bims-carter Biomed News
on CAR-T Therapies
Issue of 2025–06–22
twenty-six papers selected by
Luca Bolliger, lxBio
  1. Emerging frontiers in adoptive cell therapies: innovations, challenges, and future perspectives.
  2. The neurological toll of CAR T cell therapy.
  3. CAR-NK, a Splendid Strategy for Cancer, Especially for Gynecologic Tumor.
  4. Technologies for chimeric antigen receptor transgene delivery.
  5. A bibliometric analysis of challenges and advancements in the integrated application of nanoparticles and chimeric antigen receptor T cell therapy.
  6. Innovative approaches to CAR-T cell therapy: the role of lipid metabolism pathways.
  7. Predictive value of preclinical models for CAR-T cell therapy clinical trials: a systematic review and meta-analysis.
  8. B cell antigens: A key to optimizing CAR-T cell therapy.
  9. Cord blood-derived iNK T cells as a platform for allogeneic CAR T cell therapy.
  10. In vivo CAR T cell generation to treat cancer and autoimmune disease.
  11. Latest updates on pathogenesis mechanisms and management strategies for cytokine release syndrome, neurotoxicity, and hemophagocytic lymphohistiocytosis related to CAR-T cell therapies.
  12. Unsupervised Machine Learning-Based Process Analytical Tools for Near Real-Time Cell Morphology Analysis During CAR-T Cell Manufacturing.
  13. The Role of Radiotherapy in Relapsed or Refractory Diffuse Large B-Cell Lymphoma Post-CAR-T Therapy: A Systematic Literature Review.
  14. T-Cell Redirecting Strategies in Large B-Cell Lymphoma and Follicular Lymphoma.
  15. Nanomaterials Mediated Enhancement of CAR-T for HCC: Revolutionizing Immunotherapy Strategies.
  16. The Role of Exosomes and Extracellular Vesicles in Joint Preservation and Articular Cartilage Regeneration: Where Are We Now?
  17. Breaking barriers: exploring blood-brain barrier crossing mechanisms with nanomedicine for effective glioma treatment.
  18. Autoimmune Complications of Lymphoproliferative Diseases.
  19. Real-world healthcare costs for patients treated with chimeric antigen receptor T-cell therapy in Canada.
  20. Generative AI - Assisted Adaptive Cancer Therapy.
  21. Exploring AAV-Mediated Gene Therapy for Inner Ear Diseases: from Preclinical Success to Clinical Potential.
  22. Molecular hydrogen therapy: A "democratic" emerging strategy against aging and age-related diseases.
  23. Unlocking the potential: advancements and applications of gene therapy in severe disorders.
  24. Interferon-Stimulated Genes: Novel Targets in Renal Pathogenesis.
  25. Biomimetic extracellular vesicles derived from chimeric antigen receptor monocytes to treat glioblastoma: An efficient and safe intranasal drug delivery nanoplatform.
  26. Immune checkpoint inhibitors in cancer therapy: what lies beyond monoclonal antibodies?
  1. Med Oncol. 2025 Jun 15. 42(7): 261
    Emerging frontiers in adoptive cell therapies: innovations, challenges, and future perspectives.
    Anmol Dogra, Ranjeet Kumar Yadav, Himanshu Singh, Vimal Datt.
      Adoptive cell therapy (ACT) is a ground-breaking development in cancer treatment that uses modified immune cells to target and eradicate tumors precisely. ACT is a type of immunotherapy in which T cells are genetically manipulated to produce chimeric antigen receptor (CAR) T cells, tumor-infiltrating lymphocytes (TILs), and T cell receptors. CAR-T cell therapy, with its promising effects, has transformed the area of ACTs, notably for hematologic malignancies. ACT is not ideal, and it can cause significant side effects, limiting its use in clinical trials. One of the most promising approaches to reducing side effects is to give adoptive T cells the ability to target neoantigens, which are unique to tumor cells. In this review, we focused on the principles, benefits, challenges, and pre-clinical, translational, and clinical research on ACT, as well as safety concerns such as cytokine release syndrome and neurotoxicity. We also discussed combination approaches, personalized approaches, and emerging technologies involved in maximizing ACT efficacy.
    Keywords:  Adoptive cell therapy; CAR-T cells; Clinical studies; Emerging technologies; Translational research; Tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.1007/s12032-025-02808-z
  2. Cell. 2025 Jun 12. pii: S0092-8674(25)00501-X. [Epub ahead of print]188(12): 3097-3098
    The neurological toll of CAR T cell therapy.
    Meghan B Ward, Giedre Krenciute.
      Understanding acute and long-term adverse events following CAR T cell therapy for cancer remains a crucial area of investigation as CAR T cells become more prominent in the clinic. In this issue of Cell, Geraghty and Acosta-Alvarez et al. investigate the mechanisms underlying cognitive decline in animal models following CAR T cell therapy for hematological, solid, and CNS malignancies.
    DOI:  https://doi.org/10.1016/j.cell.2025.04.031
  3. Immun Inflamm Dis. 2025 Jun;13(6): e70210
    CAR-NK, a Splendid Strategy for Cancer, Especially for Gynecologic Tumor.
    Yisen Cao, Liying Wang, Liang Wang.
       BACKGROUND: NK cells are a class of innate lymphocytes capable of nonspecifically killing tumor cells without MHC restriction or prior sensitization. Recent advancements in biotechnology, particularly the development of chimeric antigen receptors (CAR) and related technologies, have enabled targeted tumor cell elimination. CAR endows NK cells with enhanced functionality, with the extracellular domains typically consisting of single-chain variable fragments (scFv) for targeting specific antigens. CAR-NK cells have shown excellent results in several preclinical studies and clinical trials for hematologic malignancies. However, their clinical application in the treatment of solid tumors is still insufficient. Current treatments for gynecological cancers primarily involve surgery, chemotherapy, and radiotherapy, all of which often present substantial side effects and variable efficacy. While CAR-T cell therapy has shown effectiveness in certain gynecological tumors, its clinical application is hindered by severe side effects, such as Cytokine Release Syndrome (CRS) and Graft-Versus-Host Disease (GVHD). CAR-NK cell therapy offers improved safety profiles in clinical applications.
    OBJECTIVE: This review aims to systematically evaluate recent methodological innovations in CAR-NK engineering and their translational potential in tumor-targeted treatment, providing valuable insights for clinical trials and studies.
    METHODS: Electronic databases, including PubMed and Web of Science were searched for relevant literature. Keywords are as follows: CAR-NK cell; Chimeric antigen receptor; Solid tumor; cell therapy; gynecological cancers.
    RESULTS: CAR-NK engineering has innovations such as multi-targeted CAR design, gene editing for enhanced persistence, and "off-the-shelf" CAR-NK cells compared to CAR-T cells.
    CONCLUSION: CAR-NK cell therapy combines safety and anti-tumor efficacy, particularly for gynecological cancers.
    Keywords:  CAR‐NK cell; cell therapy; chimeric antigen receptor; gynecological cancers; solid tumor
    DOI:  https://doi.org/10.1002/iid3.70210
  4. Trends Mol Med. 2025 Jun 19. pii: S1471-4914(25)00122-4. [Epub ahead of print]
    Technologies for chimeric antigen receptor transgene delivery.
    Yudian Xiao, Bowen Wu, Qiuping Zhou, Fan Wu, Nei Li, Chenqi Xu, Xuexiang Han.
      Ex vivo chimeric antigen receptor (CAR) T cell therapy has achieved clinical success in hematological malignancies; yet, viral transduction risks insertional mutagenesis. Developing safe and efficient nonviral approaches for the genetic engineering of T cells and other immune cells is the key to next-generation immunotherapy for cancer and noncancerous diseases. mRNA is an emerging modality for CAR engineering because of its transient expression and minimal risks. As a clinically validated nonviral vector, lipid nanoparticles (LNPs) are gaining popularity for ex vivo/in vivo mRNA-based CAR engineering of immune cells, making cell therapy safer and affordable. This review discusses the progress, delivery approaches, and challenges of CAR therapy and highlights mRNA-LNP advancements in shaping future CAR immune cell therapy for oncology and non-oncology.
    Keywords:  cell immunotherapy; chimeric antigen receptor; gene delivery; lipid nanoparticle; mRNA; virus
    DOI:  https://doi.org/10.1016/j.molmed.2025.05.011
  5. Hum Vaccin Immunother. 2025 Dec;21(1): 2518634
    A bibliometric analysis of challenges and advancements in the integrated application of nanoparticles and chimeric antigen receptor T cell therapy.
    Yang Gao, Yang Zhou, Xiaolin He, Hongwei Lin, Keying Fang, Qijun Hou, Huafang Wang, Honghao Zhang, Yixi Zhang, Yuhua Li.
      In recent years, the integration of nanoparticles with chimeric antigen receptor T-cell (CAR-T) therapy has advanced rapidly, garnering considerable attention from both academic and industrial sectors. However, a comprehensive analysis of key trends and emerging frontiers in this interdisciplinary field remains lacking. To address this gap, we conducted a bibliometric analysis of 515 publications indexed in the Web of Science Core Collection from 2013 to 2024. Using VOSviewer, CiteSpace, and R-bibliometrix, we analyzed publication trends, influential journals, national and institutional contributions, leading authors, and high-impact references. Keyword co-occurrence analyses were performed in VOSviewer, applying a minimum occurrence threshold of five. Citation bursts and clustering analyses of references and keywords were conducted using CiteSpace with default detection settings. Our analysis revealed major research hotspots, especially the optimization of CAR-T cell manufacturing processes and strategies to overcome barriers within the immunosuppressive tumor microenvironment. Looking forward, research is expected to focus increasingly on nanotechnologies such as lipid nanoparticles, precision cell tracking, and siRNA delivery platforms. These innovations hold substantial promise for enhancing the therapeutic efficacy of CAR-T therapies, particularly in the treatment of solid tumors, where conventional approaches remain inadequate. By identifying emerging directions and influential research trends, our analysis highlights the dynamic synergy between nanoparticles and CAR-T therapies, helping to fuel groundbreaking advances in tumor immunotherapy. This study provides data-driven insights that inform clinical trial design, foster interdisciplinary collaboration, and demonstrate the field's strong potential to transform future cancer treatment paradigms.
    Keywords:  Chimeric antigen receptor T cell therapy; bibliometrics; cell engineering; nanoparticle; tumor immunotherapy; tumor microenvironment
    DOI:  https://doi.org/10.1080/21645515.2025.2518634
  6. J Transl Med. 2025 Jun 17. 23(1): 670
    Innovative approaches to CAR-T cell therapy: the role of lipid metabolism pathways.
    Minjie Guo, Yuting Zhang, Xiao Yuan, Xu Wang.
      The efficient response structure of chimeric antigen receptor T (CAR-T) cells has led to significant success in the treatment of hematological malignancies. However, when confronted with the challenges associated with solid tumors, CAR-T cells have increasingly exhibited limitations, including inadequate infiltration and a shortened lifespan. Consequently, enhancing CAR-T cells to broaden their applicability across a wider range of malignancies has emerged as an urgent priority. Nutrient metabolism is integral to the entire lifecycle of CAR-T cells, with lipid metabolism serving as a critical pathway for sustaining the energy supply of memory T cells. This aspect is essential for the long-term survival of CAR-T cells and underpins their overall efficacy. This article aims to explore the impact of tumors on T-cell lipid metabolism, drawing on existing research findings, and analyzing strategies for improving CAR-T cells from this perspective. It is hoped that this investigation will provide new insights for enhancing the efficacy of CAR-T cell therapies.
    Keywords:  CAR-T cell; Co-stimulatory domains; Cytokines; Lipid metabolism; T cell
    DOI:  https://doi.org/10.1186/s12967-025-06718-6
  7. J Immunother Cancer. 2025 Jun 12. pii: e011698. [Epub ahead of print]13(6):
    Predictive value of preclinical models for CAR-T cell therapy clinical trials: a systematic review and meta-analysis.
    David Andreu-Sanz, Lisa Gregor, Emanuele Carlini, Daniele Scarcella, Carsten Marr, Sebastian Kobold.
      Background Experimental mouse models are indispensable for the preclinical development of cancer immunotherapies, whereby complex interactions in the tumor microenvironment can be somewhat replicated. Despite the availability of diverse models, their predictive capacity for clinical outcomes remains largely unknown, posing a hurdle in the translation from preclinical to clinical success. Methods This study systematically reviews and meta-analyzes clinical trials of chimeric antigen receptor (CAR)-T cell monotherapies with their corresponding preclinical studies. Adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a comprehensive search of PubMed and ClinicalTrials.gov was conducted, identifying 422 clinical trials and 3,157 preclinical studies. From these, 105 clinical trials and 180 preclinical studies, accounting for 44 and 131 distinct CAR constructs, respectively, were included. Results Patients' responses varied based on the target antigen, expectedly with higher efficacy and toxicity rates in hematological cancers. Preclinical data analysis revealed homogeneous and antigen-independent efficacy rates. Our analysis revealed that only 4% (n=12) of mouse studies used syngeneic models, highlighting their scarcity in research. Three logistic regression models were trained on CAR structures, tumor entities, and experimental settings to predict treatment outcomes. While the logistic regression model accurately predicted clinical outcomes based on clinical or preclinical features (Macro F1 and area under the curve (AUC)>0.8), it failed in predicting preclinical outcomes from preclinical features (Macro F1<0.5, AUC<0.6), indicating that preclinical studies may be influenced by experimental factors not accounted for in the model. Conclusion These findings underscore the need to better understand the experimental factors enhancing the predictive accuracy of mouse models in preclinical settings.
    Keywords:  Chimeric antigen receptor - CAR; Hematologic Malignancies; META-ANALYSIS; Solid tumor; T cell
    DOI:  https://doi.org/10.1136/jitc-2025-011698
  8. Int Rev Immunol. 2025 Jun 19. 1-28
    B cell antigens: A key to optimizing CAR-T cell therapy.
    Purva Khodke, Dhananjay Hasurkar, Aakanksha Upadhyay, Aditi Shedge, Rhea Sippy, Bajarang Vasant Kumbhar.
      B-cells are vital immune cells that differentiate into plasma cells to produce antibodies targeting specific antigens. They also act as Antigen Presenting Cells, displaying processed antigens on Major Histocompatibility Complex class-II molecules to activate helper T-cells. This process triggers immune response and memory development. B-cells have surface antigens crucial for their function, which are often overexpressed in B cell cancers, making them targets for therapies like Chimeric Antigen Receptor (CAR) T-cell therapy. However, the choice of antigen is crucial. Tumor associated antigens are common but can cause off-target effects, while tumor specific antigens are more specific but less common. Furthermore, the precise epitope on the antigen recognized by the CAR-T cells significantly influences activation, which can also depend on the epitope's distance from the B-cell membrane. To facilitate the identification of extracellular regions of tumor antigens for CAR interactions, this review models tumor antigen structures embedded in the lipid bilayer, analyzing their roles and functions. Specifically, the characterization of B-cell surface antigens, encompassing their structural features and their potential as targets for CAR-T therapy are discussed. Each antigen is meticulously examined to gain insights into their specific roles within B cell biology and their potential as therapeutic targets. In conclusion, this review highlights the importance of understanding B cell antigens for the development of effective CAR-T cell therapies. The insights into antigen structures and functions presented here can guide the selection of optimal targets and the design of CAR-T cells to combat B cell malignancies effectively.
    Keywords:  AlphaFold; B-Cell; CAR-T cell therapy; antigens; distal/proximal epitope
    DOI:  https://doi.org/10.1080/08830185.2025.2515839
  9. Front Immunol. 2025 ;16 1621260
    Cord blood-derived iNK T cells as a platform for allogeneic CAR T cell therapy.
    Maison Grefe, Abel Trujillo-Ocampo, Jelita Clinton, Hong He, Ling Yu, Dan Li, Qing Ma, Elizabeth J Shpall, Jeffrey J Molldrem, Jin S Im.
      CD1d-restricted invariant Natural Killer (iNK) T cells are a suitable candidate for allogeneic Chimeric Antigen Receptor (CAR) T cell therapy as they do not cause graft-versus-host disease (GvHD) due to the monomorphic nature of CD1d proteins. However, the phenotypic and functional heterogeneity of iNK T cells from adult donors (AD) may lead to the inconstant CAR-iNK T cell products. Cord blood-derived (CB) iNK T cells, in contrast, exhibit inter-donor homogeneity in phenotype including uniform CD4 expression and are enriched in memory iNK T cell populations. Thus, we evaluated the preclinical therapeutic potential of iNK T cells derived from cord blood (CB) as an off the shelf CAR T cell therapy platform, given the dominant presence of CD4+ iNK T cells. First, CB-derived iNK T cells were extremely enriched with CD4+ iNK T cells that express various NK receptors and display iNK-TCR mediated cytotoxicity but in a lesser degree than AD-derived CD4- iNK T cells. When engineered with an 8F4CAR targeting the acute myeloid leukemia-associated antigen PR1 presented in HLA-A2*01, CB-8F4CAR-iNK T cells showed a greater expansion capacity with higher CD62L expression than AD-8F4CAR-iNK T cells but with similar 8F4CAR expression and iNK T purity. CB-8F4CAR-iNK T cells displayed in vitro cytotoxicity against PR1/HLA-A2+ primary Acute Myeloid Leukemia (AML) and cell lines better than AD-8F4CAR iNK T cells and maintained potent cytotoxicity in repeated antigenic challenges. Moreover, CB-8F4CAR-iNK T cells showed anti-leukemia activity in vivo in a dose dependent manner. Lastly, CB-8F4CAR-iNK T cells were polarized to produce Th2-biased cytokines but in a lesser amount after 8F4CAR-mediated leukemia cytolysis compared to iNK-TCR mediated activation. In conclusion, consistent CD4+ phenotype, superior expansion capacity, and enhanced CD62L expression of CB-CAR-iNK T cells suggest that they may provide an alternative off-the-shelf source for effective CAR-iNK T cell therapy, while reducing the risk of severe cytokine release syndrome through their immunomodulatory properties. Thus, our results support the potential use of CB-iNK T cells as an allogeneic CAR-T cell therapy platform as they maintain a potent cytotoxicity with potentially better safety profile given a Th2-biased cytokine production upon activation.
    Keywords:  CAR T cell therapy; acute myeloid leukemia; chimeric antigen receptor; cord blood; invariant natural killer t cells
    DOI:  https://doi.org/10.3389/fimmu.2025.1621260
  10. Science. 2025 Jun 19. 388(6753): 1311-1317
    In vivo CAR T cell generation to treat cancer and autoimmune disease.
    Theresa L Hunter, Yanjie Bao, Yan Zhang, Daiki Matsuda, Romina Riener, Annabel Wang, John J Li, Ferran Soldevila, David S H Chu, Duy P Nguyen, Qian-Chen Yong, Brittany Ross, Michelle Nguyen, James Vestal, Scott Roberts, Diana Galvan, Jerel Boyd Vega, Donald Jhung, Matthew Butcher, Josephine Nguyen, Stanley Zhang, Claudia Fernandez, Jeffrey Chen, Carolina Herrera, Yi Kuo, E Michael Pica, Goutam Mondal, Andrew L Mammen, John Scholler, Steven P Tanis, Stuart A Sievers, Aric M Frantz, Gregor B Adams, Laura Shawver, Ramin Farzaneh-Far, Michael Rosenzweig, Priya P Karmali, Adrian I Bot, Carl H June, Haig Aghajanian.
      Chimeric antigen receptor (CAR) T cell therapies have transformed treatment of B cell malignancies. However, their broader application is limited by complex manufacturing processes and the necessity for lymphodepleting chemotherapy, restricting patient accessibility. We present an in vivo engineering strategy using targeted lipid nanoparticles (tLNPs) for messenger RNA delivery to specific T cell subsets. These tLNPs reprogrammed CD8+ T cells in both healthy donor and autoimmune patient samples, and in vivo dosing resulted in tumor control in humanized mice and B cell depletion in cynomolgus monkeys. In cynomolgus monkeys, the reconstituted B cells after depletion were predominantly naïve, suggesting an immune system reset. By eliminating the requirements for complex ex vivo manufacturing, this tLNP platform holds the potential to make CAR T cell therapies more accessible and applicable across additional clinical indications.
    DOI:  https://doi.org/10.1126/science.ads8473
  11. Ann Hematol. 2025 Jun 19.
    Latest updates on pathogenesis mechanisms and management strategies for cytokine release syndrome, neurotoxicity, and hemophagocytic lymphohistiocytosis related to CAR-T cell therapies.
    Xin Wang, Xiaoyuan He, Tao Zhang, Jile Liu, Mingfeng Zhao.
      Nowadays, chimeric antigen receptor (CAR) -T cell therapy has shown significant efficacy in treating hematological tumors, with an obvious increase in patient survival rates. However, with the widespread application of CAR-T, the incidence of CAR-T related adverse events has gradually increased, including cytokine release syndrome (CRS), immune effector cell associated neurotoxicity syndrome (ICANS), and hemophagocytic lymphohistiocytosis (HLH). These complications may be life-threatening, so early diagnosis and intervention treatment are crucial for the prognosis of patients. In this review, we first comprehensively summarize the latest insights into the pathogenesis and clinical manifestations of CRS, ICANS, and HLH after CAR-T, with a focus on elaborating on the specific mechanisms and related pathways of the inflammatory storm caused by a large number of cytokines after CAR-T. We also discussed the established prevention and management strategies for the three complications mentioned above, and demonstrated the effectiveness of the treatment by introducing the therapeutic effects of various treatment methods in current clinical or preclinical trials. In addition, we provide a prospective perspective on the measures and modifications currently being studied to mitigate the toxicity associated with CAR-T cell therapy.
    Keywords:  Chimeric antigen receptor (CAR)-T cell therapies; Cytokine release syndrome; Hemophagocytic lymphohistiocytosis; Immune effector cell-associated neurotoxicity syndrome
    DOI:  https://doi.org/10.1007/s00277-025-06467-y
  12. Biotechnol Bioeng. 2025 Jun 16.
    Unsupervised Machine Learning-Based Process Analytical Tools for Near Real-Time Cell Morphology Analysis During CAR-T Cell Manufacturing.
    Nidhi G Thite, Michael Yarnell, Terry J Fry, Matthew Seefeldt, Christopher P Calderon, Theodore W Randolph.
      Cell therapies like Chimeric Antigen Receptor (CAR)-T cell therapy deliver living cells to patients as active pharmaceutical ingredients. Manufacturing of these cells is complex, often yielding, heterogeneous products and high failure rates. Quality control (QC) assays used in CAR-T cell production primarily provide end-point product testing. Real-time process monitoring would be ideal to reduce failure rates and ensure final product quality. However, current analytical tools often fall short due to the heterogeneity of CAR-T cell products and their sensitivity to process changes. In this study, we showcase unsupervised image-based machine learning as a process analytical tool (PAT) for near real-time process monitoring during the production of CAR-T cells. Flow imaging microscopy (FIM) images of T cells collected from nine healthy donors were recorded during the activation, lentiviral-based transduction (expressing CD19 CAR protein), and expansion stages of CAR-T cell production. These images were used to train a Variational Autoencoder (VAE), allowing quantitative tracking of changes in cell morphologies during the various stages of production of CAR-T cells from each donor. Findings include observation of a new, transient population in T cells transduced to express CAR protein. This population was absent in T cells that were not transduced. The density of the new population was proportional to the transduction efficiency determined by traditional stain-based flow cytometry assays. Together, this study demonstrates the utility of using VAEs as a PAT tool for monitoring patient-to-patient variability and early detection of process deviations/upsets.
    Keywords:  machine learning; microscopy; process analytical technology; process monitoring
    DOI:  https://doi.org/10.1002/bit.70005
  13. Technol Cancer Res Treat. 2025 Jan-Dec;24:24 15330338251351065
    The Role of Radiotherapy in Relapsed or Refractory Diffuse Large B-Cell Lymphoma Post-CAR-T Therapy: A Systematic Literature Review.
    Andrea Emanuele Guerini, Eneida Mataj, Paolo Borghetti, Luca Triggiani, Mario Levis, Fabio Matrone, Gabriele Simontacchi, Stefania Nici, Stefano Riga, Mirsada Katica, Marco Lorenzo Bonù, Alessandra Tucci, Luigi Spiazzi, Stefano Maria Magrini, Michela Buglione di Monale.
      IntroductionHistorically, the management of relapsed or refractory diffuse large B-cell lymphoma (r/r-DLBCL) involved chemotherapy and autologous stem cell transplant, though outcomes were often suboptimal. Chimeric antigen receptor T-cell (CAR-T) therapy has transformed the therapeutic landscape for r/r-DLBCL, achieving high response rates and improving progression-free and overall survival. However, a significant proportion of patients relapse after CAR-T, and optimal treatment strategies for post-CAR-T relapse remain unclear. Radiotherapy (RT), a highly effective treatment for lymphoma, is increasingly recognized for its potential role as both a bridging therapy and a salvage option following CAR-T relapse.MethodsA comprehensive literature review was conducted using databases including PubMed, Scopus, EMBASE, and Cochrane Library, with search terms combining "radiotherapy," "radiation therapy," "lymphoma," and "CAR T-cell." A total of 690 records were screened, and 14 studies were included in the analysis after applying inclusion and exclusion criteria.ResultsRT demonstrates high response rates in CAR-T relapsed DLBCL, with overall response rates (ORR) ranging from 35% to 82.4% and complete response rates (CRR) from 17% to 59%. One-year local control rates ranged between 62% and 84%. Salvage RT showed comparable or superior outcomes to systemic therapies in multiple studies, particularly in patients with localized relapses. The toxicity profile of RT was favorable, particularly when modern techniques such as IMRT were employed. Case reports and retrospective series highlighted its effectiveness in achieving durable responses and controlling localized disease progression.ConclusionsRadiotherapy is a safe and effective treatment option for patients with DLBCL relapsed or refractory after CAR-T therapy. It achieves high local control rates and favorable outcomes, particularly in patients with localized relapse. Incorporating RT into the therapeutic workflow may enhance the management of this challenging population. Further prospective studies are needed to define its role and optimize treatment sequencing.
    Keywords:  CAR-T; CAR-T CELL; DLBCL; LYMPHOMA; RADIATION THERAPY; RADIOTHERAPY; refractory; relapsing; salvage
    DOI:  https://doi.org/10.1177/15330338251351065
  14. Hematol Oncol. 2025 Jun;43 Suppl 2 e70068
    T-Cell Redirecting Strategies in Large B-Cell Lymphoma and Follicular Lymphoma.
    Gloria Iacoboni.
      The advent of chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment landscape of relapsed/refractory large B-cell lymphoma (LBCL). After achieving regulatory approval in third line (3L+), randomized trials confirmed superiority over standard-of-care salvage chemoimmunotherapy (CIT) and autologous stem-cell transplantation in patients experiencing progressive disease within 12 months of first-line treatment. On the other hand, bispecific antibodies (BsAbs) are approved in the 3L+, while trials are exploring their potential in an earlier setting, usually in combination with CIT. In follicular lymphoma (FL), both T-cell redirecting strategies are approved in 3L+. The higher response rate with CAR T cells in FL comes at the cost of an increased toxicity risk and logistical barriers, in comparison with off-the-shelf BsAbs. This review focuses on the role of CAR T cells and BsAbs in LBCL and FL, paying special attention to available results and sequencing approaches.
    Keywords:  CAR T cells; bispecific antibodies; diffuse large B‐cell lymphoma; follicular lymphoma
    DOI:  https://doi.org/10.1002/hon.70068
  15. Int J Nanomedicine. 2025 ;20 7489-7500
    Nanomaterials Mediated Enhancement of CAR-T for HCC: Revolutionizing Immunotherapy Strategies.
    Xudong Liu, Ye Liu, Danyu Zhao, Dehong Shan, Chenghao Guo, Lianqun Jia.
      Hepatocellular carcinoma (HCC) presents significant challenges due to its aggressive nature and resistance to conventional treatments. While CAR-T therapy has shown promise in hematologic cancers, its application in HCC is limited by the tumor microenvironment (TME), insufficient T-cell infiltration, and antigenic heterogeneity. Nanomaterials offer a promising solution by enhancing CAR-T cell delivery, activation, persistence, and overcoming the immunosuppressive TME. This review focuses on the application of nanoparticles in CAR-T therapy, highlighting recent advancements in nanomaterials-based mRNA delivery, photothermal remodeling, and hydrogel platforms. Furthermore, nanomaterials-enhanced imaging tools enable real-time monitoring of CAR-T cell activity, improving therapeutic precision and safety. By addressing current limitations, nanomaterial-mediated CAR-T therapy holds the potential to transform HCC treatment, paving the way for more effective and personalized cancer immunotherapy.
    Keywords:  CAR-T; HCC; immunotherapy; nanomaterials; tumor microenvironment
    DOI:  https://doi.org/10.2147/IJN.S527315
  16. Clin Sports Med. 2025 Jul;pii: S0278-5919(24)00126-1. [Epub ahead of print]44(3): 415-424
    The Role of Exosomes and Extracellular Vesicles in Joint Preservation and Articular Cartilage Regeneration: Where Are We Now?
    Zachariah Gene Wing Ow, Keng Lin Wong.
      Exosomes and extracellular vesicles (EVs) are an emerging technology in the field of orthobiology. This "cell-free" cell therapy can bring the potential of cell therapy into orthopedic surgery applications without the hassle of cell therapy logistics. However, the dream of producing an off-the-shelf regenerative therapy drug faces challenges, such as optimization of dosage, frequency, and consistency of therapy efficacy. In this review, we look at the role of exosomes and EVs in treating cartilage diseases, discuss the efficacy of these treatment modalities in the preclinic settings, and summarize current clinical state and challenges for this novel therapy in cartilage repair.
    Keywords:  Cartilage repair; Exosomes; Extracellular vesicles
    DOI:  https://doi.org/10.1016/j.csm.2024.08.002
  17. 3 Biotech. 2025 Jul;15(7): 213
    Breaking barriers: exploring blood-brain barrier crossing mechanisms with nanomedicine for effective glioma treatment.
    Syed Hammad Ali, Hiba Ali, Midhat Shafi, Abdul Malik.
      This review comprehensively highlights recent studies on the potential immunotherapy targets and nanomedicine strategies to enhance glioma treatment by overcoming the blood-brain barrier (BBB). Various nanoparticles, such as liposomes, poly (lactic-co-glycolic acid) (PLGA), and gold nanoparticles (AuNPs), have shown a significant ability to cross the BBB and deliver therapeutic agents to glioma. Surface modification of nanoformulation with transferrin, insulin, and trans-activator of transcription (TAT) peptides has proven enhanced cellular uptake and tumor suppression. Self-targeting carbon dots (CDs) have shown effectiveness even without targeting ligands, indicating their broad potential for crossing the BBB. Polymeric nanocapsules (PNCs) encapsulating Methotrexate significantly reduced tumor volumes in animal models of glioma. Additionally, fucoidan-encapsulated Vismodegib nanoparticles effectively crossed the BBB and exhibited minimal toxicity in healthy brain tissue. Synthetic protein nanoparticles (SPNPs) loaded with small interfering RNA (siRNA) achieved an 87.5% long-term survival rate in glioma-bearing mice. Novel systems, such as lipid-calcium phosphate (LCP) nanoparticles and poly (β-L-malic acid), have been utilized to effectively deliver siRNA and immune checkpoint inhibitors, respectively, across the blood-brain barrier (BBB), thereby downregulating programmed death-ligand 1 (PD-L1) expression and regulatory T cell (Treg) activity. Chimeric Antigen Receptor (CAR) T cell therapies combined with nanoparticle-based drug delivery systems enhanced brain tumor-specific targeting and improved immune cell infiltration. Despite the success in preclinical studies, challenges remain regarding nanoparticle biocompatibility, off-target effects, and regulatory approval. Nevertheless, these findings support the potential of multifunctional nanomedicines for glioma therapy by enabling BBB penetration, immune modulation, and targeted drug delivery, which can be further improved.
    Keywords:  Blood–brain barrier; CAR T cells; Glioma; Immune evasion; Nanomedicine
    DOI:  https://doi.org/10.1007/s13205-025-04378-3
  18. Hematol Oncol. 2025 Jun;43 Suppl 2 e70063
    Autoimmune Complications of Lymphoproliferative Diseases.
    Wilma Barcellini, Bruno Fattizzo.
      Peripheral autoimmune cytopenias may complicate a fraction of lymphoproliferative disorders (LPD), particularly chronic lymphocytic leukemia, non-Hodgkin B-cell lymphomas, angioimmunoblastic T-cell lymphoma and large granular lymphocytic leukemia. The most frequent complications are autoimmune hemolytic anemia and immune thrombocytopenia, followed by pure red cell aplasia, autoimmune neutropenia and other systemic/organ specific autoimmune diseases. The latter are less frequently reported and probably underdiagnosed, and include systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, antiphospholipid syndrome and disorders of the hemostatic system. Therapy is mainly directed at the specific autoimmune complication when it arises in the context of a non-active LPD. However, autoimmune complications that are refractory to first line therapy usually require an LPD-directed treatment. Of note, several B-cell and T cell directed therapies that are used in LPD are also indicated or in trials for primary autoimmune cytopenias, underlying the overlapping pathogenic mechanisms between LPD and autoimmunity.
    Keywords:  autoimmune hemolytic anemia; autoimmune neutropenia; chronic lymphocytic leukemia; immune thrombocytopenia; lymphoproliferative diseases
    DOI:  https://doi.org/10.1002/hon.70063
  19. Leuk Lymphoma. 2025 Jun 17. 1-9
    Real-world healthcare costs for patients treated with chimeric antigen receptor T-cell therapy in Canada.
    Lisa Masucci, John Kuruvilla, Beate Sander, Anca Prica, William W L Wong, Kelvin K W Chan.
      Chimeric antigen receptor T-cell (CAR-T) therapy is a practice changing high-cost therapy; however, little is known about the real-world cost of CAR-T. We estimated the acute healthcare costs associated with CAR-T for patients with r/r DLBCL. We performed a retrospective cohort study of patients who received CAR-T between 1 January 2020 and 31 August 2021 at Princess Margaret Cancer Center, Toronto, Ontario. Costs were divided into distinct costing phases. Mean total costs per phase and by service category were calculated. Fifty-three patients received CAR-T. The mean age was 61 years and the majority were male (60%). The total mean costs per patient were: C$11,180 (95% CI: $7712-14,649) for the pretreatment phase (30 days), C$511,983 (average product cost C$473,127) (95% CI: $504,472-520,666) for the treatment phase, and C$41,620 (95% CI: $29,935-52,933) for the post-treatment phase (100 days). This cost information may inform cost-effectiveness analyses for CAR-T as well as reimbursement decisions.
    Keywords:  CAR T-cell therapy; Real-world; cost analysis
    DOI:  https://doi.org/10.1080/10428194.2025.2518440
  20. Cancer Control. 2025 Jan-Dec;32:32 10732748251349919
    Generative AI - Assisted Adaptive Cancer Therapy.
    Youcef Derbal.
      Adaptive combination therapy is deemed the most intuitive strategy to thwart therapeutic resistance through dynamic treatment tuning that accounts for cancer evolutionary dynamics. However, higher accuracy and reliability of treatment response predictions would be needed, in addition to the need for clinically feasible models of adaptive combination therapy that consider newly approved therapeutics and the growing multimodal data being available about cancer. Grounded in nonlinear system control theory, this review offers a perspective on exploiting GenAI learning and inferencing capabilities to predict treatment response and recommend treatments in the context of adaptive cancer therapy. Results from nonlinear system identification, control theory and deep learning are integrated within an adaptive cancer control framework to leverage the continuously expanding data about cancer and its treatment towards GenAI-enhanced adaptive therapy. The resulting models and their analysis contribute to a much-needed conceptual clarity about the research and translational pathways that would be needed to realize GenAI-assisted cancer treatments. In particular, they underscore that access to clinical data, deep learning opacity, and clinical validation present critical challenges that require adequate attention to pave the way towards acceptance and integration of GenAI in real-world oncology workflows.
    Keywords:  adaptive cancer therapy; adaptive treatment planning; adaptive treatment scheduling; cancer treatment; clinical decision support systems; generative artificial intelligence; large language models; rapid learning healthcare systems; treatment response monitoring
    DOI:  https://doi.org/10.1177/10732748251349919
  21. Adv Sci (Weinh). 2025 Jun 20. e08397
    Exploring AAV-Mediated Gene Therapy for Inner Ear Diseases: from Preclinical Success to Clinical Potential.
    Fan Wu, Wuhui He, Yun Xiao, Qiong Wu, Qing Zhang, Tiesong Zhang, Lei Xu, Xinyi Pang.
      Hearing loss imposes a significant global health burden and often results from genetic factors and various external influences, such as noise exposure and the use of ototoxic drugs. Recent advancements in adeno-associated virus (AAV)-mediated gene therapy offer promising new avenues for the treatment of inner ear diseases. Clinical trials of AAV-mediated gene therapies show impressive preliminary results, although further research is needed to evaluate the safety and long-term effects of these therapies. Preclinical AAV-mediated gene therapy is notable for its high transduction efficiency and safety. In this article, the development of AAV-mediated gene therapies is reviewed for inner ear diseases, categorizing these therapies by their strategies for treating hereditary hearing loss, including gene replacement and cluster regularly interspaced short palindromic repeat-based methods. AAV-mediated hair cell regeneration therapy is also reviewed for acquired hearing loss, as well as methods to prevent acquired hearing loss. In this article, it is hoped to provide a comprehensive overview of recent progress in AAV-mediated gene therapy and its future potential, thereby highlighting the importance of this therapy for researchers and clinicians in the field.
    Keywords:  AAVs; acquired hearing loss; cochlear; gene therapies; genetic hearing loss; inner ears; sensory hair cells
    DOI:  https://doi.org/10.1002/advs.202408397
  22. Ageing Res Rev. 2025 Jun 13. pii: S1568-1637(25)00148-5. [Epub ahead of print]110 102802
    Molecular hydrogen therapy: A "democratic" emerging strategy against aging and age-related diseases.
    Giovanni Brandi, Chiara Delbaldo, Marzia Deserti, Valeria Relli, Simone Rimedio, Andrea Palloni, Chiara Deiana, Gioconda Saccoccio, Raffaele Ingenito, Simona Tavolari.
      Aging represents the main risk factor for the development of several diseases, including cardiovascular and metabolic conditions, neurodegenerative disorders and cancer. As the number of elderly people is increasing worldwide, different strategies to counteract age-related diseases have been investigated. Recently, the use of molecular hydrogen (H2) as a preventive and therapeutic approach has been proposed due to its antioxidant and anti-inflammatory properties, its ability to regulate cell senescence and death, and to restore intestinal eubiosis. Although the studies investigating the role of H2 in slowing-down aging and age-related diseases are still limited, current findings support the idea that its administration may be able to affect different hallmarks of these processes. The "democratic" characteristics of H2 rely on its potential widespread use due to its pleiotropic activity, the lack of toxicities and low costs. In this review we provide a comprehensive state of the art on current knowledge on the molecular and clinical features of aging and age-related diseases. Current therapeutic approaches to slow down these processes will be also discussed, with a main focus on the potential use of H2 as an innovative preventive and therapeutic strategy.
    Keywords:  Aging; Dysbiosis; Inflammation; Molecular hydrogen; Oxidative stress
    DOI:  https://doi.org/10.1016/j.arr.2025.102802
  23. Ann Med. 2025 Dec;57(1): 2516697
    Unlocking the potential: advancements and applications of gene therapy in severe disorders.
    Rahul G Ingle, Gehan M Elossaily, Mohd Nazam Ansari, Shivani Makhijani.
       INTRODUCTION: Several severe disorders, such as inherited diseases (e.g. cystic fibrosis and beta thalassemia), genetic diseases (e.g. malignant tumors and diabetes), and infectious diseases (e.g. HIV) are pose significant challenges to human health.
    BACKGROUND: Over the past few decades, researchers have been working on gene therapies, and currently, terrible dreams have come true. To date, the Food and Drug Administration (FDA) has approved multiple gene therapies such as Kynamro for familial hypercholesterolaemia, Exondys51 for duchenne muscular dystrophy, Spinraza for spinal muscular atrophy, etc., rest for cancer, infectious diseases, and rare diseases.
    DISCUSSION: The authors have summarized recent advances in gene therapy, its background, molecular basis (e.g. viral and non-viral vectors), gene-editing techniques (e.g. CRISPR/Cas9, TALEN, ZFN), and its foremost applications in severe disorders, such as cancer, monogenic disorders (e.g. spinal muscular atrophy), polygenic disorders (e.g. autism), neurogenic disorders (e.g. Parkinson disease and Alzheimer's disease), and infectious diseases (e.g. HIV).
    CHALLENGES: In addition, we explored the major challenges faced by gene therapies during targeted delivery, immunogenicity, efficacy, and safety.
    CONCLUSION: To date, most of the promising approaches, such as different vectors, target cell populations, and both in vivo and ex vivo have paved the foundation for applications of gene therapies. Additionally, advances in enhancing the immune system that would certainly lower the healthcare costs. This review highlights the translatory potential of gene therapy in revolutionizing the treatment landscape for severe disorders.
    Keywords:  Apoptosis; cancer; gene therapy; genetic disorders; infectious diseases; neurodegenerative disorders; nucleic acids
    DOI:  https://doi.org/10.1080/07853890.2025.2516697
  24. Kidney Dis (Basel). 2025 Jan-Dec;11(1):11(1): 390-401
    Interferon-Stimulated Genes: Novel Targets in Renal Pathogenesis.
    Meng Jia, Shuangxu Han, Liang Li, Yi Fu, Di Zhou.
       Background: Kidney diseases are a prevalent global health concern, and despite ongoing research, there remains a lack of fully effective clinical treatments to prevent or halt their progression. Consequently, it is encouraged to identify novel biomarkers, establish early diagnostic methods, pinpoint key molecular pathways, and develop innovative therapeutic targets for more effective management of renal disorders.
    Summary: Interferons (IFNs), a group of cytokines, play pivotal roles in immune responses, particularly in antiviral and antiproliferative activities. IFNs trigger a cascade of signaling events that lead to the induction of interferon-stimulated genes (ISGs), which are essential for controlling viral infections and regulating immune responses. This review explores the impact of interferon-related genes on renal disorders, focusing on the mechanisms, therapeutic approaches, and consequences of enhanced interferon signaling in the kidney.
    Key Messages: Most diagnostic and therapeutic strategies targeting ISGs are still far from clinical implementation. The better understanding of ISG-regulated pathophysiology and the progress of new intervention approaches are expected to facilitate the clinical translation of ISGs-based diagnosis and therapy of kidney diseases.
    Keywords:  Immune regulation; Interferon signaling; Interferon-stimulated genes; Renal pathogenesis; Therapeutic target
    DOI:  https://doi.org/10.1159/000546141
  25. Bioact Mater. 2025 Oct;52 228-243
    Biomimetic extracellular vesicles derived from chimeric antigen receptor monocytes to treat glioblastoma: An efficient and safe intranasal drug delivery nanoplatform.
    Qihong Cheng, Minjie Wang, Zijie Zhou, Huitang Xia, Shaojie Yu, Jianglin Zheng, Kai Zhu, Xudong Li, Xuan Wang, Tao Xin, Xiaobing Jiang, Junjun Li.
       Background: Extracellular vesicles (EVs) have emerged as a promising pharmacotherapeutic modality for glioblastoma (GBM) drug delivery. However, the clinical translation of EVs remains restricted due to their low yield and demanding extraction steps. Therefore, extracellular vesicle mimetics (EVMs), as alternatives to EVs, have received much attention.
    Results: Herein, inspired by the inherent GBM tropism of monocytes and the editable target recognition ability of chimeric antigen receptors (CARs), we present the synthesis and systemic evaluation of a doxorubicin (DOX)-loaded nanoplatform (termed CAR-EVMs@DOX) generated by loading DOX into EVMs derived from CAR-modified monocytes (CAR-EVMs) via a modified extrusion method. Due to insufficient GBM drug delivery efficacy and great systemic toxicity caused by the resistance of the blood-brain barrier (BBB), CAR-EVMs@DOX can be administered intranasally to bypass the BBB, resulting in dramatic GBM-targeted migration and accumulation in the GBM site. Moreover, compared with intravenous administration, intranasal delivery of CAR-EVMs@DOX increases tumor inhibition efficacy while protecting against DOX-induced cardiotoxicity.
    Conclusions: The findings of our study demonstrate that the intranasal administration of the facile and well-designed nanoplatform CAR-EVMs@DOX is an advanced drug delivery tactic for GBM therapy, with the potential for future clinical translation.
    Keywords:  Chimeric antigen receptors; Extracellular vesicle mimetics; Glioblastoma; Intranasal administration; Membrane extrusion
    DOI:  https://doi.org/10.1016/j.bioactmat.2025.05.032
  26. Med Oncol. 2025 Jun 19. 42(7): 273
    Immune checkpoint inhibitors in cancer therapy: what lies beyond monoclonal antibodies?
    Mohammad Reza Zamani, Pavel Šácha.
      Immune checkpoints are critical in modulating immune responses and maintaining self-tolerance. Cancer cells can exploit these mechanisms to evade immune detection, making immune checkpoints attractive targets for cancer therapy. The introduction of immune checkpoint inhibitors (ICIs) has transformed cancer treatment, with monoclonal antibodies targeting CTLA-4, PD-1, and PD-L1 demonstrating clinical success. However, challenges such as immune-related adverse events, primary and acquired resistance, and high treatment costs persist. To address these challenges, it is essential to explore alternative strategies, including small-molecule and peptide-based inhibitors, aptamers, RNA-based therapies, gene-editing technologies, bispecific and multispecific agents, and cell-based therapies. Additionally, innovative approaches such as lysosome-targeting chimeras, proteolysis-targeting chimeras, and N-(2-hydroxypropyl) methacrylamide copolymers are emerging as promising options for enhancing treatment effectiveness. This review highlights significant advancements in the field, focusing on their clinical implications and successes.
    Keywords:  Cancer therapy; Immune checkpoint inhibitors; Immunotherapy; Monoclonal antibodies; Small molecules
    DOI:  https://doi.org/10.1007/s12032-025-02822-1
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