bims-carter Biomed News
on CAR-T Therapies
Issue of 2025–06–08
24 papers selected by
Luca Bolliger, lxBio



  1. Crit Rev Oncol Hematol. 2025 May 29. pii: S1040-8428(25)00173-8. [Epub ahead of print]213 104785
      Ovarian cancer poses a significant threat to women's health, and the limitations of current treatments demand the exploration of new therapeutic solutions. Chimeric antigen receptor (CAR) T cell therapy, a novel form of immunotherapy, has demonstrated substantial efficacy in the treatment of hematological malignancies and holds considerable promise for ovarian cancer treatment. This paper provides a comprehensive review of the application of CAR-T cell therapy in ovarian cancer, with a detailed discussion of therapeutic targets such as mesothelin, MUC16, and FOLR1, along with associated clinical trials. Presently, the application of CAR-T cell therapy in ovarian cancer is confronted with challenges including immunosuppression within the tumor microenvironment (TME), tumor heterogeneity, target-related issues, toxic reactions, and limitations in cell efficacy. To address these challenges, strategies such as modulating immunosuppressive cells, employing dual-target strategies, optimizing target selection and CAR structure, enhancing cell performance, and utilizing combination therapies are proposed. Future research directions are likely to focus on the expansion of combination therapies, the application of nanotechnology, the advanced development of personalized medicine, and the exploration of immune cell diversification. Although CAR-T cell therapy remains in its nascent stages for the treatment of ovarian cancer, ongoing research and technological advancements are anticipated to yield significant breakthroughs, potentially offering more effective treatment options for patients with ovarian cancer.
    Keywords:  CAR-T cell; Combination therapy; Ovarian cancer; Targets; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.critrevonc.2025.104785
  2. Front Immunol. 2025 ;16 1583116
      Chimeric antigen receptor T (CAR-T) cell therapy has undergone vigorous development in recent years, yet it still faces significant challenges and difficulties in its clinical application and further development. A systematic synthesis of global trends in CAR-T clinical trials is essential to identify knowledge gaps, optimize treatment strategies, and guide future research directions. This review analyzed 1,580 CAR-T clinical trials registered at ClinicalTrials.gov as of April 2024, and extracted characteristic data in multiple dimensions, including target specificity, treatment indication, and development stage etc. The transparency of trial outcomes was assessed by validation with articles published in PubMed/Google Scholar. Additionally, it is complemented by investigator surveys assessing to barriers to CAR-T development, prospects, and recommendations.
    Keywords:  chimeric antigen receptor T-cell; clinical trials; clinicaltrials.gov; hematological malignancies; publication following search queries: condition/disease or intervention/treatment: “CAR T”; solid tumors; “CAR T cell”; “chimeric antigen receptor”
    DOI:  https://doi.org/10.3389/fimmu.2025.1583116
  3. Med Oncol. 2025 May 31. 42(7): 228
      Chimeric Antigen Receptor T-cell (CAR-T) therapy represents a groundbreaking advance in oncology, leveraging patient-specific immune cells to target malignant tumours precisely. By equipping T cells with synthetic receptors, CAR-T therapy achieves remarkable antitumor effects and offers hope for durable cancer control. However, several limitations persist, including antigen scarcity, immunosuppressive tumour microenvironments, and T-cell exhaustion. CRISPR-Cas9 gene editing has enhanced CAR-T potency by knocking out immune checkpoints (PD-1, CTLA-4) and improving persistence, while RNA interference (RNAi) silences immune-evasion genes (e.g. SOCS1). Nanozyme-based delivery systems enable precise CRISPR-Cas9 delivery (> 70% editing efficiency) and tumour targeting, overcoming instability and off-target effects. Innovations like SUPRA CARs, armoured CAR-T cells (e.g. IL-12/IL-21-secreting TRUCKs), and dual checkpoint inhibition synergize to reprogram the tumour microenvironment, reducing relapse by 40% in trials. Despite progress, high costs, manufacturing hurdles, and ethical concerns (e.g. germline editing risks) remain critical barriers. Emerging solutions include universal off-the-shelf CAR-Ts, hybrid nano-CRISPR systems, and AI-driven design, paving the way for scalable, personalised immunotherapy. This review highlights breakthroughs in CRISPR, RNAi, and nanotechnology, underscoring CAR-T therapy's transformative potential while addressing translational challenges for broader clinical adoption.
    Keywords:  CAR-T therapy; CRISPR-Cas9 in oncology; Cancer immunotherapy; Genetic engineering; Nanozymes in cancer; Tumour microenvironment
    DOI:  https://doi.org/10.1007/s12032-025-02783-5
  4. Clin Transl Immunology. 2025 ;14(6): e70025
       Objectives: Chimeric antigen receptor (CAR) T-cell therapies have revolutionised the treatment of blood-based malignancies. The use of manual CAR T-cell manufacturing methods is one of the challenges that contributes to these delays. As CAR T therapy emerges as a potential first- or second-line treatment option for these cancers, the demand for these therapies continues to rise. However, challenges persist in ensuring that the patients who need these therapies receive them in a timely manner. Automated CAR T-cell manufacturing methods that use software to control the equipment used in the process can help overcome the roadblocks associated with manual manufacturing, ultimately enabling a reduction in variability, increased efficiency, improved product quality and better data management. This paper aims to present an end-to-end semi-automated methodology for manufacturing CAR T cells using the Cell Therapy Systems (CTS™) Cellmation software - an off-the-shelf software solution - to control physically connected modular cell therapy instruments that eliminates the roadblocks associated with manual manufacturing.
    Methods: T cells from healthy donors were isolated and processed into CAR T cells using a semi-automated, connected, multi-instrument setup that leveraged electroporation and a CRISPR/Cas system for delivering the CD19-CAR construct to the T cells. Flow cytometry was used to assess cell type composition, cell viability and expression of T-cell activation markers throughout the process. We also measured exhaustion marker expression on T cells, T-cell receptor (TCR) knock-out, CAR knock-in and cytotoxic activity against NALM6 cells.
    Results: The results demonstrated the successful generation of functional CAR T cells using a semi-automated instrument workflow. The results were similar to the results from CAR T cells manufactured using non-automated processes; however, the successful connection and control of the instruments using automated software present an exciting opportunity for process developers and manufacturers who want to reduce manual touchpoints in their cell therapy manufacturing process.
    Conclusion: The method that we describe in this paper could be beneficial to process development and manufacturing teams that might require flexibility in their CAR T cell manufacturing workflow and want to take advantage of modular systems that can be automated using the Cellmation software to reduce the problems associated with manual handling.
    Keywords:  CAR T cells; CAR T‐cell manufacturing; automation; cell therapy
    DOI:  https://doi.org/10.1002/cti2.70025
  5. Front Immunol. 2025 ;16 1514994
      Human epidermal growth factor receptor 2 (HER2) is highly expressed in various solid tumors, and its abnormal activation is closely associated with poor tumor prognosis, establishing it as a prominent target in contemporary research. The successful clinical treatment of multiple HER2-positive tumors with HER2 antibodies has prompted researchers to design chimeric antigen receptor T (CAR-T) cells targeting HER2 for solid tumor immunotherapy. To date, the development of CAR structures has progressed to the fifth generation, with most HER2-CAR-T cell structures being modified based on the second-generation CAR architecture. This review will delineate the structure and cytotoxic mechanism of HER2-CAR-T cells, elucidate the difficulties and optimization strategies for HER2-CAR-T cell therapy, and summarize recent clinical applications and advancements.
    Keywords:  CAR-T; CARs structure; HER2; clinical application; optimization strategies; solid tumors
    DOI:  https://doi.org/10.3389/fimmu.2025.1514994
  6. Cytokine. 2025 May 30. pii: S1043-4666(25)00120-6. [Epub ahead of print]192 156973
      Despite the remarkable clinical success of chimeric antigen receptor (CAR)-T cell therapy in hematologic malignancies, the therapeutic efficacy of conventional second-generation CAR-T cells in treating solid tumors remains suboptimal, primarily due to three major biological barriers: (1) the immunosuppressive tumor microenvironment (TME), (2) inadequate tumor infiltration capacity, and (3) T cell exhaustion mechanisms. To overcome these limitations, innovative fourth-generation "armored" CAR-T cell platforms have been engineered with integrated cytokine-secreting modules designed to potentiate anti-tumor responses through localized immunomodulation. These advanced cellular therapeutics achieve targeted delivery of various immunostimulatory cytokines directly within the TME, thereby orchestrating three critical therapeutic effects: (I) remodeling of the immunosuppressive niche, (II) enhancement of immune cell persistence, and (III) neutralization of immunosuppressive signaling networks. This comprehensive review systematically examines the translational applications of cytokine-secreting CAR-engineered immune cells, including CAR-T, CAR-NK, and CAR-iNKT cell platforms, in solid tumor immunotherapy, with particular emphasis on multiple classes of immunomodulatory cytokines that enhance cytotoxic potential, promote immune cell survival, and counteract TME-mediated immunosuppression. We critically evaluate preclinical and clinical evidence demonstrating the therapeutic efficacy of cytokine-armed CAR-engineered cells across various tumor models, including hematological malignancies, glioblastoma, and neuroblastoma. Furthermore, this review addresses current translational challenges, particularly cytokine-associated toxicity profiles and innovative strategies for achieving spatiotemporal control of cytokine release, while discussing their potential implications for advancing clinical outcomes in solid tumor immunotherapy.
    Keywords:  Interleukin CAR-T CAR-NK CAR-iNKT proliferation persistence
    DOI:  https://doi.org/10.1016/j.cyto.2025.156973
  7. Hum Vaccin Immunother. 2025 Dec;21(1): 2509483
      In recent years, chimeric antigen receptor T cell (CAR-T) immunotherapy has made considerable progress in the treatment of glioblastoma. The aim of this study was to comprehensively explore the prospects and future trends of CAR-T immunotherapy for glioblastoma through systematic bibliometric analysis. Publications pertaining to glioblastoma and CAR-T immunotherapy from 2008 to 2024 were extracted from the Web of Science Core Collection. Utilizing VOSviewer (version 1.6.20), CiteSpace (version 6.3.R1), and R 4.3.3, this study concentrated on evaluating contributions from countries, institutions, authors, and journals, while also identifying research hotspots and emerging trends. A total of 570 publications were identified, demonstrating an annual growth rate of 31.71%. The USA led the field with 269 publications, followed by China (113). The University of Pennsylvania, Harvard University, and the University of California System emerged as the most prolific institutions. Frontiers in Immunology published the most articles (42), while Clinical Cancer Research garnered the highest number of citations (2,867). Recent keyword bursts (2022-2024) underscored an increasing focus on combination therapy approaches and outcomes, particularly emphasizing "radiotherapy" (strength 3.49), "solid tumor" (strength 3.49), and "efficacy" (strength 2.79). In recent years, research on CAR-T immunotherapy for glioblastoma has gradually shifted from the exploration of basic mechanisms to the application of clinical combination therapy, and this shift in research direction indicates that CAR-T immunotherapy has a relatively mature technology and great clinical translation potential. In the coming years, CAR-T immunotherapy is expected to usher in a golden era and benefit more patients suffering from glioblastoma.
    Keywords:  CAR-T immunotherapy; Glioblastoma; bibliometric analysis; immunotherapy efficacy; tumor microenvironment
    DOI:  https://doi.org/10.1080/21645515.2025.2509483
  8. medRxiv. 2025 May 16. pii: 2025.05.15.25327612. [Epub ahead of print]
       Background: Chimeric antigen receptor (CAR) T cells are a leading immunotherapy for refractory B-cell malignancies, but their impact is constrained by toxicity and incomplete long-term efficacy. Daily (circadian) rhythms in immune function may offer a lever to boost therapeutic success. Studies suggest that time of day influences immune-based therapies, including vaccines, hematopoietic stem cell transplantation, and checkpoint inhibitors for cancer. However, the clinical relevance of biological rhythms to CAR-T cell therapy remains unknown.
    Methods: We retrospectively analyzed CAR-T cell survival and complications based on infusion time at two geographically distinct hospitals in St. Louis, Missouri (n=363), and Portland, Oregon (n=307) between 2018 and 2024. The primary outcome was 90-day overall survival (OS). Secondary outcomes included event-free survival (EFS), cytokine release syndrome (CRS), immune cell-associated neurotoxicity syndrome (ICANS), ICU admission, shock, respiratory failure, and infection. We quantified the independent relationship between infusion time and outcomes using multivariable mixed effects logistic regression, adjusting for patient, oncological, and treatment characteristics.
    Findings: Morning CAR-T cell infusions were associated with higher overall survival and lower rates of neurotoxicity before and after adjusting for confounders. Each hour earlier in the day that CAR-T cell treatment was given corresponded to a 22% increase in the odds of 90-day OS (adjusted odds ratio [aOR] 0·78, 95% CI 0·66-0·92, p=0·004). Simultaneously, for every hour CAR-T cell infusion was delayed, the adjusted odds of severe ICANS rose by 17% (aOR 1·17, 95% CI 1·01-1·34, p=0·031), and anakinra prescription rose by 26% (aOR 1·26, 95% CI 1·07-1·49, p=0·006). In contrast, we did not find an association between infusion time and severe CRS (aOR 0·96, 95% CI 0·74-1·23, p=0·73). Temporal patterns were most pronounced in women and patients receiving CD19-targeting CAR-T cell products for leukemia or lymphoma.
    Interpretation: Time of day is a potent and easily modifiable factor that could optimize CAR-T cell clinical performance.
    Funding: National Institutes of Health.
    Research in context: Evidence before this study: A review of PUBMED-cited articles shows that fundamental immune processes exhibit daily (circadian) rhythms in activity, leading immune-based therapies to vary in clinical efficacy based on the time of day. For example, the effectiveness of vaccines, checkpoint inhibitor therapy for cancer, and hematopoietic stem cell transplantation varies with the time of day they are administered to patients. One immunotherapy where dosing time remains unexplored in clinical data is CAR-T cells, a cell-based treatment for refractory B-cell cancers. Currently, the timing of CAR-T therapy is largely determined by staff availability. We hypothesized that CAR-T cell clinical safety and efficacy vary with administration time. If this hypothesis is correct, scheduling CAR-T cell infusions for specific times of day might improve the performance of this key treatment at minimal cost.Added value of this study: This study reveals that the clinical performance of CAR-T cells varies substantially with administration time. It informs practice by showing that morning CAR-T cell infusions correlate with optimal therapeutic index based on better survival and less neurotoxicity. The study also identifies women and patients receiving anti-CD19 CAR-T cells as subgroups that may benefit the most from timed CAR-T cell infusions.Implications of all the available evidence: This study on CAR-T cells should be understood in the context of growing evidence that circadian rhythms in immunity are broadly clinically translatable. The findings should prompt prospective trials that test time-of-day prioritization and, if validated, changes to CAR-T cell practice patterns. The findings also have implications for clinical trials applying CAR-T cells to new indications. Without controlling for time-of-treatment, diurnal rhythms in CAR-T cell effectiveness could be a significant confounder that could lead to false-negative or false-positive conclusions.
    DOI:  https://doi.org/10.1101/2025.05.15.25327612
  9. Chaos. 2025 Jun 01. pii: 063104. [Epub ahead of print]35(6):
      Malignant gliomas (MGs) are among the most aggressive primary brain tumors, characterized by a high degree of resistance to therapy and poor prognosis. In this work, we develop a mathematical model to investigate the dynamics of MG under the combined effects of chemotherapy and chimeric antigen receptor cell therapy. The proposed model is a five-dimensional dynamical system incorporating impulsive inputs that correspond to the clinical administration of chemotherapy and immunotherapy. We demonstrate the non-negativity of solutions for non-negative initial conditions, ensuring the biological relevance of the model. We show that if we apply both therapies only once, the trajectories are attracted to an invariant surface corresponding to the tumor carrying capacity. Conversely, under constant administration of both treatments, we identify parameter ranges in which tumor eradication is achievable. Furthermore, we numerically study various treatment combinations to determine optimal protocols at the population level. To this end, we generate a cohort of 104 virtual patients with model parameters sampled uniformly within clinically relevant ranges and carry out in silico trials. Our findings indicate that tumor growth rate, chemotherapy efficacy, and tumor-induced immunosuppression are the key determinants of survival outcomes. We believe that our results provide new theoretical insights into treatment optimization and offer a framework for refining the design of clinical trials for MG therapies.
    DOI:  https://doi.org/10.1063/5.0260252
  10. Ther Innov Regul Sci. 2025 Jun 03.
      Chimeric antigen receptor T-cell (CAR-T) therapy uses autologous T cells from patients to eliminate malignant targets. Cryopreservation of cellular starting materials, particularly fresh leukocytes, is an important step before production. While this promising specialized immune therapy is advancing, regulations have evolved, as specified in the US (21CFR1271) and Europe (EU Annex 1, 1394/2007). Cryopreservation is considered by this as minimal manipulation or is not considered as substantial manipulation unless there is alteration of relevant biological cell characteristics or cellular engineering. Similar consideration has been made by health authorities in Australia and South Korea. Conversely, the health authority in Japan determines if the starting material is applicable to Good Gene, Cellular, and Tissue-based Products Manufacturing Practice based on scientific data regarding the impact on product quality and safety. Whereas regulations have evolved in the US and EU, this is the first article to systemically review, from a manufacturer's perspective, the specific regulatory positions taken towards cryopreservation in Asia-Pacific (APAC) countries, i.e. Japan, Australia and South Korea. These positions generally consider that formulation and cryopreservation should be performed in a closed system, thus protecting cellular starting materials from contaminant exposure with a low-risk approach. Local and centralized cryopreservation logistics are discussed along with optimal implementation practices. The impact of geographic access on cryopreservation logistics, as well as the importance of careful evaluation of logistical and cost aspects for successful supply of CAR-T therapies in APAC, are also discussed.
    Keywords:  Asia Pacific; Chimeric antigen receptor; Health care economics; Immunotherapy; Regulatory
    DOI:  https://doi.org/10.1007/s43441-025-00808-9
  11. Semin Oncol Nurs. 2025 Jun 01. pii: S0749-2081(25)00105-6. [Epub ahead of print] 151912
       OBJECTIVES: Adoptive cell therapy (ACT) is a growing personalized immuno-oncology approach, delivered both in standard of care (SOC) and clinical trial (CT) settings. Understanding patient and informal caregivers (ICs) experiences is crucial to optimizing care. This qualitative systematic review explores the ACT experience across three elements: actors (patients and ICs), settings (CT and SOC), and phases of the care continuum.
    METHODS: A systematic search was conducted across Medline, Embase, CINAHL, APA PsycInfo, Cochrane, Web of Science, ProQuest Dissertations & Theses, and Google Scholar up to May 8, 2024. Studies were appraised using the JBI Critical Appraisal Checklist for Qualitative Research, with data extracted and synthesized using a meta-aggregation approach. MAXQDA was used to generate co-occurrence networks between key elements and inductively derived codes. A comparative sentiment analysis highlighted emotional differences between CT and SOC settings.
    RESULTS: Nineteen qualitative studies were included, capturing experiences of patients (n = 19) and ICs (n = 7) receiving chimeric antigen receptor T cell (n = 17) and tumor-infiltrating lymphocyte (n = 2) therapy in CT (n = 13) and SOC (n = 9) settings. Findings revealed phase-specific challenges across physical, cognitive, psychological, emotional, social, financial, professional, communication, and informational domains. These challenges originate from ACT-related toxicities, care pathway complexity, and the novel nature of the therapy.
    CONCLUSIONS: This review identifies the key challenges faced by patients and ICs throughout the ACT care pathway, emphasizing the need for tailored interventions based on the phase and setting, as well as improved support systems.
    IMPLICATIONS FOR NURSING PRACTICES: Recommended strategies include developing decision support tools, establishing caregiver support programs, and implementing navigation services to enhance patient and ICs experiences.
    Keywords:  Adoptive cell therapy (ACT); Caregiver burden; Oncology nursing; Person-centered care; Qualitative studies; Systematic review
    DOI:  https://doi.org/10.1016/j.soncn.2025.151912
  12. Br J Haematol. 2025 Jun 04.
      Allogeneic haematopoietic stem cell transplantation (allo-HSCT) has been reported to further sustain long-term leukaemia-free survival following chimeric antigen receptor T-cell (CAR-T) therapy. It remains unclear whether bridging CAR-T to allo-HSCT results in higher treatment-related toxicity and mortality. We conducted a retrospective study to compare outcomes between allo-HSCT after CAR-T or conventional chemotherapy. After propensity score matching, 62 patients with prior CAR-T therapy and 124 patients with chemotherapy were ultimately included. Patients in the CAR-T cohort had a longer duration time from diagnosis to transplant (p < 0.001) and more advanced disease status before HSCT (p < 0.001) than that of the chemotherapy cohort. Patients with prior CAR-T cell therapy had a lower 28-day platelet engraftment rates [Hazard Rate (HR) = 1.38, 95% Confidence Interval (CI), 1.02-1.87, p = 0.037]. Multivariate analysis revealed that CAR-T therapy increased the risk of moderate to severe chronic graft-versus-host disease (cGVHD) (HR = 2.5, 95% CI, 1.01-6.19, p = 0.048). Compared with patients in the chemotherapy cohort, those in the CAR-T cell cohort experienced a higher incidence of transplantation-associated thrombotic microangiopathy (6.5% vs. 0.8%, p = 0.03) and probable/possible invasive fungal disease (10.0% vs. 3.3%, p = 0.08). The relapse rate, non-relapse mortality, and survival were comparable between cohorts. Caution should be exercised in allo-HSCT following CAR-T therapy because of the higher risk of platelet engraftment failure and cGVHD compared to chemotherapy.
    Keywords:  allogeneic haematopoietic stem cell transplantation; chimeric antigen receptor T‐cell therapy; propensity score‐matched analysis; treatment‐related toxicities
    DOI:  https://doi.org/10.1111/bjh.20180
  13. Cell Commun Signal. 2025 Jun 05. 23(1): 271
      Cancer immunotherapy, which boosts the immune system to recognize and attack malignant cells, has revolutionized traditional cancer treatment paradigms. Approaches such as chimeric antigen receptor T cell (CAR-T) therapy and immune checkpoint inhibitors (ICIs) have demonstrated promising therapeutic outcomes, leading to the approval of numerous immuno-oncology agents by the US Food and Drug Administration (FDA) over the past few decades. Immuno-oncology agents, mainly based on conventional full-length antibodies or their derivatives, are widely used in cancer immunotherapy. However, their large size, unwanted immunogenicity, poor solubility, complex molecular architectures, and limited tumor penetration pose significant challenges that must be addressed. Nanobodies, which are single-domain antibody fragments originating from the variable regions of camelid heavy-chain immunoglobulins, represent the smallest known antigen-binding fragments. In addition to their small size (~ 15 kDa), nanobodies possess a range of advantageous properties, including high stability, strong specificity and affinity for target antigens, low immunogenicity, and cost-effective production. Nonetheless, their short serum half-life and lack of Fc-mediated functions may limit efficacy, which can be addressed by Fc fusion, albumin binding, or multivalent construct design. These properties enable nanobodies to support multifunctional constructs, such as bispecific CARs, nanobody-secreting CARs, dual ICI-containing molecules, and trispecific immune cell-engaging antibodies. In recent years, a growing number of nanobody-based immuno-oncology agents have progressed into preclinical and clinical trials, with several products approved by the US FDA and China's National Medical Products Administration for cancer therapy. In this review, we explore the unique properties of nanobodies and provide a comprehensive summary of recent preclinical and clinical advancements in nanobody-based immuno-oncology agents, with a focus on their applications in CAR-T cells, ICIs, and immune cell-engaging antibodies. Through their unique capacity to integrate innovative molecular engineering with translational clinical development, nanobody-based therapeutics are poised to revolutionize current paradigms in cancer immunotherapy.
    Keywords:  CAR-T therapy; Cancer immunotherapy; Immune cell engaging antibodies; Immune checkpoint inhibitors; Nanobody
    DOI:  https://doi.org/10.1186/s12964-025-02270-4
  14. Per Med. 2025 Jun 05. 1-7
      Understanding the regional differences in approved gene therapies, clinical trial development, and regulatory frameworks is crucial for ensuring equitable access and addressing justice issues in advanced therapeutics. This review aimed to evaluate the differences between the US, the EU, Japan, and China and offer policy recommendations to promote harmonization between these countries and regions. Gene therapy approvals show significant regional disparities, with the US leading with 23 approved therapies, followed by the EU with 16. Few products are accessible worldwide reflecting challenges in obtaining cross-border approvals. Moreover, access is uneven within regions like the EU, with high-income countries having better accessibility. High costs and complex reimbursement processes exacerbate these issues, with some products being withdrawn from the market due to pricing disputes. Regulatory differences, such as differing data needs, further delay access in countries, like Japan, where gene therapy products are unavailable until years after a product is ready for approval. Clinical trial activity mirrors these disparities, with China's growing number of trials potentially reshaping the landscape. Harmonizing regulations across regions could streamline the approval process for therapies, making them more efficient and reducing disparities. Furthermore, key solutions include incentivizing cost reductions, adopting innovative payment models, and aligning evidence/reimbursement requirements.
    Keywords:  ELSI; Gene therapy; access; clinical trials; ethical issues; gene therapies; regulatory systems; reimbursement
    DOI:  https://doi.org/10.1080/17410541.2025.2515002
  15. Research (Wash D C). 2025 ;8 0723
      Natural killer (NK) cells, serving as pivotal mediators of innate immunity, play an important role in antitumor immunity. Immune checkpoint can be expressed on the surface of NK cells and meticulously regulates their activation states and effector functions through complex signaling networks. In recent years, tumor immunotherapy strategies focusing on NK cell immune checkpoints have demonstrated remarkable advancements. This review systematically elucidates the expression profiles, signaling pathways, and the immune checkpoint molecule regulatory mechanisms localized on the NK cell membrane (e.g., NKG2A, KIRs, and TIGIT) or intracellularly (e.g., BIM, Cbl-b, and EZH2) during tumor immune evasion. Particular attention is devoted to dissecting the regulatory mechanisms through which these immune checkpoint molecules influence NK cell-mediated cytotoxicity, cytokine secretion, proliferative capacity, and tunable modulation of NK cell immune checkpoint expression by diverse factors within the tumor microenvironment. Furthermore, this review comprehensively summarizes preclinical advancements in NK cell immune checkpoint blockade strategies, including single checkpoint blockade, combinatorial checkpoint approaches, and their integration with conventional therapeutic modalities. Additionally, emerging therapeutic advancements, such as gene-editing technologies and chimeric antigen receptor-NK (CAR-NK) cell therapy, are evaluated for their prospective applications in immunotherapy based on NK cells. By thoroughly elucidating the molecular regulatory networks underlying NK cell immune checkpoints and their mechanisms of action within the complex tumor microenvironment, this review aims to provide critical theoretical insights and translational foundations to foster the development of innovative tumor immunotherapy strategies, improvement of combination therapies, and realization of personalized precision medicine.
    DOI:  https://doi.org/10.34133/research.0723
  16. bioRxiv. 2025 May 23. pii: 2025.05.20.650777. [Epub ahead of print]
      Negative regulators of T cell function represent promising targets to enhance the intrinsic antitumor activity of CAR T cells against solid tumors. However, the endogenous immune ecosystem in solid tumors often represents an immunosuppressive therapeutic barrier to CAR T cell therapy, and it is currently unknown whether deletion of negative regulators in CAR T cells reshapes the endogenous immune landscape. To address this knowledge gap, we developed CAR T cells targeting B7-H3 in immune-competent osteosarcoma models and evaluated the intrinsic and extrinsic effects of deleting a potent negative regulator called Regnase-1 (Reg-1). Deletion of Reg-1 not only improved the effector function of B7-H3-CAR T cells but also endowed them with the ability to create a proinflammatory landscape characterized by an influx of IFNγ-producing endogenous T cells and NK cells and a reduction of inhibitory myeloid cells, including M2 macrophages. Thus, deleting negative regulators in CAR T cells enforces a non-cell-autonomous state by creating a proinflammatory tumor microenvironment.
    DOI:  https://doi.org/10.1101/2025.05.20.650777
  17. Naunyn Schmiedebergs Arch Pharmacol. 2025 Jun 03.
      Cancer immunotherapy aims to use the immune system of the body for improved therapeutic effects on tumors. Currently, one of the more encouraging interventions under evaluation involves the use of immune checkpoint blockade, which offers longer benefit periods and greater patient tolerance than previous interventions for solid malignancies. Nevertheless, a majority of patients never respond or gradually acquire resistance; hence, a suboptimal effect of the therapy ensues. Resistance to such treatments may arise from tumor-specific factors, host factors, and environmental influences. There is growing evidence that the gut microbiome is an important modulator not only of the efficacy of these treatments but also of toxicities. Current studies are focused on the identification of key microbial profiles from both preclinical and clinical samples associated with immunotherapeutic response and antitumor activities. Elucidation of this complex interaction may provide ways to modulate gut microbial communities to improve patient outcomes. The current review addresses the components responsible for resistance against immune checkpoint inhibitors and highlights the crucial linkage between gut microbiome-immune interactions. We further summarize some recent clinical findings and explore prospective avenues for research in this evolving area of cancer treatment.
    Keywords:  Gut microbiome; Immune checkpoint inhibitors; Immunotherapy; Therapeutic resistance
    DOI:  https://doi.org/10.1007/s00210-025-04315-4
  18. Front Immunol. 2025 ;16 1562248
      T cell receptor (TCR) signaling, also known as signal 1, plays a crucial role in the activation and proliferation of T cells. The question of whether TCR signaling exerts a deterministic role in T cell fate determination is an area of active investigation. It has been particularly challenging to address this question due to the complexities associated with genetic manipulation of TCR signaling components, which often disrupts thymic T cell development or impairs T cell activation upon TCR engagement. Recent study demonstrates that the TCR-Lck/Fyn axis directly induces STAT3 phosphorylation and synergizes with pro-inflammatory cytokines to optimize STAT3 phosphorylation during Th17 cell differentiation. Additionally, the TCR-Lck/Fyn-AKT/mTOR axis negatively regulates Treg cell differentiation. In CD8+ T cells, persistent high-affinity antigen stimulation drives differentiation along the exhaustion pathway, while acute infection or intermediate antigen levels promote differentiation into effector and memory T cells, although the underlying mechanism remains to be fully elucidated. Collectively, these studies provide compelling evidence that TCR signaling has a deterministic impact on T cell fate. This review summarizes recent advances in understanding how TCR signaling shapes T cell fate determination.
    Keywords:  T cell differentiation; T cell exhaustion; T cell fate; TCR signal strength; TCR signaling; Tpex; immunometabolism; memory T cells
    DOI:  https://doi.org/10.3389/fimmu.2025.1562248
  19. Nat Med. 2025 Jun 01.
      Glioblastoma (GBM) is the most common primary brain cancer in adults and carries a median overall survival (OS) of 12-15 months. Effective therapy for recurrent GBM (rGBM) following frontline chemoradiation is a major unmet medical need. Here we report the dose escalation and exploration phases of a phase 1 trial investigating intracerebroventricular delivery of bivalent chimeric antigen receptor (CAR) T cells targeting epidermal growth factor receptor (EGFR) epitope 806 and interleukin-13 receptor alpha 2 (IL-13Rα2), or CART-EGFR-IL13Rα2 cells, in patients with EGFR-amplified rGBM. Primary endpoints included dose-limiting toxicity, determination of the maximum tolerated dose and recommended dose for expansion, and occurrence of adverse events. Secondary endpoints included objective radiographic response, duration of response, progression-free survival and OS. A total of 18 patients received CART-EGFR-IL13Rα2 cells. The maximum tolerated dose was determined to be 2.5 × 107 cells. Of the 18 patients, 10 (56%) experienced grade 3 neurotoxicity; none had grade 4-5 neurotoxicity. Of 13 patients, 8 (62%) with measurable disease at the time of CAR T cell infusion experienced tumor regression, with one confirmed partial response by Modified Response Assessment in Neuro-Oncology criteria (objective radiographic response, 8%; 90% confidence interval, 0-32%) and one patient with ongoing durable stable disease lasting over 16 months. Median progression-free survival was 1.9 months (90% confidence interval, 1.1-3.4 months), and median OS was not yet reached at the time of data cut-off (median follow-up time, 8.1 months). These findings indicate that intracerebroventricular delivery of bivalent CART-EGFR-IL13Rα2 is feasible and appears safe. CART-EGFR-IL13Rα2 cells are bioactive and exhibit a signal of antitumor effect in rGBM. ClinicalTrials.gov registration: NCT05168423 .
    DOI:  https://doi.org/10.1038/s41591-025-03745-0
  20. Probiotics Antimicrob Proteins. 2025 Jun 02.
      Probiotics are living microbes that provide health benefits when administered in appropriate quantities. Probiotics maintain a balanced gut microbiota that has a remarkable influence on human physiology and nutrition; also, they have been recognised for their other advantages, including their beneficial effects on the skin, oral cavity, brain, immune system, vaginal tract, and so on. Probiotic microbes have been consumed by humans through traditionally fermented meals for many millennia. Bacteria, such as lactic acid bacteria, are considered innocuous and provide beneficial compounds for human health. Increased understanding of the gut microbiota has led to remarkable advancements in probiotic research. A wide range of probiotic products, including functional foods, nutritional products, and food supplements, have previously been introduced to the worldwide market. Probiotics provide numerous health benefits, extending beyond improved nutritional status to managing and preventing disorders in both intestinal and other non-intestinal sites such as the skin, brain, and oral cavity. The emphasis on the benefits of bacteria for health has recently moved from live, viable probiotics to inactive probiotic-derived microbes. These recently discovered non-viable bacteria are gerobiotics, psychobiotics, immunobiotics, oralbiotics, cardiobiotics, dermabiotics, urogeniobiotics, and gastrobiotics. Metabolites from probiotics can improve physiological health and provide therapeutic effects. The current review provides an overview of the various categories based on the potential health benefits.
    Keywords:  Cardiobiotics; Dermabiotics; Gastrobiotics; Gerobiotics; Immunobiotics; Oralbiotics; Probiotics; Psychobiotics; Urogeniobiotics
    DOI:  https://doi.org/10.1007/s12602-025-10601-7
  21. J Transl Med. 2025 Jun 03. 23(1): 620
       BACKGROUND: Adoptive transfer of regulatory T cells (Tregs) has provided promising results in treating autoimmune disorders, transplant rejection and graft versus-host disease in early clinical trials. However, major challenges remain for developing a standardized and robust good manufacturing practice (GMP)-compliant cell product which is severely hampered by low frequency of Tregs in circulation and laborious ex vivo expansion.
    METHODS: Paediatric thymuses routinely obtained during heart surgery have been shown by us and others to be a valuable source of large numbers of pure Tregs (Thy-Tregs). Here we show results from our process development approach including systematic laboratory-scale testing of activation reagents, restimulation timing, and cryopreservation to translate our expansion protocol of Thy-Tregs into a clinical grade cell product.
    RESULTS: Thy-Tregs obtained through CD8+ cell depletion and subsequent CD25+ enrichment were expanded with αCD3/αCD28 beads in the presence of Rapamycin and IL-2 for 10-23 days using G-Rex bioreactors. We successfully embedded bead removal and final formulation of a cryopreserved cell product ready to be used at bedside transfusion.
    CONCLUSION: This process has proved the capability of efficiently producing high number of functional Thy-Tregs, which will be administered as cell therapy in children undergoing heart transplantation (ATT-Heart, ISRCTN15374803), and enhancing the potential of using expanded Thy-Tregs for broad-ranging therapeutic applications.
    Keywords:  Clinical trial; GMP; Immuno-therapy; Thy-Tregs
    DOI:  https://doi.org/10.1186/s12967-025-06561-9
  22. Cureus. 2025 May;17(5): e83323
      Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by immune dysregulation, including impaired regulatory T cell (Treg) function. Low-dose interleukin-2 (Ld-IL-2) therapy has emerged as a promising approach to selectively expand Tregs and restore immune tolerance in SLE. This systematic review evaluates current evidence on the efficacy and safety of Ld-IL-2 therapy in patients with SLE. A comprehensive literature search was conducted across PubMed, Scopus, Web of Science, the Cochrane Library, and the Virtual Health Library for studies published up to April 10, 2025. Eligible studies included randomized controlled trials, cohort studies, and open-label trials that investigated Ld-IL-2 therapy in adult patients with SLE. Data were extracted on study design, patient demographics, intervention details, clinical and immunologic outcomes, adverse events, and predictive biomarkers. Risk of bias was assessed using the Modified Downs and Black checklist. Seven studies met the inclusion criteria, encompassing a total of 517 patients with active SLE. All studies reported significant expansion of Treg populations following Ld-IL-2 treatment. Clinical outcomes consistently showed reductions in disease activity scores, such as SLEDAI and BILAG, with SRI-4 response rates ranging from 43% to 65.5%. Ld-IL-2 therapy was well tolerated, with adverse events primarily limited to mild injection-site reactions and flu-like symptoms. No serious treatment-related infections or concerns about immunogenicity were observed. Several studies identified baseline biomarkers, including low complement C3 levels, elevated PD-1^hi^ Tregs, and reduced CD4+ T cell counts, as predictors of treatment response. Ld-IL-2 therapy appears to be a safe and effective immunomodulatory treatment for patients with SLE, capable of enhancing Treg function and reducing disease activity. While current evidence is encouraging, larger multicenter randomized trials are warranted to establish standardized treatment protocols and validate predictive biomarkers for optimized patient selection.
    Keywords:  biomarkers; immunotherapy; interleukin-2; low-dose il-2; regulatory t cells; safety; sledai; systemic lupus erythematosus
    DOI:  https://doi.org/10.7759/cureus.83323