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PubMed2026

Clinical outcomes of Epstein-Barr virus infection/reactivation following CAR-T cell therapy: A systematic review.

BACKGROUND: Epstein-Barr virus (EBV) infection or reactivation is an emerging but underrecognized complication following chimeric antigen receptor T-cell (CAR-T) therapy and is likely associated with treatment-induced immune dysregulation. Data regarding its clinical impact remain limited. OBJECTIVE: To evaluate the reported occurrence, clinical manifestations, and outcomes of EBV infection or reactivation in adults undergoing CAR-T therapy. METHODS: A systematic review was conducted in accordance with the PRISMA 2020 guidelines. PubMed, Embase, and Cochrane CENTRAL were searched from inception to March 2025 for studies reporting EBV infection or reactivation after CAR-T therapy in adults. Due to limited and heterogeneous data, results were synthesized descriptively. RESULTS: Five studies comprising 80 patients were included (median age, 55 years; 52.6% male among patients with reported sex data [10/19]). Across the included studies, 11 EBV infection/reactivation events were identified among 80 described CAR-T recipients, representing 13.8% of the reported sample rather than a true incidence estimate. Among events with usable individualized timing data, the median interval from CAR-T infusion to EBV detection/reactivation was 9.8 months (approximate range, 1-44 months). Because EBV surveillance strategies and definitions were inconsistently reported across studies, this proportion should not be interpreted as a true incidence estimate. Four patients (36.4%) developed EBV-associated disease, including three cases of EBV-related lymphoproliferative disorder and one case of EBV-associated diffuse large B-cell lymphoma. Among seven patients with reported post-CAR-T treatment response, four achieved Complete Remission/ Continuous Complete Remission; treatment response should be interpreted separately from final survival status. Confirmed EBV-related mortality occurred in 2/11 patients with reported EBV infection/reactivation and in 2/4 patients with EBV-associated disease; all-cause mortality could not be reliably estimated because patient-level vital status could not be fully attributed to the EBV-reactivated subgroup. Reported toxicities predominantly consisted of low-grade cytokine-release syndrome; however, toxicity data were limited. CONCLUSION: Although infrequently reported, EBV infection or reactivation after CAR-T therapy may be associated with substantial morbidity and mortality among affected patients. However, the available evidence is limited by the small sample size, heterogeneous study designs, and inconsistent EBV surveillance practices.

Humans↗

PubMed2026

CRISPR-Engineered CAR-T Cell Therapy for Epstein-Barr Virus-Associated Nasopharyngeal Carcinoma: A Review of Emerging Therapeutic Prospects.

Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) remains a clinically challenging malignancy, particularly in recurrent or metastatic disease where durable responses to chemoradiotherapy and immune checkpoint blockade are limited. The viral aetiology of NPC provides a strong biological rationale for immune-based treatment; however, translation of chimaeric antigen receptor (CAR) T-cell therapy into this solid tumour setting is constrained by poor tumour trafficking, antigen heterogeneity, limited surface accessibility of EBV latent antigens, T-cell exhaustion, and an immunosuppressive tumour microenvironment. This review critically evaluates the emerging therapeutic prospects of CRISPR-engineered CAR-T cell therapy for EBV-associated NPC. It synthesises evidence on EBV latency biology, NPC immune evasion, solid-tumour CAR-T limitations, and genome-engineering strategies including conventional CRISPR-Cas9, base editing, prime editing, and double-strand-break-sparing targeted integration. Particular attention is given to genotoxicity, chromosomal rearrangements, chromosome loss, bystander and off-target editing, manufacturing heterogeneity, and the regulatory and biological barriers that currently separate technical feasibility from NPC-specific clinical implementation. Available clinical evidence from checkpoint blockade, EBV-specific adoptive T-cell therapy, base-edited CAR-T cells in haematologic malignancy, and early CRISPR-edited T-cell trials supports the feasibility of immune and genetic redirection but does not establish efficacy of a clinically validated CRISPR-engineered CAR-T platform for NPC. Future development should prioritise surface-accessible antigen validation, fit-for-purpose selection of editing technology, genomic safety, scalable manufacturing, and biomarker-driven early-phase trials.

Humans↗

PubMed2026

Safety profiles of CAR-T cell therapy in systematic autoimmune diseases: a systematic review and analysis.

BACKGROUND: Chimeric antigen receptors (CARs)-T cell therapy is emerging as a potent approach for autoimmune diseases. However, its application in autoimmune conditions remains limited, and safety outcomes observed in malignancies can't reliably serve as a reference. Therefore, it's necessary to summarize the safety profiles in autoimmune diseases to provide evidence for future expanding trials. METHODS: A systematic review was conducted to analyze the CAR-T therapy safety in rheumatic diseases via database searches up to December 2025. Studies reporting safety data were included, while abstracts, reviews, and cases with malignancies were excluded. Factors associated with cytokine release syndrome (CRS) were analyzed using Firth's penalized logistic regression. RESULTS: This study included 38 studies, involving a total of 115 patients with autoimmune disease. Severe adverse events were rare. CRS and immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 70.4% and 4.3% of patients, respectively. Most CRS were low-grade. Multivariate analysis identified BCMA-targeted therapy and allogeneic CAR-T products may as independent factors associated with a reduced risk of CRS. Transient hematologic toxicity and hypogammaglobulinemia were frequently reported, with infections occurring in nearly half of the patients. However, prolonged cytopenia and severe infection were infrequent. CONCLUSION: Based on the current available evidence, CAR-T therapy appears to have a generally manageable safety profile in autoimmune diseases, supporting its potential as a promising treatment option for patients with relapsed or refractory autoimmune diseases. However, these findings remain preliminary, and further expanded studies are warranted in the future to provide higher-level evidence.

Humans↗

PubMed2026

Detection of cytokine release syndrome using wearables and cytokine profiling following CAR-T therapy for myeloma.

BACKGROUNDChimeric antigen receptor T-cell (CAR-T) therapies have revolutionized treatment for relapsed/refractory multiple myeloma (RRMM). However, cytokine release syndrome (CRS), a common and potentially severe complication, requires inpatient monitoring, limiting access and increasing costs. Wearable devices could support outpatient CAR-T delivery, but feasibility for CRS detection versus standard care remains unproven.METHODSWe conducted a prospective, single-center observational pilot study to assess the feasibility of using wearable devices for monitoring vital signs and detecting CRS. Thirty patients receiving idecabtagene vicleucel (ide-cel) or ciltacabtagene autoleucel (cilta-cel) were enrolled; 25 with sufficient monitoring data were evaluable. Sensors collected skin and axillary temperature, oxygen saturation, respiratory and heart rate, and motion. Peripheral blood cytokines were analyzed pre- and postinfusion using a multiplex proteomic platform. The primary outcome was feasibility, assessed by CRS detection sensitivity and specificity; secondary outcomes included adherence, lead time, and performance of models integrating wearable and cytokine data.RESULTSCRS occurred in 20 of 25 patients. The best-performing wearable model detected 18 or 20 CRS episodes with a sensitivity of 0.72 (mean 0.75; 95% CI 0.60-0.91) and a specificity of 0.80 (mean 0.76; 95% CI 0.68-0.84), and a median lead time of 7:00 hours before nursing recognition. Median adherence during high-risk periods was 71%. Cytokine changes paralleled temperature elevations, and IFN-γ emerged as a consistent biomarker.CONCLUSIONWearable devices are feasible for early CRS detection and may support outpatient CAR-T care. Larger outpatient studies are warranted.TRIAL REGISTRATIONThis study did not meet the criteria for ClinicalTrials.gov registration.

Humans↗

PubMed2026

Engineered Bacteriophages in Cancer Immunotherapy: Emerging Concepts and Potential Integration with CAR-T Cell Therapy.

Due to antigen heterogeneity, restricted immune cell trafficking and an immunosuppressive, nutrient-restricted tumour microenvironment, solid tumours remain resistant to modern immunotherapies. Engineered bacteriophages offer a modular framework to overcome these obstacles: programmable virus-like particles with scalable production. Through genome engineering, capsid decoration with mammalian cell-targeting ligands, or hybrid AAV/phage systems, engineered bacteriophages can display tumour-associated antigens, enhance receptor-mediated uptake and deliver therapeutic payloads such as cytokines, chemokines and suicide genes without naturally infecting mammalian cells. These features support their use as vaccine platforms, immunological adjuvants and targeted gene-delivery vehicles. These may enable more precise, tumour-localized therapeutic intervention. Phages can engage innate immune pathways, including TLR9, TLR3/7/8, cGAS-STING and AIM2, promoting dendritic cell maturation and inflammatory mediators that may convert immunologically "cold" tumours into inflamed microenvironments. Their multivalent antigen display enhances B- and T-cell priming, while cDC1-mediated cross-presentation supports cytotoxic CD8+ T-cell responses and immunological memory. In CAR-T therapy, engineered phages may improve tumour homing through chemokine modulation, support persistence through local cytokine delivery, reduce antigen escape by presenting multiple tumour epitopes, and limit T-cell exhaustion through dominant-negative receptor strategies or local checkpoint blockade. This review summarizes engineering approaches, delivery systems, manufacturing, biodistribution, dosing, and safety issues, including immunogenicity, pre-existing anti-phage antibodies and horizontal gene transfer. It also distinguishes therapeutic engineered phage particles from phage display technologies used for molecular discovery. Despite encouraging results integrating modified bacteriophages with CAR-T cell therapy, the evidence remains mostly preclinical, indicating both substantial translational prospects and crucial obstacles for future clinical development.

CAR-T cell therapy↗

PubMed2026

CAR-T Cell Therapy: Manufacturing Platforms and Clinical Consequences.

Chimeric antigen receptor (CAR) T-cell therapy has transformed hematological cancer care, yet variability in efficacy, durability, and safety cannot be explained solely by antigen selection or patient factors. We propose that manufacturing platforms are active biological determinants of outcome. Viral vectors, used in all licensed products, provide stable genomic integration and durable expression but are limited by cost, cargo capacity, and centralized production. Nonviral strategies, including transposons, CRISPR knock-ins, and messenger RNA delivery, enable faster, less-expensive manufacturing with larger payloads, while introducing distinct safety and persistence profiles. This review presents a three-layer mechanistic framework that reframes manufacturing as biology: integration biology determines genomic risk and transgene stability; clonal fitness shapes persistence, dominance, and exhaustion; and epigenomic imprinting, influenced by gene transfer method, cytokines, and culture stress, preconfigures functional trajectories. Clinical observations link platform choice to immune recovery, where prolonged B-cell aplasia and delayed T-cell reconstitution contribute to infection-related nonrelapse mortality, and hematopoietic reserve at apheresis emerges as a practical predictor. Finally, manufacturing is positioned as the key to democratizing cell therapy. Decentralized, nonviral production aligned with regulatory standards may enable equitable access and transition CAR-T therapy from innovation to sustainable global care.

Humans↗

PubMed2026

Clinical evidence on non-viral CAR-T cell therapies for solid tumors: a scoping review.

BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy in solid tumors is hindered by the immunosuppressive tumor microenvironment and by toxicities associated with viral-vector manufacturing. Non-viral gene delivery platforms have emerged as a potential alternative, though clinical evidence remains fragmented. METHODS: Following an a priori protocol registered on the Open Science Framework (OSF; https://doi.org/10.17605/OSF.IO/2TPQS) and adhering to JBI/PRISMA-ScR guidelines, a systematic search was conducted across four databases from inception through May 15, 2026. Patient-level data were extracted to describe cellular persistence and clinical outcomes across strictly non-viral delivery platforms. RESULTS: Four early-phase studies met the inclusion criteria, encompassing 28 heavily pretreated patients with metastatic solid tumors. Two non-viral platforms were identified: mRNA electroporation (n=19; intravenous in 13, intratumoral in 6) and the piggyBac transposon system (n=9). Across both mRNA routes, transient CAR-T persistence (<7 days) was observed, with no objective responses (ORR 0%), though disease stabilization yielded a disease control rate (DCR) of 53%; cross-route comparison is limited by differing distribution profiles. The piggyBac system showed longer persistence (~28 days) and a DCR of 78%, including the only documented objective response (ORR 11%). No Grade ≥3 cytokine release syndrome or neurotoxicity was reported in any of the 28 patients, and no tocilizumab or systemic corticosteroids were required. CONCLUSIONS: Within this limited early-phase evidence base, no severe toxicities attributable to non-viral platforms were reported, and the evidence identifies knowledge gaps warranting prospective investigation. mRNA platforms showed transient persistence and disease stabilization in 53% of patients. One partial response was documented with the piggyBac platform in a single patient; however, this outcome cannot be attributed to the delivery platform given simultaneous differences in target antigen, tumor histology, route of administration, and geographic setting. No firm conclusions regarding comparative platform performance can be drawn from this evidence base. SYSTEMATIC REVIEW REGISTRATION: https://doi.org/10.17605/OSF.IO/2TPQS, identifier OSF.IO/2TPQS.

Humans↗

PubMed2026

In vivo CAR-T therapy: The shift from ex vivo culturing to direct in situ immune reprogramming.

CAR T-cell therapy using chimeric antigen receptors (CARs) has provided a radical shift in the treatment of several hematological malignancies, producing high response rates and durable remissions. However, conventional ex vivo manufacturing is limited by complex processing steps, high costs, variability in product quality, and clinically relevant delays that restrict patient eligibility. In vivo manufacturing has emerged as a next-generation approach in which immune cells are reprogrammed directly within the patient, eliminating the need for exogenous handling and culture. This strategy uses viral and non-viral delivery platforms, including lentiviral vectors, adeno-associated viruses, lipid nanoparticles, and targeted polymer systems, together with DNA, mRNA, and genome editing tools such as CRISPR-based technologies. Early feasibility data are supported mainly by preclinical models and translational studies, while safety remains a central concern due to potential immunotoxicity, off-target transduction, and regulatory challenges. This review highlights key engineering strategies enabling in vivo CAR T-cell generation, summarizes emerging clinical research and development, and discusses future opportunities for expanding in vivo CAR T-cell therapies as scalable immunotherapy platforms.

Humans↗

PubMed2025

Recipient-derived vs. donor-derived CAR-T-cell therapy in relapsed B-cell acute lymphoblastic leukemia patients after transplantation: A multi-center retrospective study.

BACKGROUND: Chimeric antigen receptor T (CAR-T) cells have been demonstrated to be an effective treatment for relapsed B-cell acute lymphoblastic leukemia (B-ALL) following allogeneic hematopoietic stem cell transplantation (allo-HSCT). T cells for CAR-T therapy can be derived from the peripheral blood (recipient) of the patient or donor. Despite having identical genomes, the different maturation environments of these T cells can lead to functional differences. This study aimed to compare the clinical outcomes of CAR-T cells derived from these two sources. METHODS: This multicenter, retrospective cohort study collected clinical data from 36 patients who experienced B-ALL relapse after allo-HSCT and received CD19 CAR-T cell therapy between January 2016 and October 2023 across seven centers. The primary endpoint was complete remission (CR)/CR with an incomplete hematologic recovery (CRi) rate at 28 days post-CAR-T cell infusion. Secondary endpoints included the 2-year overall survival (OS) rate, 2-year event-free survival (EFS) rate, incidence of graft-versus-host disease (GVHD), cytokine release syndrome (CRS), and CAR-T cell-related encephalopathy syndrome (CRES). RESULTS: A retrospective analysis was performed on 36 patients: 12 in the recipient group and 24 in the donor group. The recipient and donor groups showed no statistically significant differences in CR/CRi rates (83.3% vs. 100.0%, P = 0.105), 2-year EFS rates (50.8% vs. 51.6%, P = 0.617), or 2-year OS rates (49.5% vs. 63.6%, P = 0.215). In addition, the incidences of GVHD, CRS, and CRES did not significantly differ between the two groups. Further analysis within the donor group revealed 12 matched sibling donors (MSDs) and 12 haploidentical donors (HIDs). The 2-year EFS rate was statistically significantly greater in the HID group than in the MSD group (75.0% vs. 30.7%, P = 0.043), whereas no significant differences were observed in the CR/CRi rates, 2-year OS, or the incidence of GVHD, CRS, and CRES between these subgroups. CONCLUSIONS: Both recipient-derived and donor-derived CD19 CAR-T cell therapies are effective treatment options for B-ALL relapsed post-allo-HSCT patients. HID-derived CAR-T cells offer a longer EFS and may be considered the optimal choice. TRIAL REGISTRATION: Chinese Clinical Trial Registry, No. ChiCTR2400085297.

Adolescent↗

PubMed2026

The future of TCR-Treg therapies is renewables.

Cell therapy has longstanding roots in haematopoietic stem cell transplantation and early immune cell transfers in infectious disease and transplantation, where patient- or donor-derived cells have achieved therapeutic benefit in selected contexts. The modern era has been driven largely by oncology, with engineered modalities such as tumour-infiltrating lymphocytes, CAR-T cells and TCR-engineered T cells delivering transformative responses but requiring complex, costly manufacturing. These platforms are now being adapted for autoimmune diseases to induce durable, antigen-specific immune tolerance, yet broad application is limited by safety concerns, process complexity and access. Non-engineered cell therapies for autoimmunity, including mesenchymal stem cells, polyclonal regulatory T cells and tolerogenic dendritic cells, have shown acceptable safety and proof-of-principle for immune re-education, but clinical responses have been modest and inconsistent, with limited scalability. Engineered approaches such as CAR-T cells can induce reversible B cell depletion in B cell-mediated rheumatic diseases but only addresses antibody-driven pathology and not T cell-mediated autoimmunity. TCR-engineered Tregs have emerged as a promising antigen-specific strategy, offering localized, antigen-linked suppression with bystander tolerance. Preclinical and early clinical data suggest superior potency, stability and disease control compared with polyclonal Tregs at similar or lower doses, but translation is constrained by the rarity and fragility of Tregs and by labour-intensive, CAR-T-like manufacturing. This review highlights emerging solutions for closed, automated and decentralised production, and discusses allogeneic approaches using gene-edited or banked Tregs with HLA engineering or matching. Together, these advances support the development of scalable, "off-the-shelf" TCR-Treg products with potential to provide safe, affordable tolerance-restoring therapies for autoimmune disease.

Humans↗

PubMed2026

Efficacy of R-GDP therapy as salvage chemotherapy for relapsed or refractory diffuse large B-cell lymphoma.

R-GDP has been established as an effective salvage treatment for Rel/Ref DLBCL. We aimed to clarify the efficacy of R-GDP therapy. We included 41 consecutive patients with Rel/Ref DLBCL, who received R-GDP therapy as salvage chemotherapy at our hospital between January 2014 and August 2024. Thirty-three patients received R-GDP therapy as a 2nd-line regimen, whereas 8 received R-GDP as a 3rd or later-line regimen. The ORR was 70.7%. 23 out of 25 relapsed patients (92%) responded to R-GDP therapy, whereas only 6 out of 16 refractory patients responded (37.5%). With regard to the duration of response, the response rates in 19 patients with late relapse (at least 12 months) and 6 with early relapse (less than 12 months) were 94.7% and 83.3% (p = 0.43). Overall, the 2-year PFS and OS rates were 48.8% and 74.2%, respectively. 18 responders underwent ASCT with a 2-year PFS after ASCT of 61.2%. Although CAR-T is recommended in patients with Rel/Ref DLBCL, R-GDP is a realistic option given the limited availability of immediate CAR-T therapy. Further studies including genomic profiles are warranted to identify factors that can predict a response to R-GDP in Rel/Ref DLBCL.

Humans↗

PubMed2026

Efficient and precise programmable DNA knock-in without double-strand breaks.

Programmable gene knock-in holds substantial promise for treating genetic diseases and advancing cell therapies. However, achieving precise and efficient kilobase-scale DNA fragment integration remains challenging1,2. Here we report CRISPR kilobase-scale nickase-targeting (KNIT) editing for efficient, precise and programmable kilobase-scale DNA insertion without double-strand DNA cleavage, which is enabled through the coupling of a Cas9 nickase with a DNA donor recruiting system. KNIT editing facilitates programmable integration of DNA fragments from 0.7 kb to more than 10 kb and is effective across genomic loci and cell types. It achieves up to 89% efficiency and markedly reduces unintended insertion-deletion mutation (indels) rates, translocations and off-target editing. The system supports repeated insertion editing and multiloci gene knock-in with minimal translocations. Its enhanced version, KNIT editor 2, further improves efficiency via a single transfection. Moreover, in mutant cells with a pathological mutation, KNIT editing restores normal gene expression by inserting a therapeutic gene into a safe harbour locus or its native locus. Notably, KNIT editing enables non-viral and programmable chimeric antigen receptor T cell (CAR-T cell) engineering without double-strand breaks and with clinically relevant efficiencies. Moreover, the engineered CAR-T cells exhibit effective antitumour activity in vitro and in mouse models. Therefore, by achieving programmable and site-specific kilobase-scale DNA insertions without double-strand breaks while reducing unintended outcomes, KNIT editing provides a versatile platform for advancing personalized medicine.

Animals↗

PubMed2026

The molecular landscape of chordoma: Current frontiers from multi-omics to artificial intelligence.

Chordoma is a rare and aggressive malignant bone tumor of the axial skeleton that has historically challenged clinicians due to its complex anatomical locations and a high recurrence rate of up to 85%. This review synthesizes the most recent advances in chordoma research and offers an overview of how multi-omics, advanced immunology, and artificial intelligence are reshaping the treatment paradigm. Central to its pathogenesis is the T-box transcription factor Brachyury, which this review highlights as both the pathognomonic diagnostic marker and the primary therapeutic vulnerability. Cutting-edge innovations targeting this driver include covalent small-molecule binders, targeted protein degradation, and peptide-centric CAR-T cells designed to attack the intracellular oncoprotein. The tumor immune microenvironment is functionally dynamic, and new dimensions in cellular therapy, such as dual-specific CAR constructs and NK-cell platforms, are being engineered to neutralize immunosuppressive factors. Beyond biological insights, the review emphasizes the role of computational biology, specifically how deep-learning and machine-learning models achieve expert-level precision in tumor segmentation and personalized survival forecasting. By integrating genomic, transcriptomic, epigenomic, and proteomic data, multiomics approaches can fully elucidate chordoma subtypes and underlying resistance mechanisms, ultimately paving the way for more precise and personalized therapeutic strategies.

Humans↗

PubMed2026

In vivo immune cell engineering from bench to clinical reality.

Adoptive immune cell therapies, exemplified by chimeric antigen receptor T cells, have transformed the treatment of hematological malignancies. However, their broader clinical application is limited by complex ex vivo manufacturing, high cost, and safety concerns. In vivo immune cell engineering has emerged as an alternative strategy that delivers genetic instructions directly to immune cells, thereby generating or modulating therapeutic immune cells within the body and reducing the reliance on individualized in vitro operations. These advances underscore the need for a systematic evaluation of this emerging field. Therefore, this review systematically summarizes the mechanistic principles and delivery strategies underlying in vivo immune cell engineering, with an emphasis on in vivo CAR-T cell generation and the engineering of other immune cells. We then discuss major viral and non-viral delivery platforms and clarify how these platforms influence cargo delivery, cell specificity, and functional immune-cell programming. We further discuss recent preclinical and emerging clinical advances across cancer, autoimmune diseases, and degenerative diseases, while examining key translational challenges, including delivery specificity, off-target effects, controllability, persistence, and manufacturing standardization. Overall, although the field of in vivo immune cell engineering is advancing rapidly, its clinical success will depend on coordinated improvements in delivery precision, therapeutic efficacy, safety, and controllable immune-cell programming.

Cancer immunotherapy↗

PubMed2025

Digestive cancers: mechanisms, therapeutics and management.

Cancers of the digestive system are major contributors to global cancer-associated morbidity and mortality, accounting for 35% of annual cases of cancer deaths. The etiologies, molecular features, and therapeutic management of these cancer entities are highly heterogeneous and complex. Over the last decade, genomic and functional studies have provided unprecedented insights into the biology of digestive cancers, identifying genetic drivers of tumor progression and key interaction points of tumor cells with the immune system. This knowledge is continuously translated into novel treatment concepts and targets, which are dynamically reshaping the therapeutic landscape of these tumors. In this review, we provide a concise overview of the etiology and molecular pathology of the six most common cancers of the digestive system, including esophageal, gastric, biliary tract, pancreatic, hepatocellular, and colorectal cancers. We comprehensively describe the current stage-dependent pharmacological management of these malignancies, including chemo-, targeted, and immunotherapy. For each cancer entity, we provide an overview of recent therapeutic advancements and research progress. Finally, we describe how novel insights into tumor heterogeneity and immune evasion deepen our understanding of therapy resistance and provide an outlook on innovative therapeutic strategies that will shape the future management of digestive cancers, including CAR-T cell therapy, novel antibody-drug conjugates and targeted therapies.

Humans↗

PubMed2026

Genetic Mutation and Epigenetic Silencing Drive Antigen-Negative Relapse in CD7 CAR T-Treated T-cell Lymphoid Malignancies.

UNLABELLED: CD7 is a promising target for chimeric antigen receptor (CAR) T-cell therapy in T-cell lymphoid malignancies; however, antigen loss-mediated relapse has emerged as a major challenge. In this study, we systematically analyzed the genetic and epigenetic alterations of paired specimens (pretreatment and relapsed) from 10 patients with T-cell lymphoma/leukemia receiving CD7 CAR T cells. Overall, we identified three distinct mechanisms underlying CD7 loss: first, frameshift insertion (patient 4; c.164dupG:p.R55fs) or deletion (patient 7; c.122delG:p.G41Efs*19) resulting in truncation of the CD7 transmembrane domain in two of 10 patients; second, hypermethylation of the CD7 promoter in seven of 10 patients without CD7 mutation; third, simultaneous occurrence of promoter region hypermethylation and multiple in-frame mutations with predicted functional interference in one of 10 patients (patient 2). Collectively, these findings demonstrate that both clonal heterogeneity and epigenetic plasticity drive antigen-negative relapse in T-cell lymphoid malignancies under the selective pressure of CD7 CAR T-cell therapy. SIGNIFICANCE: Understanding mechanisms of antigen-negative relapse is critical for developing effective CD7-targeting CAR-T therapies against T-cell lymphoid malignancies. Our study identifies both genetic truncation mutations and epigenetic silencing as contributors to CD7-negative relapse. Monitoring and preventing these events is warranted to improve treatment outcomes.

Humans↗

PubMed2026

Standardized Xenograft Models for Preclinical Cancer Research.

Xenograft models are the principal in vivo platform of preclinical oncology and the most established experimental link between cell culture and clinical investigation. From the carcinogen-exposed rabbit models of the early twentieth century through the current generation of humanized patient-derived xenograft (PDX) systems, these platforms have evolved in response to the demands of translational cancer research. This review critically examines the biological principles, methodological standards, and translational applications of the principal xenograft platforms in current use. Cell line-derived xenograft (CDX) models remain the most widely used and most cost-effective modality for preclinical efficacy testing, offering the reproducibility, scalability, and accessibility that have sustained their role across oncology drug development pipelines for decades. PDX models have emerged as the preferred platform for co-clinical trial design, predictive biomarker discovery, and personalized oncology applications, preserving the genomic landscape, intratumor heterogeneity, and histological architecture of the donor tumor across serial passages. The engraftment biology of PDX systems, including immunodeficient host strain selection, implantation site, tumor source, and passage biology, is reviewed, together with humanized and autologous humanized configurations that extend the platform to immune checkpoint inhibitors, bispecific T-cell engagers, and chimeric antigen receptor T (CAR-T) cell therapy evaluation. This review addresses preclinical-to-clinical translation as a function of immunological divergence, incomplete tumor microenvironment recapitulation, and standardization. Formal frameworks, including the PDX Model Minimal Information (PDX-MI) standard and the Minimal Information for Standardization of Humanized Mice (MISHUM), are examined alongside global biobank infrastructure and emerging AI-driven translational modeling approaches.

Animals↗

PubMed2025

Gene regulation technologies for gene and cell therapy.

Gene therapy stands at the forefront of medical innovation, offering unique potential to treat the underlying causes of genetic disorders and broadly enable regenerative medicine. However, unregulated production of therapeutic genes can lead to decreased clinical utility due to various complications. Thus, many technologies for controlled gene expression are under development, including regulated transgenes, modulation of endogenous genes to leverage native biological regulation, mapping and repurposing of transcriptional regulatory networks, and engineered systems that dynamically react to cell state changes. Transformative therapies enabled by advances in tissue-specific promoters, inducible systems, and targeted delivery have already entered clinical testing and demonstrated significantly improved specificity and efficacy. This review highlights next-generation technologies under development to expand the reach of gene therapies by enabling precise modulation of gene expression. These technologies, including epigenome editing, antisense oligonucleotides, RNA editing, transcription factor-mediated reprogramming, and synthetic genetic circuits, have the potential to provide powerful control over cellular functions. Despite these remarkable achievements, challenges remain in optimizing delivery, minimizing off-target effects, and addressing regulatory hurdles. However, the ongoing integration of biological insights with engineering innovations promises to expand the potential for gene therapy, offering hope for treating not only rare genetic disorders but also complex multifactorial diseases.

Humans↗