such as flow cytometry, immunohistochemistry, and transcriptomic profiling, and AI-assisted predictive models to optimize therapeutic sequencing and expand access to personalized immunotherapy.
    Keywords:  CAR-NK; CAR-T; CD19; antigen escape; bispecific antibodies; diffuse large B-cell lymphoma; immunotherapy; loncastuximab; tafasitamab; treatment sequencing
    DOI:  https://doi.org/10.3390/ijms26178662
  42. Int J Nanomedicine. 2025 ;20 10541-10566
    Advances in Lipid-Based Nanomedicine: Pathway Specific siRNA Therapy and Optimizing Delivery for Hepatocellular Carcinoma.
    Karkaz M Thalij, Huay Woon You, Kiran Balasaheb Aher, Girija Balasaheb Bhavar, Smita Tukaram Kumbhar, Mohammad Habeeb.
      Hepatocellular carcinoma (HCC) is a major global health issue, ranking as the sixth most common cancer and a leading cause of cancer-related deaths worldwide. Risk factors for HCC include chronic hepatitis B and C, obesity, alcohol abuse, diabetes, and metabolic disorders. Current treatments, such as surgery, transplantation, and chemotherapy, are often ineffective in advanced stages due to tumor resistance and the inability to target key oncogenic pathways. Recent advances in small interfering RNA (siRNA) therapy offer a promising solution to silence these pathways and hinder tumor progression. Nanoparticles, especially lipid-based nanoparticles (LNPs) like liposomes, solid lipid nanoparticles, exosomes etc. have emerged as an effective platform for siRNA delivery. LNPs provide critical advantages, including protection of siRNA from enzymatic degradation, improved cellular uptake, and precise tumor targeting through functionalization strategies. Compared to polymeric and metallic nanocarriers, LNPs demonstrate superior biocompatibility, biodegradability, and safety profiles. Furthermore, their ability to exploit natural mechanisms, such as apolipoprotein E (ApoE)-mediated uptake via low-density lipoprotein receptors on hepatocytes, enhances liver-specific delivery. This review explores advancements in siRNA therapeutics for HCC, highlighting nanoparticle-based delivery, cell signaling targets, and synthesis strategies. It also examines AI's role in optimizing siRNA design, formulation, and personalized treatment. These innovations enhance pathway-specific therapies, advancing clinical translation and improving HCC outcomes.
    Keywords:  cell signalling; hepatocellular carcinoma; lipid nanomedicine; siRNA; targeted delivery
    DOI:  https://doi.org/10.2147/IJN.S532246
  43. Dev World Bioeth. 2025 Sep 10.
    Making Advanced Therapies Affordable and Accessible: Two Strategic Approaches.
    Ubaka Ogbogu, Lauren Albrecht.
      This article explores two complementary strategies for addressing the affordability and access challenges facing advanced therapies. As high development costs and limited market access have led to the withdrawal of several therapies, the article examines how these barriers create 'valleys of death' that prevent innovation from reaching patients. Through the case of Glybera and other examples, it outlines a rehabilitative approach focused on reforming current systems through improved reimbursement schemes, regulatory streamlining, and more efficient manufacturing. It also presents a transformative approach that embeds affordability and access from the beginning of the research and development process, encouraging local innovation, equitable intellectual property practices, and adaptive regulatory frameworks. Lessons from the COVID-19 vaccine experience demonstrate the real-world potential of these strategies to ensure that promising therapies are not only developed, but also equitably delivered worldwide.
    Keywords:  COVID‐19 vaccine; Glybera; access and affordability; advanced therapies; global health equity; medicines reimbursement schemes; valley of death
    DOI:  https://doi.org/10.1111/dewb.70004
  44. Curr Opin Rheumatol. 2025 Sep 08.
    A comprehensive review of systemic sclerosis-primary biliary cholangitis overlap: emerging evidence for a distinct clinical subtype.
    Areeka Memon, Manvitha Nadella, Morgan Emokpae, David N Assis.
       PURPOSE OF REVIEW: To synthesize current knowledge on the genetic, immunopathogenic, and clinical presentations of systemic sclerosis (SSc) and primary biliary cholangitis (PBC) with a focus on their co-occurrence as a clinically relevant overlap syndrome. This narrative review summarizes preclinical and clinical studies addressing SSc-PBC overlap.
    RECENT FINDINGS: Genomic studies highlight shared susceptibility loci between SSc and PBC. Furthermore, SSc-PBC overlap patient sera reveals anticentromere antibodies which cross-react with an antigenic motif on pyruvate dehydrogenase-E2 (structural core of pyruvate dehydrogenase complex catalyzing formation of acetyl coA), the most common target of antimitochondrial antibodies in PBC. Similar profibrotic cytokines and T regulatory cell profiles are identified in sera and skin and liver biopsies of patients with SSc and PBC respectively. Analysis of clinical phenotypes reveals that SSc-PBC overlap patients have reduced incidence of pulmonary fibrosis and pulmonary arterial hypertension compared to SSc alone, and less severe hepatic involvement compared to PBC alone.
    SUMMARY: SSc-PBC overlap remains an understudied disease process. This review summarizes current knowledge and outlines future directions to guide research and improve care for patients with this distinct clinical overlap.
    Keywords:  limited cutaneous systemic sclerosis; primary biliary cholangitis; systemic sclerosis; systemic sclerosis–primary biliary cholangitis; systemic sclerosis–primary biliary cholangitis overlap
    DOI:  https://doi.org/10.1097/BOR.0000000000001127
  45. Int Immunopharmacol. 2025 Sep 08. pii: S1567-5769(25)01494-8. [Epub ahead of print]165 115503
    Gut microbiome and rheumatoid arthritis: Revisiting the gut-joint axis.
    Bhupinder Kapoor, Monica Gulati.
      Over the past few decades, the scientific perspective on gut microbiota has undergone a profound transformation, particularly with the emergence and advancement of microbiome research. Next-generation sequencing technologies have emerged as a foundational tool in microbiome research, facilitating comprehensive characterization of microbial communities across diverse sample types and ecological niches. Significant alterations in gut microbiota composition have been observed in disease states compared to healthy individuals, suggesting a direct association between gut dysbiosis and host health status. Initially, alterations in gut microbiota were primarily thought to be associated with gastrointestinal disorders. With advancing research, however, it has become evident that gut dysbiosis is also implicated in a broad spectrum of extra-intestinal conditions, including neurological, dermatological, metabolic, and musculoskeletal diseases. The present review provides a comprehensive analysis of preclinical and clinical studies elucidating the role of gut dysbiosis in the pathogenesis and progression of rheumatoid arthritis. Advancements in the understanding of the gut-joint axis have facilitated the development of novel therapeutic modalities, including probiotics, prebiotics, synbiotics, and fecal microbiota transplantation, that have been comprehensively discussed in present review.
    Keywords:  Fecal microbiota transplantation; Gut microbiota; Gut-joint axis; Microbiome; Prebiotics; Probiotics; Rheumatoid arthritis
    DOI:  https://doi.org/10.1016/j.intimp.2025.115503
  46. Adv Healthc Mater. 2025 Sep 13. e02110
    Redox-Active Nanozymes in Metabolic Modulation for Precision Therapeutics.
    Wenying Zhang, Meifang Wang, Ping'an Ma, Jun Lin.
      Nanozyme metabolic therapy leverages the catalytic activity of artificial enzymes to reprogram dysregulated metabolic pathways at disease sites, offering a targeted approach to restore physiological homeostasis. This review uniquely focuses on redox-active nanozymes and their roles in modulating key metabolic circuits (e.g., glucose, lactate, lipid, and xanthine metabolism) across diverse pathological contexts. While cancer remains the most extensively explored domain, emerging uses of nanozymes in bacterial infections, cardiovascular diseases, diabetes, obesity, and inflammatory disorders, where mechanistic understanding is still evolving, are also highlighted. By selectively altering metabolite levels and enzymatic activities, nanozymes enable precise metabolic control with high catalytic specificity. Nanozymes are systematically categorized based on their redox mechanisms and the metabolic pathways they influence, and discuss representative examples across disease contexts. Finally, the review concludes by outlining current challenges and emphasizing the translational potential of nanozymes as programmable metabolic modulators, aiming to expand their impact beyond oncology into broader clinical applications.
    Keywords:  catalytic therapy; metabolic modulation; nanozymes; precision therapeutics; redox mechanism
    DOI:  https://doi.org/10.1002/adhm.202502110
  47. Clin Transplant Res. 2025 Sep 12.
    Regulatory T cell therapy in solid organ transplantation: clinical applications and laboratory monitoring strategies.
    Minjeong Nam.
      Regulatory T cells (Tregs) play a fundamental role in maintaining immunological homeostasis and sustaining immune tolerance. In solid organ transplantation, Tregs have emerged as a promising strategy of cellular immunotherapy capable of reducing allograft rejection and mitigating long-term complications. Early-phase clinical studies have established the safety and feasibility of adoptive Treg therapy. Building on these pivotal findings, Treg therapy has created a solid foundation for translational application. However, successful clinical implementation requires a deeper understanding of Treg biology, clarification of their mechanisms of action, and the development of reliable strategies for in vivo monitoring. This review provides a detailed overview of Treg mechanisms, ongoing clinical trials, and methodological approaches for evaluating their phenotype and function through cell-based, protein-based, and gene-based assays. In addition, it highlights key considerations for optimizing therapeutic efficacy and ensuring safety, with the ultimate aim of advancing Treg therapy toward routine clinical use in solid organ transplantation.
    Keywords:  Immunologic monitoring; Immunotherapy; Regulatory T cell; Transplantation
    DOI:  https://doi.org/10.4285/ctr.25.0040
  48. Indian J Dermatol. 2025 Sep-Oct;70(5):70(5): 257-266
    Etiopathogenesis and Current Management of Oncogenic Pruritus - A Narrative Review.
    Sahana Srihari, Shreya Poddar, Najeeba Riyaz, S Praveen Kumar, Deepti Chigullapalli, Vikas Shankar, Kapil Vyas, Raejesh Verma, Prabhakar Sangolli, Kumar Mittal, Indrashis Podder.
      Oncogenic pruritus or malignancy associated pruritus is an emerging cause of systemic pruritus in patients with malignancies. It is a debilitating condition and worsens the patient's quality of life, often interfering with their palliative care. Oncogenic pruritus can arise de-novo in such patients due to release of pruritogens and other inflammatory mediators from tumour cells into blood stream, or it may present as a component of paraneoplastic syndrome. A detailed history and clinical examination are necessary to rule out other causes of systemic pruritus. Objective evaluation of itch is recommended using various scales to evaluate the treatment response and assessing its severity. There is lack of clinical trials concerning the management of oncogenic pruritus and most information is derived from sporadic case reports. Despite being an important and emerging cause of pruritus during malignancy, this diagnosis is often missed and remains under-reported due to lack of awareness about this entity. This narrative review highlights the current understanding of this condition focusing on its causes, pathogenesis, diagnosis, and management, along with newer investigational drugs. These authors hope that the present review will generate awareness about this condition among treating physicians and enable its early diagnosis and appropriate management.
    Keywords:  Malignancy associated pruritus; management; oncogenic pruritus; pathogenesis
    DOI:  https://doi.org/10.4103/ijd.ijd_523_24
  49. Tissue Eng Regen Med. 2025 Sep 08.
    Clinical Efficacy of Stem Cell Therapy in Neurotraumatic and Neurodegenerative Conditions: A Comparative Review.
    Jun Beom Ku, Ray J Pak, Sarah S Ku, Robert D Holland, Han-Soo Kim.
       BACKGROUND: Neurotraumatic conditions, such as spinal cord injury, brain injury, and neurodegenerative conditions, such as amyotrophic lateral sclerosis, pose a challenge to the field of rehabilitation for its complexity and nuances in management. For decades, the use of cell therapy in treatment of neurorehabilitation conditions have been explored to complement the current, mainstay treatment options; however, a consensus for standardization of the cell therapy and its efficacy has not been reached in the medical community. This study aims to provide a comparative review on the very topic of cell therapy use in neurorehabilitation conditions in an attempt to bridge the gap in knowledge.
    METHODS: Studies were searched from the PubMed database published from 2014 to 2024 employing the terms including but not exclusive to "spinal cord injury," "brain injury," "amyotrophic lateral sclerosis," "regenerative medicine," "cell therapy," and "stem cell." Following the PRISMA 2020 statement, the studies were screened, included, and excluded. Thirty three studies were identified and selected for this review.
    RESULTS: Countless researchers investigated the efficacy of various stem cell products for the treatment of numerous neurotraumatic conditions, such as spinal cord injury, traumatic brain injury, and neurodegenerative conditions such as amyotrophic lateral sclerosis. The recent decade of studies suggest that in neurotraumatic conditions, bone-marrow-derived and neural stem cells can be effective, and in neurodegenerative conditions, such as ALS, mesenchymal and neural stem cells can be efficacious.
    CONCLUSION: Emerging data from the latest research is encouraging to the patients suffering from neurotraumatic and neurodegenerative conditions, which present themselves as a need for further studies with improved standardization in study design, including cell source specification, differentiation and culture method, and outcome measures to ensure a wide applicability.
    Keywords:  Amyotrophic lateral sclerosis; Cell therapy; Spinal cord injury; Traumatic brain injury
    DOI:  https://doi.org/10.1007/s13770-025-00757-2
  50. J Multidiscip Healthc. 2025 ;18 5405-5419
    Ethical and Legal Governance of Generative AI in Chinese Healthcare.
    Jinrun Jia, Shiqiao Zhao.
      The application of generative artificial intelligence (AI) technology in the healthcare sector can significantly enhance the efficiency of China's healthcare services. However, risks persist in terms of accuracy, transparency, data privacy, ethics, and bias. These risks are manifested in three key areas: first, the potential erosion of human agency; second, issues of fairness and justice; and third, questions of liability and responsibility. This study reviews and analyzes the legal and regulatory frameworks established in China for the application of generative AI in healthcare, as well as relevant academic literature. Our research findings indicate that while China is actively constructing an ethical and legal governance framework in this field, the regulatory system remains inadequate and faces numerous challenges. These challenges include lagging regulatory rules; an unclear legal status of AI in laws such as the Civil Code; immature standards and regulatory schemes for medical AI training data; and the lack of a coordinated regulatory mechanism among different government departments. In response, this study attempts to establish a governance framework for generative AI in the medical field in China from both legal and ethical perspectives, yielding relevant research findings. Given the latest developments in generative AI in China, it is necessary to address the challenges of its application in the medical field from both ethical and legal perspectives. This includes enhancing algorithm transparency, standardizing medical data management, and promoting AI legislation. As AI technology continues to evolve, more diverse technical models will emerge in the future. This study also proposes that to address potential risks associated with medical AI, efforts should be made to establish a global AI ethics review committee to promote the formation of internationally unified ethical and legal review mechanisms.
    Keywords:  ethics; generative artificial intelligence; healthcare; law; policy
    DOI:  https://doi.org/10.2147/JMDH.S541271
  51. Support Care Cancer. 2025 Sep 13. 33(10): 853
    MASCC/ISOO Clinical Practice Statement: dental evaluation and management prior to treatment for hematologic malignancies and CAR T-cell therapy.
    Yehuda Zadik, Judith E Raber-Durlacher, Joel B Epstein, Alessandra Majorana, Wanessa Miranda-Silva, Sujin Yang, Nicole Blijlevens, Sharon Elad.
       PURPOSE: A MASCC/ISOO Clinical Practice Statement (CPS) aims to provide clinicians with a guide for managing oral conditions in cancer patients. This CPS addresses dental care prior to chemotherapy, hematopoietic cell transplantation, chimeric antigen receptor (CAR) T-cell therapy, and other treatments for hematologic malignancies in pediatric, adult, and elderly patients. Guidance on optimal timing for resuming dental treatment post-therapy is also included.
    METHODS: This CPS was developed through a critical evaluation of the literature, followed by a structured discussion of a group of leading experts, members of the Oral Care Study Group of MASCC/ISOO. Information is presented in succinct bullet points and a table to create a practical manual on the best standards of care.
    RESULTS: Patients undergoing anti-cancer therapy require a thorough dental assessment and treatment. Pre-therapy dental care aims to prevent oral infection, systemic pathogen spread, oral pain, local irritation, and risk of aspiration and to educate patients on oral hygiene and managing the expected common oral complications. This preventive approach supports oral intake, relieves pain, prevents treatment interruptions, enhances quality of life, and potentially reduces mortality. This CPS outlines the essential considerations for the dental evaluation and treatment, focusing on key dental diagnoses, procedural prioritization, and timing relative to the hemato-oncologic therapy.
    CONCLUSIONS: This CPS provides clinicians with strategies for effective dental clearance, improving patient outcomes and minimizing complications during and after anti-cancer therapy. CAR T-cell therapy introduces additional considerations in the dental treatment plan before and immediately after the cytoreductive therapy.
    Keywords:  CAR-T therapy, Chemotherapy; Cancer; Dental infection; Geriatric; Hemato-oncology; Hematopoietic cell transplantation; Leukemia; Neutropenia; Pediatric; Prevention
    DOI:  https://doi.org/10.1007/s00520-025-09845-4
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