bims-carter Biomed News
on CAR-T Therapies
Issue of 2025–06–29
twenty-six papers selected by
Luca Bolliger, lxBio
  1. The next innovations in chimeric antigen receptor T cell immunotherapies for cancer.
  2. Chimeric antigen receptor T cell therapy for autoimmune diseases.
  3. Disarming myeloid resistance in CAR T therapy.
  4. Allogeneic CART progress: platforms, current progress and limitations.
  5. Unleashing the power of CAR-M therapy in solid tumors: a comprehensive review.
  6. CAR Beyond αβ T Cells: Unleashing NK Cells, Macrophages, and γδ T Lymphocytes Against Solid Tumors.
  7. Chimeric Antigen Receptor (CAR) T-cell Therapy: Engineering Immune Cells To Treat Liver Diseases.
  8. Barriers and solutions for CAR-T therapy in solid tumors.
  9. CAR-T Cell Therapy for Acute Myeloid Leukemia: Where Do We Stand Now?
  10. Chimeric Antigen Receptor T Cell Production for Brain Cancers.
  11. Engineered immune cell therapies for solid tumors: pharmacological advances, clinical outcomes, and future directions.
  12. Neurological complications of CAR T cell therapy for cancers.
  13. Chimeric antigen receptor cell therapy: A revolutionary approach transforming cancer treatment to autoimmune disease therapy.
  14. Transduction of γδ T cells with Baboon envelope pseudotyped lentiviral vector encoding chimeric antigen receptors for translational and clinical applications.
  15. Enhancing CAR-T cell efficacy through IFN ablation.
  16. The 1000 + mouse project: large-scale spatiotemporal parametrization and modeling of preclinical cancer immunotherapies.
  17. Cytokine release syndrome and CAR T Cell therapy: Modulating the intensity of the inflammatory response and resolution within the tumor microenvironment.
  18. An iPSC-derived CD19/BCMA CAR-NK therapy in a patient with systemic sclerosis.
  19. Optogenetic control of T cells for immunomodulation.
  20. Can we cure bullous skin diseases?
  21. Memory matters: T cell phenotype shapes CAR T cell fate.
  22. AI-Assisted Cell Culture System.
  23. Microbiota interaction with Tregs: a target for colitis.
  24. Unveiling Exosome Potential: Transforming Treatments for Neurodegeneration.
  25. T cells responses after vaccination: a regulatory perspective.
  26. A current update of the development of Chimeric Antigen Receptor T-cell therapy and kidney disease.
  1. Cytotherapy. 2025 May 23. pii: S1465-3249(25)00720-0. [Epub ahead of print]
    The next innovations in chimeric antigen receptor T cell immunotherapies for cancer.
    Kusala Anupindi, Julia Malachowski, Isabella Hodson, Daniel Zhu, Carl H June, Bruce L Levine.
      Chimeric antigen receptor (CAR) T cell therapy has transformed cancer treatment and the field of immunotherapy. Although CAR T cell therapy has demonstrated considerable clinical success for the treatment of B cell malignancies, expanding its therapeutic efficacy and accessibility for other hematological malignancies and solid tumors remains a challenge. Key limitations include manufacturing constraints and therapeutic hurdles, such as CAR T cell persistence, proliferation, tumor trafficking and treatment-related toxicities. To overcome the unique challenges associated with CAR T cell therapy, novel technological advancements in CAR design, delivery, and T cell functionality can be leveraged. This review will explore three innovative approaches: gene editing and silencing, armoring strategies and in vivo CAR gene delivery. These approaches are all aimed at enhancing the accessibility and therapeutic efficacy of CAR T cell therapy in hematological malignancies.
    Keywords:  CAR T cell therapy; T cell; advanced therapies; cancer immunotherapy; cellular therapy; gene therapy
    DOI:  https://doi.org/10.1016/j.jcyt.2025.05.010
  2. Curr Opin Immunol. 2025 Jun 24. pii: S0952-7915(25)00072-X. [Epub ahead of print]95 102596
    Chimeric antigen receptor T cell therapy for autoimmune diseases.
    Wen Nie, Xinyu Yang, Mingrui Ma, Xiaogang Xu, Jin Hou.
      Autoimmune diseases represent a significant global health burden, characterized by aberrant immune responses leading to tissue damage and functional impairment. Despite advancements in immunosuppressive therapies, achieving sustained remission remains challenging, necessitating innovative therapeutic approaches. Chimeric antigen receptor (CAR) T cell therapy, a groundbreaking immunotherapy originally developed for oncology, has emerged as a promising strategy in the treatment of autoimmune diseases. By engineering autologous or allogeneic T cells to target specific immune components, CAR-T cell therapy has demonstrated profound efficacy in preclinical and clinical studies across diverse autoimmune disorders. Early clinical applications in refractory systemic lupus erythematosus highlight its potential to induce durable immune reprogramming, achieving drug-free remission and resolving multiorgan involvement. Moreover, its success extends to other autoimmune disorders, including systemic sclerosis, myasthenia gravis, and rheumatoid arthritis. However, challenges such as immune-related toxicity, persistence of therapeutic cells, and antigen escape remain key barriers. This review synthesizes recent advancements in CAR-T technology, clinical outcomes in autoimmune disease trials, and emerging strategies to optimize safety and efficacy, underscoring the transformative potential of CAR-T cell therapy in revolutionizing autoimmune disease management and highlighting the need for further large-scale clinical trials to realize its full clinical applicability.
    DOI:  https://doi.org/10.1016/j.coi.2025.102596
  3. Cancer Cell. 2025 Jun 17. pii: S1535-6108(25)00252-1. [Epub ahead of print]
    Disarming myeloid resistance in CAR T therapy.
    John M Warrington, Nathan Singh.
      Uncovering mechanisms of resistance to chimeric antigen receptor (CAR) T cell therapy for B cell lymphoma is of paramount importance. In this issue of Cancer Cell, Stahl et al. identify a CSF1R+ myelo-monocytic population that disrupts CAR T cell function and show that inhibition of CSF1R enhances efficacy of CD19-targeted CAR T cells.
    DOI:  https://doi.org/10.1016/j.ccell.2025.06.003
  4. Front Immunol. 2025 ;16 1557157
    Allogeneic CART progress: platforms, current progress and limitations.
    Ameneh Shokati, Maryam Sanjari-Pour, Mahshid Akhavan Rahnama, Saghar Hoseinzadeh, Mohammad Vaezi, Mohammad Ahmadvand.
      Allogenic chimeric antigen receptor T (CAR-T) cells have advantages compared to autologous T cell therapies such as availability cells for production, a suitable HLA-matched donor (if graft-vs-host-disease and rejection effects are to be avoided and also lower risks associated with transduction methods in process of autologous CAR-T cells). In recent years, the additional editing and non-editing technologies are helping to make allogenic CAR-T therapies a hopeful future treatment. Universal off-the-shelf CAR-T cells can be solved key issues include preventing graft-versus-host disease (GVHD) and time consumption and other challenges faced to allogenic CAR-T cells. Here, we have highlighted the improvement in CAR-T development, particularly in engineering allogenic CAR-T, clinical practices related to these, pre-clinical and clinical studies and their successes which investigated in recent 10 years related to treatment of hematological malignancies and cancers by allogenic CAR-T cells.
    Keywords:  allogeneic CAR T cells; editing technology; graft-versus-host disease; non-editing technology; off-the-shelf CART cell
    DOI:  https://doi.org/10.3389/fimmu.2025.1557157
  5. Front Immunol. 2025 ;16 1615760
    Unleashing the power of CAR-M therapy in solid tumors: a comprehensive review.
    Ahsen Morva, Ana Belén Arroyo, Liudmila Andreeva, Ana Tapia-Abellán, Ginés Luengo-Gil.
      Chimeric antigen receptor (CAR) macrophage therapy represents a promising new frontier in cancer immunotherapy, with the potential to overcome the limitations of CAR-T cell approaches, particularly in solid tumours. This comprehensive review focuses on the current state and future prospects of CAR macrophage technology, emphasising its applications in solid malignancies across preclinical and early clinical development. The key topics covered included CAR design optimisation, macrophage sources and engineering strategies, mechanisms of antitumour activity, in vivo efficacy in animal models, initial clinical trial results, and challenges for broader implementation. The unique properties of macrophages, including tumour penetration and microenvironment modulation, offer significant advantages over T cell-based therapies in solid-tumour settings. However, strategies to enhance persistence, maintain proinflammatory phenotypes, and improve manufacturing are required. Although early research suggests additional applications beyond oncology, including for infectious and inflammatory diseases, this review primarily concentrates on the oncologic potential of CAR-M therapies. Continued optimisation and larger randomised trials will be critical to establish clinical efficacy and define the role of this approach in the treatment of solid tumours.
    Keywords:  CAR-M; advances in research; cellular immunotherapy; chimeric antigen receptor; macrophages
    DOI:  https://doi.org/10.3389/fimmu.2025.1615760
  6. Vaccines (Basel). 2025 Jun 19. pii: 654. [Epub ahead of print]13(6):
    CAR Beyond αβ T Cells: Unleashing NK Cells, Macrophages, and γδ T Lymphocytes Against Solid Tumors.
    Yunjia Xian, Lu Wen.
      Chimeric antigen receptor (CAR)-engineered cell therapy represents a landmark advancement in cancer immunotherapy. While αβ CAR-T therapy has demonstrated remarkable success in hematological malignancies, its efficacy in solid tumors remains constrained mainly by factors such as antigen heterogeneity, immunosuppressive microenvironments, and on-target/off-tumor toxicity. To overcome these limitations, emerging CAR platforms that utilize alternative immune effectors, including natural killer (NK) cells, macrophages, and γδ T lymphocytes, are rapidly gaining traction. This review systematically analyzes the mechanistic advantages of CAR-NK, CAR-M, and CAR-γδ T cell therapies, while critically evaluating persistent challenges in clinical translation, including limited cell persistence, manufacturing scalability, and dynamic immune evasion mechanisms. We further discuss innovative strategies to enhance therapeutic efficacy through some viable strategies. By bridging fundamental immunology with translational engineering, this work provides a roadmap for developing CAR therapies capable of addressing the complexities of solid tumor eradication.
    Keywords:  CAR-M; CAR-NK; CAR-T; CAR-γδ T; cancer immunotherapy; cell therapy; solid tumor
    DOI:  https://doi.org/10.3390/vaccines13060654
  7. J Hepatol. 2025 Jun 20. pii: S0168-8278(25)02274-3. [Epub ahead of print]
    Chimeric Antigen Receptor (CAR) T-cell Therapy: Engineering Immune Cells To Treat Liver Diseases.
    Elmar Jaeckel, Scott L Friedman, Michael Hudecek, Ulrike Protzer.
      Endogenous T cells recognize antigens through human leukocyte antigen (HLA)/peptide complexes. However, the polymorphism of HLA has posed significant challenges to the development of broadly applicable adoptive T-cell therapies. Engineered T cells can circumvent this barrier by targeting surface antigens independently from HLA through a synthetic chimeric antigen receptor (CAR) with an antibody-derived recognition domain fused to intracellular signaling motifs. CAR-T cell therapies have transformed the treatment of B-cell malignancies in hematology, and recent studies demonstrate therapeutic potential against solid tumors. This review presents an overview of CAR technology's fundamental principles and achievements, focusing on CAR-T cell applications in hepatic viral infections, autoimmune liver disease, and hepatobiliary tumors. Emerging senolytic therapies that target senescent cells and hepatic fibrosis are highlighted alongside regulatory CAR-T cells that induce liver-specific immune tolerance in transplantation. Future and ongoing research is reviewed that seeks to enhance the specificity, efficacy, and safety of CAR-based therapies as "living drugs" that facilitate targeted, sustained, and personalized interventions for liver diseases.
    DOI:  https://doi.org/10.1016/j.jhep.2025.06.007
  8. Cancer Gene Ther. 2025 Jun 27.
    Barriers and solutions for CAR-T therapy in solid tumors.
    Zhihao Tu, Yuelin Chen, Zhimi Zhang, Wanrong Meng, Ling Li.
      Chimeric antigen receptor (CAR)-T cell therapy has emerged as a transformative approach for cancer treatment, particularly in hematologic malignancies. However, barriers in the development of effective CAR-T therapies for solid tumors, including antigenic escape, tumor immunosuppressive microenvironments, severe toxicities, and limitations in preclinical models, hinder its scalability and broader clinical implementation. To overcome these barriers, strategies have been developed in recent years, such as optimizing CAR designs, enhancing CAR-T cell infiltration, neutralizing immunosuppressive cells, remodeling metabolism of CAR-T cells, eliminating antigen escape, mitigating toxicities, advancing preclinical models, and in situ programming CAR-T cells. Here, we discuss current barriers and potential strategies for CAR-T cell therapy in solid tumors. Ultimately, we present perspectives on these advanced strategies for broader clinical adoption of CAR-T cell therapy.
    DOI:  https://doi.org/10.1038/s41417-025-00931-7
  9. Curr Oncol. 2025 May 30. pii: 322. [Epub ahead of print]32(6):
    CAR-T Cell Therapy for Acute Myeloid Leukemia: Where Do We Stand Now?
    Pilar Lloret-Madrid, Pedro Chorão, Manuel Guerreiro, Pau Montesinos.
      Background: Patients with refractory and relapsed acute myeloid leukemia (R/R AML) face a dismal prognosis. CAR-T therapy has emerged as a potential treatment option. This study assesses the available clinical evidence on CAR-T in R/R AML, focusing on safety and efficacy outcomes. Methods: We included studies on CAR-T therapy for R/R AML published from June 2014 to January 2025. Data on patient and disease characteristics, CAR-T constructs, response rates, post-CAR-T allogeneic HSCT (allo-HSCT), and safety outcomes were analyzed. Results: Twenty-five CAR-T clinical trials involving 296 patients were identified. The most frequently targeted antigens were CD33, CD123, and CLL-1, while CD7, CD19, NKG2D, and CD38 were also explored. Responses were heterogeneous and often short-lived when not consolidated with allo-HSCT. Cytokine release syndrome and neurotoxicity were generally low grade and manageable. Prolonged and severe myelosuppression was a frequent limiting toxicity, often requiring allo-HSCT to restore hematopoiesis. Disease progression was the leading cause of death, followed by infections. Conclusions: CAR-T cell therapy may represent a feasible therapeutic strategy, particularly as bridging to allo-HSCT to mitigate myelotoxicity and improve long-term outcomes. Nevertheless, it remains in the early stages of development and faces significant efficacy and safety challenges that must be addressed in future trials to enable the expansion of this promising therapeutic approach for a population with high unmet medical needs.
    Keywords:  CAR-T cell therapy; acute myeloid leukemia; relapsed or refractory AML
    DOI:  https://doi.org/10.3390/curroncol32060322
  10. Methods Mol Biol. 2025 ;2944 163-171
    Chimeric Antigen Receptor T Cell Production for Brain Cancers.
    William T Maich, Benjamin Brakel, Chitra Venugopal, Sheila K Singh.
      Chimeric Antigen Receptor (CAR) T cells are T cells that have been engineered to specifically recognize antigens of interest on target cells, may that be in cancer or other pathologies. To date, CAR T cell therapy has solely been approved for use in liquid cancers, with many groups and trial working on CAR T cells for solid tumors. Herein, we describe the outline CAR T cell production using human peripheral blood mononuclear cells (PBMCs) and third-generation packaging vectors for use in in vitro and in vivo experimental assays.
    Keywords:  Brain cancer; CAR T cell; Cytotoxicity assays; Lentiviral transduction; PBMCs; T cell
    DOI:  https://doi.org/10.1007/978-1-0716-4654-0_13
  11. Front Pharmacol. 2025 ;16 1614325
    Engineered immune cell therapies for solid tumors: pharmacological advances, clinical outcomes, and future directions.
    Ziyad M Althafar.
      Solid tumors, accounting for around 90% of human cancers, present unique challenges due to antigen heterogeneity, immunosuppressive microenvironments, and limited accessibility for conventional pharmacotherapies. Immunotherapies, particularly engineered immune cell therapies, exploit the immune-tumor interplay, offering novel pharmacological strategies for solid malignancies. Genetic engineering enhances adoptively transferred cells, such as T cell receptor therapy, chimeric antigen receptor (CAR)-T cells, tumor-infiltrating lymphocytes (TILs), natural killer cells, and CAR-macrophages, by optimizing their targeting and effector functions. Clinically, TIL delivery has shown significant responses in advanced melanoma, with lifileucel gaining United States FDA approval as a pioneering TIL therapy for solid tumors. Ongoing trials further explore these approaches, revealing promising outcomes in overcoming immunosuppressive barriers. However, challenges persist, including optimizing combination therapies, streamlining manufacturing for off-the-shelf accessibility, and mitigating pharmacotoxicity. This review synthesizes recent advances in engineered immune cell therapies for solid tumors, emphasizing their pharmacological mechanisms, clinical efficacy, and translational potential. By addressing current hurdles, such as enhancing tumor penetration and minimizing adverse effects, this article outlines future directions to refine these therapies as safe, effective pharmacological tools in oncology.
    Keywords:  CAR-T cell therapy; engineered immune cell therapy; pharmacological mechanisms; solid tumor immunotherapy; tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.3389/fphar.2025.1614325
  12. Nat Rev Neurol. 2025 Jun 25.
    Neurological complications of CAR T cell therapy for cancers.
    Philipp Karschnia, Jörg Dietrich.
      Genetically engineered chimeric antigen receptor (CAR) T cells have emerged as a powerful treatment option in patients with B cell malignancies, but neurological adverse effects are common and hamper the success of such therapies. Immune effector cell-associated neurotoxicity syndrome encompasses a wide range of acute neurological adverse effects, including encephalopathy with alterations in cognition and behaviour, language, motor function and coordination. In patients treated with CAR T cells for CNS malignancies, a more localized on-tumour, on-target neurotoxicity syndrome termed tumour inflammation-associated neurotoxicity can develop acutely, resulting in localized oedema with mass effect or in electrophysiological dysfunction with neurological symptoms. Following B cell maturation antigen-targeting CAR T cell therapies, delayed neurological complications, including cranial nerve palsies and a unique delayed-onset parkinsonism syndrome, are increasingly recognized. Management of neurological complications includes symptomatic treatments such as antiepileptic drugs or cerebrospinal fluid diversion, temporary immunosuppression with corticosteroids, various cytokine-targeting agents, and other distinct approaches depending on the nature of the toxicity. As our understanding of the mechanisms that contribute to the various neurological adverse effects of CAR T cell and other T cell-engaging therapies increases, novel treatment strategies to alleviate symptoms, as well as innovative CAR designs, promise to improve the safety and neurotoxicity of these powerful immunotherapies.
    DOI:  https://doi.org/10.1038/s41582-025-01112-8
  13. Autoimmun Rev. 2025 Jun 23. pii: S1568-9972(25)00119-3. [Epub ahead of print]24(9): 103859
    Chimeric antigen receptor cell therapy: A revolutionary approach transforming cancer treatment to autoimmune disease therapy.
    Ruifan Wen, Binbin Li, Feifeng Wu, Jueyi Mao, Tasnim Azad, Yang Wang, Junquan Zhu, Xin Zhou, Haotian Xie, Xinying Qiu, Marady Hun, Jidong Tian, Liang Zhang, Kimsor Hong, Chuan Wen.
      Currently, autoimmune disorders are predominantly managed with broad-spectrum immunosuppressive agents and monoclonal antibodies, which can alleviate disease symptoms but are rarely curative and are frequently associated with significant adverse effects. Autoreactive B cells play a key role in the pathogenesis of many autoimmune diseases; however, B-cell-depleting therapies such as rituximab have shown limited efficacy in certain autoimmune diseases, primarily due to the persistence of autoreactive B cells within lymphoid tissues and sites of inflammation. Consequently, there is an urgent need for more effective and targeted therapies for patients with severe and refractory autoimmune conditions. In this context, recent advancements in genetic engineering have facilitated the application of cell-based therapies, which have transitioned from oncology to treating autoimmune diseases. Therapies utilizing chimeric antigen receptor (CAR) engineered immune cells have emerged as a promising and potentially curative approach. Clinical trials targeting CD19-expressing B cells in B cell-driven autoimmune diseases, such as systemic lupus erythematosus (SLE), have yielded encouraging results, demonstrating durable remissions in otherwise treatment-resistant cases. In addition, novel strategies are being developed to broaden the therapeutic scope of CAR-based therapies in autoimmunity, including chimeric autoantibody receptor (CAAR)-T cells designed to eliminate autoantigen-specific B cells selectively and CAR-engineered regulatory T cells (CAR-Tregs) aimed at achieving antigen-specific immune modulation and restoration of self-tolerance. Despite these advances, several challenges persist, including short and long-term safety concerns, limited in vivo persistence, and the high costs associated with personalized cell manufacturing. Innovations in CAR design, such as logic-gated CARs, inducible suicide switches, and universal CAR constructs, are under active investigation to enhance safety, control, scalability, and clinical accessibility.
    Keywords:  Autoimmune disease; CAR-NK; CAR-T; CAR-cell therapy; Chimeric antigen receptor (CAR); Immunotherapy
    DOI:  https://doi.org/10.1016/j.autrev.2025.103859
  14. Front Immunol. 2025 ;16 1548630
    Transduction of γδ T cells with Baboon envelope pseudotyped lentiviral vector encoding chimeric antigen receptors for translational and clinical applications.
    Lorraine Pinot, Aylin Saßor, Nina Möker, Congcong Zhang, Els Verhoeyen, José Villacorta Hidalgo, Rimas J Orentas.
      γδ T cells represent a promising cell platform for adoptive cell therapy. Their natural anti-tumor reactivity and HLA-independent target cell recognition make them an attractive platform for allogeneic adoptive immunotherapy clinical interventions. Initial clinical trials exploring allogeneic γδ T-cell therapies have demonstrated encouraging safety profiles. However, their therapeutic efficacy, especially against solid tumors, remains limited. This highlights the need for further optimization of γδ T cell products to improve anti-tumor potency, such as the increased targeting induced by the expression of a chimeric antigen receptors (CAR). However, a critical challenge in the development of CAR-γδ T cell therapies has been optimizing transduction efficiency with standard vector formats allowing for optimal CAR transgene expression that then produces an optimal therapeutic product. Here we present an effective method for enhancing CAR transgene expression in γδ T cells using a Baboon-pseudotyped lentiviral vector (BaEV-LV), comparing it to the conventional vesicular-stomatitis-virus-G protein (VSV-G) LVs. BaEV-LV significantly enhanced the transduction efficiency of γδ T cells with CARs, while conserving the beneficial cell product composition and phenotype of untransduced γδ T cells. The γδ T cells transduced with BaEV-LV CARs demonstrated significantly enhanced cytotoxicity against B7H3-expressing tumor cells in both 2D and 3D in vitro models. Our findings represent a significant advancement in CAR-γδ T cell engineering, offering a promising new avenue for cancer immunotherapy that combines the unique properties of Vγ9Vδ2 T cells with the targeted specificity of CAR technology. This method is compatible with automated closed-system platforms such as the CliniMACS Prodigy®, facilitating Good Manufacturing Practice (GMP)-compliant production for clinical trials. This feature significantly enhances the translational potential of engineered γδ T cells, paving the way for the development of next-generation γδ T cell-based immunotherapies.
    Keywords:  CAR gd T cells; allogeneic; chimeric antigen receptor; immunotherapy; lentiviral transduction; γδ T cells
    DOI:  https://doi.org/10.3389/fimmu.2025.1548630
  15. Nat Rev Drug Discov. 2025 Jun 26.
    Enhancing CAR-T cell efficacy through IFN ablation.
    M Teresa Villanueva.
      
    Keywords:  Biotechnology; Cancer; Drug discovery; Gene therapy; Immunology; Therapeutics
    DOI:  https://doi.org/10.1038/d41573-025-00115-w
  16. bioRxiv. 2025 Mar 17. pii: 2025.03.17.643712. [Epub ahead of print]
    The 1000 + mouse project: large-scale spatiotemporal parametrization and modeling of preclinical cancer immunotherapies.
    Adam L Kenet, Sooraj Achar, Alka Dwivedi, John Buckley, Marie Pouzolles, Haiying Qin, Christopher Chien, Naomi Taylor, Grégoire Altan-Bonnet.
      Preclinical studies of chimeric antigen receptor (CAR)-T cell immunotherapies are often based on monitoring bioluminescent tumors implanted in mice to assess anti-tumor cytotoxicity. Here, we introduce maRQup ( m urine a utomatic R adiance Qu antification and p arametrization), an easy-to-use method that automatically processes bioluminescent tumor images for quantitative analysis. We demonstrate the ability of maRQup to analyze CAR-T cell treatments over >1,000 tumor-bearing mice. We compare CD19-targeting CAR-T cells comprising either a CD28 or a 4-1BB costimulatory domain, and found the former controlled the tumor burden better initially, while the latter reduced the frequency of tumor relapse. We also applied maRQup to demonstrate faster tumor growth during the initial growth phase as compared to the relapse phase and to spatiotemporally analyze the high variability in immunotherapeutic control of tumors, based on their anatomical location. maRQup provides quantitative and statistically-robust insights on preclinical experiments that will contribute to the optimization of immunotherapies.
    DOI:  https://doi.org/10.1101/2025.03.17.643712
  17. Front Pharmacol. 2025 ;16 1615526
    Cytokine release syndrome and CAR T Cell therapy: Modulating the intensity of the inflammatory response and resolution within the tumor microenvironment.
    David F Driscoll, Bruce R Bistrian.
      CAR T cell therapy achieves high degrees of success with respect to complete response and overall response rates in many hematological cancers, especially lymphomas. Compared to other immunotherapies, these "activated" blood products are plagued by a high incidence of a severe systemic inflammatory response syndrome, resulting from the exaggerated release of cytokines, chemokines, and other pro-inflammatory protein and lipid mediators. These can produce what is known as the "cytokine release syndrome" (CRS), associated with significant morbidity and mortality. Although successful CAR T cell therapy reduces the tumor load, the killing of large numbers of cancer cells and the persistence of apoptotic cellular debris within the tumor microenvironment (TME) may also be tumorigenic. We propose a single active pharmaceutical ingredient (API), the highly polyunsaturated omega-3 fatty acids eicosapentaenoic and docosahexaenoic acids, applying a refined and enriched fish oil, with multiple therapeutic targets that can be administered in precise doses. First, they rapidly modulate the intensity of the systemic inflammatory response, by modifying eicosanoid metabolism via intravenous administration. Second, as substrates for the production of specialized pro-resolving mediators (SPMs) of inflammation, they can help clear cellular debris within the TME, perhaps reducing the risks of new tumor formation. The employment of such a drug either in a prophylactic and/or a treatment manner might further improve the outcome of CAR T cell therapy.
    Keywords:  CAR T cell therapy; cytokine release syndrome; inflammation; resolution; tumor microenvironment
    DOI:  https://doi.org/10.3389/fphar.2025.1615526
  18. Cell. 2025 Jun 16. pii: S0092-8674(25)00625-7. [Epub ahead of print]
    An iPSC-derived CD19/BCMA CAR-NK therapy in a patient with systemic sclerosis.
    Xiaobing Wang, Yi Zhang, Yi Jin, Lie Dai, Yanan Yue, Jiapan Hu, Xin Liu, Kun Pang, Songying Ye, Yue Chen, Wenjing Ye, Xiaofei Shi, Xin Ma, Lehang Guo, Yanfang Liu, Na Ta, Xiaofang Zhu, Li Lin, Jiazheng Wang, Ran Yan, Ping Wang, Xiaobin Song, Yixuan Zhou, Lina Zhou, Qing Wang, Tongxiang Guan, Ting Li, Ling Zhou, Weihua Pan, Yanran He, Xin Wu, Yingyong Xu, Luhan Yang, Huji Xu.
      This study reports the first-in-human application of iPSC-derived CD19/BCMA dual-targeting chimeric antigen receptor-natural killer (CAR-NK) cells (QN-139b) in a patient with severe, diffuse cutaneous systemic sclerosis. The allogeneic product was genetically edited for reduced alloreactivity and improved in vivo performance, with no structural chromosomal abnormalities detected. The treatment led to significant B cell depletion with minimal toxicity, similar to CAR T cell therapy. The patient showed marked clinical improvements during the 6-month follow-up, including reduced autoantibodies and reversed fibrosis, which are resistant to conventional treatments. Single-cell analysis of peripheral blood revealed that the treatment shifted B cells toward more naive phenotypes and eliminated pathogenic B cells. Proteomic studies demonstrated suppression of inflammation and fibrosis, enhanced tissue regeneration, and improved angiogenesis. Pathological evaluation confirmed the elimination of infiltrated lymphocytes from affected skin along with restored skin and microvascular structure. These findings suggest QN-139b is a promising immune-modulatory treatment for severe autoimmune diseases.
    Keywords:  Autoimmune diseases; B cell depletion; CD19/BCMA dual-targeting; Systemic sclerosis; Tissue regeneration; iPSC-derived CAR-NK
    DOI:  https://doi.org/10.1016/j.cell.2025.05.038
  19. Essays Biochem. 2025 Jun 23. pii: EBC20253014. [Epub ahead of print]
    Optogenetic control of T cells for immunomodulation.
    Brendan McKee, Siyao Liu, Pauline X Cai, Zimo Yang, Tien-Hung Lan, Yubin Zhou.
      Cellular immunotherapy has transformed cancer treatment by harnessing T cells to target malignant cells. However, its broader adoption is hindered by challenges such as efficacy loss, limited persistence, tumor heterogeneity, an immunosuppressive tumor microenvironment (TME), and safety concerns related to systemic adverse effects. Optogenetics, a technology that uses light-sensitive proteins to regulate cellular functions with high spatial and temporal accuracy, offers a potential solution to overcome these issues. By enabling targeted modulation of T cell receptor signaling, ion channels, transcriptional programming, and antigen recognition, optogenetics provides dynamic control over T cell activation, cytokine production, and cytotoxic responses. Moreover, optogenetic strategies can be applied to remodel the TME by selectively activating immune responses or inducing targeted immune cell depletion, thereby enhancing T cell infiltration and immune surveillance. However, practical hurdles such as limited tissue penetration of visible light and the need for cell- or tissue-specific gene delivery must be addressed for clinical translation. Emerging solutions, including upconversion nanoparticles, are being explored to improve light delivery to deeper tissues. Future integration of optogenetics with existing immunotherapies, such as checkpoint blockade and adoptive T cell therapies, could improve treatment specificity, minimize adverse effects, and provide real-time control over immune responses. By refining the precision and adaptability of immunotherapy, optogenetics promises to further enhance both the safety and efficacy of cancer immunotherapy.
    Keywords:  CAR T cell therapy; Calcium channels; Calcium signalling; T cell receptor; cancer therapy; immune cell signaling; immune response; immunoengineering; immunotherapy; ion channel; lymphocyte; optogenetics; synthetic biology
    DOI:  https://doi.org/10.1042/EBC20253014
  20. Curr Opin Immunol. 2025 Jun 19. pii: S0952-7915(25)00065-2. [Epub ahead of print]95 102589
    Can we cure bullous skin diseases?
    Sicheng Liu, Qianjin Lu.
      Autoimmune bullous diseases (AIBDs), including pemphigus and pemphigoid, are featured as the presence of autoantibodies directed against structural proteins, resulting in severe blistering as well as considerable morbidity. Current treatments, including glucocorticoids, immunomodulators, and biologics, often fail to achieve sustained remission due to high relapse rates and significant adverse effects. This review explores the pathophysiology of AIBDs, focusing on autoreactive B and T cells, inflammatory mediators, and immune dysregulation. Existing therapeutic limitations are then analyzed, and emerging treatment options, such as chimeric antigen receptor-T therapy, regulatory T cell-based interventions, and tolerogenic vaccines, are discussed as potential curative approaches. Additionally, preventive measures, such as genetic screening and environmental risk management, are considered. By integrating novel immunotherapies and immune modulation techniques through a three-step approach - disease control, pathogenic cell elimination, and induction of immune tolerance - we may move closer toward achieving sustained remission and potentially curing of AIBDs.
    DOI:  https://doi.org/10.1016/j.coi.2025.102589
  21. Mol Ther. 2025 Jun 25. pii: S1525-0016(25)00462-9. [Epub ahead of print]
    Memory matters: T cell phenotype shapes CAR T cell fate.
    Francesco Di Meo.
      
    DOI:  https://doi.org/10.1016/j.ymthe.2025.06.011
  22. Methods Mol Biol. 2025 ;2952 149-167
    AI-Assisted Cell Culture System.
    Semim Akhtar Ahmed, Abhipsha Saikia, Shalini G Devi, Jagat C Borah.
      Artificial intelligence (AI) proves to be a great tool that makes it possible for machines to learn from experience, regulate to new inputs, and execute human-like activities. AI is already the prime driver of emerging technologies and there are further possibilities in different fields. Certainly, the technology has not yet reached its full effectiveness in many fields but there is one area where AI, integrated with automation, can greatly improve laboratory research known as cell culture. Cell culture is an essential component of present-day biomedical research, allowing researchers to study cellular activities and underlying mechanisms of different diseases in a controlled laboratory setup and environment. Conventional cell culture procedures are hands-on procedures that are time engrossing, susceptible to error and variability, making it difficult to conduct large-scale investigations or screen large numbers of probable drug candidates. Application of AI and automated cell culture procedures can improve the reproducibility of the cell culture protocols that leads to less variability, better conclusions, and finally improving in-depth investigation and drug development. AI algorithms examine data from sensors and cameras to detect alterations in cell behavior, such as changes in appearance, morphology, or growth rate, and make adaptations to the culture conditions in real-time to optimize the growth and health of the cells. Robotic systems automate cell culture tasks, while AI algorithms monitor cell behavior and make adjustments to the culture conditions in real time. AI is considered a significant game changer in 3D cell culture as researchers can grow spheroids or organoids from different cell sources simultaneously, which will ensure consistency and reproducibility. Further, researchers and scientists can create customized workflows and protocols that follow the natural flow of the cell culture process without the need for modularization and human intervention through the use of AI. Though the AI application to cell culture system offers significant change to the scientists, the laboratories, and the companies, there are different aspects of AI applications that need to be considered through vast exploration.
    Keywords:  Algorithms; Artificial intelligence; Biomedical research; Cell culture
    DOI:  https://doi.org/10.1007/978-1-0716-4690-8_9
  23. Clin Transl Oncol. 2025 Jun 26.
    Microbiota interaction with Tregs: a target for colitis.
    Keywan Mortezaee.
      Gut-resident microbiota associate with host immune system to promote homeostasis, and regulatory T cells (Tregs) are critical in the maintenance of immune balance. Tregs have immunosuppressive activity, and their presence hampers the development of inflammatory diseases. This review aims to unravel microbiome impact on Tregs in bowel inflammation and harnessing such interaction to combat colitis as a separate disease or a consequence of immune checkpoint inhibitor (ICI) therapy of cancer. Short-chain fatty acids (SCFAs) are microbial-derived metabolites associated positively with Treg generation and maintenance and being effective for hampering bowel inflammation. Treg induction shapes gut microbiota profile and support microorganism colonization in their niche and protect the host from inflammation, while suppression of Treg differentiation and activity directs microbiota-induced Th17 expansion and inducing inflammation. Thus, balancing Treg representation with Th17 cells and Treg reprogramming through manipulation of gut microbiota can offer therapy. Microbiota epithelial attachment/detachment and interaction with antigen-presenting cells (APCs) are important for the final fate of T cell signature. Fecal microbial transplantation (FMT) is a strategy for promoting normobiosis and represents a navel approach to targeting colitis. FMT with appropriate microbiota from healthy donors can reinforce microbial diversity, density and persistence to enrich their environment with transforming growth factor (TGF)-β, induce IL-10 producing APCs and reinforce gut barrier, with all these being effective for recovering Tregs, restoring intestinal homeostasis and hampering colitis. ICI therapy of cancer may predispose subjects to colitis due to the impact on microbiome and reducing Treg population. FMT promotes local Treg reorchestration, being advantageous in cancer patients.
    Keywords:  Colitis; Fecal microbial transplantation (FMT); Microbiota; Regulatory T cell (Treg); Short-chain fatty acid (SCFA)
    DOI:  https://doi.org/10.1007/s12094-025-03974-2
  24. ACS Appl Bio Mater. 2025 Jun 23.
    Unveiling Exosome Potential: Transforming Treatments for Neurodegeneration.
    Ankit Tiwari, Brijesh Singh, Gireesh Kumar Singh, Jairam Meena, Ashish Kumar Agrawal, Saroj Kumar, Gyan Modi.
      Exosomes, tiny extracellular vesicles, hold significant potential as biological nanocarriers for diverse therapeutic agents due to their exceptional ability to navigate through the barriers of biological systems. This comprehensive review delves into the capability of exosomes in the therapy of neurodegenerative disorders, concentrating on their potential for targeted drug delivery. It examines the complex processes involved in exosome-mediated drug delivery, including targeting, cellular uptake, intracellular trafficking, and therapeutic release. Insights from preclinical studies and clinical trials are exploited, highlighting the impactful applications of exosomes, particularly in the treatment of Parkinson's, Alzheimer's, ALS, and Huntington's diseases. The review also addresses challenges such as immunogenicity, scalability, and regulatory obstacles while exploring emerging technologies like advanced exosome engineering, personalized medicine, and the integration of nanotechnology. Overall, this review accentuates the potential impact of exosome-based treatments in biomedicine alongside the critical need to overcome existing barriers.
    Keywords:  blood–brain barrier; drug delivery; exosome; nanocarrier; nanotechnology; neurodegenerative disorder
    DOI:  https://doi.org/10.1021/acsabm.5c00096
  25. Front Immunol. 2025 ;16 1584738
    T cells responses after vaccination: a regulatory perspective.
    Alessandra Buoninfante, Marco Cavaleri.
      Vaccines are complex biological medicinal products developed with the aim to generate protective immunity against specific infectious diseases in a particular target population. Regulatory authorities, who have the role of approving vaccines, ensure that these meet the agreed criteria for quality, safety and efficacy, and assess their benefit and risk profile before and after a marketing authorization is granted. In the European Union/European Economic Area, the vast majority of the vaccines currently available has been approved on the basis of clinical efficacy or immunogenicity data relying on humoral immune responses. Per contrary, there are no vaccines approved based on immunogenicity endpoints exclusively focused on cell mediated immunity, despite the known relevance of T cells immunity for protection against a variety of infectious diseases. We here review a few relevant cases of vaccines targeting infectious diseases for which data on cell mediated immunity have been considered in the context of regulatory filing, and provide our perspective on the way forward.
    Keywords:  T cells; assays; cell-mediated immunity; decision making; pathogens; regulatory approval; vaccines
    DOI:  https://doi.org/10.3389/fimmu.2025.1584738
  26. Curr Opin Nephrol Hypertens. 2025 Jun 24.
    A current update of the development of Chimeric Antigen Receptor T-cell therapy and kidney disease.
    Juan León-Román, Alexandra Esteves, Gloria Iacoboni, María José Soler.
       PURPOSE OF REVIEW: Chimeric antigen receptor (CAR) T-cell therapy has marked a historic milestone for its remission rates in relapsed/refractory hematological neoplasms. Despite favorable efficacy outcomes, CAR T-cells are associated with potentially severe early and late complications, such as cytokine release syndrome (CRS), neurotoxicity, acute kidney injury (AKI), cytopenias and infections.
    RECENT FINDINGS: AKI is a common complication that normally manifests during the first week following infusion and typically shows recovery within the first month. The risk factors for AKI development include a prior history of chronic kidney disease (CKD), development of CRS or neurotoxicity, antibiotic therapy and the use of intravenous contrast, amongst others.
    SUMMARY: AKI a frequent but mild complication, with fast recovery. Future multicentric prospective studies are required to investigate the pathophysiology of AKI following CAR T-cell therapy and the potential preventive treatments. Furthermore, the impact of AKI secondary to CAR T-cell treatment in patients with prior CKD has not been analyzed in long-term follow-up studies.
    Keywords:  chimeric antigen receptor T-cell therapy; glomerular diseases; immunotherapy; onconephrology
    DOI:  https://doi.org/10.1097/MNH.0000000000001096
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