bims-carter 2026-02-01 papers

bims-carter

Biomed News

on CAR-T Therapies

Issue of 2026–02–01
38 papers selected by
Luca Bolliger, lxBio

Engineering Immunity: Current Progress and Future Directions of CAR-T Cell Therapy.
Unleashing CAR-T potential in solid tumors: overcoming intrinsic and extrinsic hurdles to improve therapy.
CAR T Cell Toxicities and Emerging Treatment Strategies.
The role of cytokines in cytokine release syndrome (CRS) after CAR T cell therapy.
From innate-like to innate: the next wave of off-the-shelf CAR immunotherapies.
Frontiers of cytokine engineering in CAR cell therapy for cancer.
The TCR and LCK: foundations for T-cell activation and therapeutic innovation.
Roads and detours for CAR T cell therapy in autoimmune diseases.
CAR-M therapy in the era of tumor immunotherapy: current research progress and engineering strategies.
The broad spectrum of cancer and immunotherapy: achievements and limitations.
Non-Genetically Modified Adoptive Cell Therapies for Solid Tumors: Current Landscape and Future Challenges.
Adaptation of lentiviral vectors for viral gene therapy and their impact on host cell biology.
The impacts of pricing and reimbursement policies on access to cell and gene therapies across Europe.
Long-term outcomes and late toxicities of CAR T-cell therapy in large B-cell lymphoma.
Emerging Cell-Based Therapies for Systemic Sclerosis: From Stem Cells to CAR-T Cells.
A comprehensive review of humanized mice applications in regulatory submissions for cell and gene therapy products.
Scalable CAR-T production in a 2-litre perfusion stirred-tank bioreactor with automated harvesting and scale-down model characterisation.
Bispecific Antibodies Versus Chimeric Antigen Receptor T-Cell Therapy in Relapsed/Refractory Diffuse Large B-Cell Lymphoma: A Comparative Narrative Review of Efficacy, Safety, and Accessibility.
The role of immune checkpoint molecules in cancers.
Innovating HTA: a call for capacity building and standardization.
A Systematic Review of Advanced Drug Delivery Systems: Engineering Strategies, Barrier Penetration, and Clinical Progress (2016-April 2025).
CAR-T cell immunotherapy of malignant melanoma.
Orphan medical devices: addressing the regulatory and access gaps in the EU and US.
Advanced immunotherapy across diseases and the role of artificial intelligence: A review.
Dual targeting of CD155 augments the antitumor efficacy of ROR1-CAR-T cells in ovarian cancer.
The RNA delivery dilemma-lipid versus polymer nanoparticle platforms.
The Role of Salivary Diagnostics in Early Detection of Systemic and Oral Diseases: A Comprehensive Review.
CXCR4 induces memory formation over exhaustion in CAR-T cells to achieve durable leukemia targeting.
VIF-Ig: A novel Fc framework for ADCC by incorporation of VHH unit.
Rational engineering of combinatorial bacterial therapies for cancer.
CAR T therapy in adult DLBCL patients in Slovenia: Evaluation of predictive scores for outcomes and adverse events.
CD200R1 promotes the development of murine γδ17 T cells.
The immunobiology and therapeutic potential of regulatory T cells in autoimmune diseases and allergic diseases.
Targeted Hepatic Delivery of Bioactive Molecules via Nanovesicles: Recent Developments and Emerging Directions.
Dysphagia Outcomes Following Chimeric Antigen Receptor T-Cell (CAR-T) Treatment in Patients with Non-Hodgkin Lymphoma.
Cytomegalovirus Lymphadenitis After Anti-CD19 Chimeric Antigen Receptor T-cell (CAR-T): An Underappreciated Etiology of Hypermetabolic Lymphadenopathy in the Post-CAR-T Setting.
Artificial Intelligence in Radiology: Advancing Precision, Accuracy, and Early Detection in Cancer Diagnosis.
The next frontier in sepsis: connected ICU data for real-world clinical decision making.

Int J Mol Sci. 2026 Jan 16. pii: 909. [Epub ahead of print]27(2):

Engineering Immunity: Current Progress and Future Directions of CAR-T Cell Therapy.

Mouldy Sioud, Nicholas Paul Casey.

  Chimeric antigen receptor (CAR)-T cell therapy has emerged as a transformative form of immunotherapy, enabling the precise engineering of T cells to recognize and eliminate pathogenic cells. In hematologic malignancies, CAR-T cells targeting CD19 or B cell maturation antigens have achieved remarkable remission rates and durable responses in patients with otherwise refractory disease. Despite these successes, extending CAR-T cell therapy to solid tumors remains challenging due to antigen heterogeneity, poor T cell infiltration, and the immunosuppressive tumor microenvironment (TME). Beyond oncology, CAR-T cell therapy has also shown promise in autoimmune diseases, where early clinical studies suggest that B cell-directed CAR-T cells can induce sustained remission in conditions such as systemic lupus erythematosus. This review highlights advances in CAR-T cell engineering, including DNA- and mRNA-based platforms for ex vivo and in vivo programming, and discusses emerging strategies to enhance CAR-T cell trafficking, persistence, and resistance to TME.

Keywords:  T cell therapy; autoimmunity; cancer; chimeric antigen receptor; lipid nanoparticles; messenger RNA; tumor microenvironment

DOI:  https://doi.org/10.3390/ijms27020909
Cancer Immunol Immunother. 2026 Jan 27. 75(2): 37

Unleashing CAR-T potential in solid tumors: overcoming intrinsic and extrinsic hurdles to improve therapy.

Zhiwei Zhang, Dawei Cui, Hao Wang, Liming Wu, Xia Liu.

  Chimeric antigen receptor (CAR) T cell therapy has shown transformative success in hematologic malignancies, yet its application in solid tumors remains limited by a combination of intrinsic and extrinsic barriers. Intrinsically, CAR-T cells face challenges such as CAR instability, T cell exhaustion, insufficient tumor infiltration, and poor persistence. Extrinsically, the tumor microenvironment (TME) acts as a formidable obstacle, with physical barriers, metabolic constraints, and immunosuppressive signals that dampen CAR-T cell function. Recent advancements in CAR transduction, genetic reprogramming, and combination therapies have revealed novel strategies to overcome these hurdles. This review explores cutting-edge innovations aimed at unleashing the full potential of CAR-T therapy in solid tumors, focusing on strategies that enhance CAR-T cell function and persistence while addressing the immunosuppressive TME. By examining both intrinsic and extrinsic factors, we provide a comprehensive framework for future research and clinical application to improve CAR-T therapy for solid tumor treatment.

Keywords:  CAR transduction; CAR-T cell; Combination therapy; Solid tumor; Tumor microenvironment

DOI:  https://doi.org/10.1007/s00262-025-04278-8
Annu Rev Med. 2026 Jan;77(1): 219-237

CAR T Cell Toxicities and Emerging Treatment Strategies.

Amanda M Lulu, Erica Steele, Daniel W Lee.

  Having already revolutionized outcomes for relapsed or refractory B cell malignancies and multiple myeloma, chimeric antigen receptor (CAR) T cell therapy is on the cusp of significantly impacting those with solid tumors. However, antitumor response is frequently associated with acute toxicities due to immune hyperactivation, including cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, immune effector cell-associated hematotoxicity, and immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome. We discuss the clinical presentations, evaluation, management, risk factors, and pathophysiologies of these toxicities and briefly describe emerging toxicity mitigation strategies.

Keywords:  CAR T cell therapy; CRS; ICAHT; ICANS; IEC-HS; chimeric antigen receptor T cell therapy; cytokine release syndrome; immune effector cell–associated hematotoxicity; immune effector cell–associated hemophagocytic lymphohistiocytosis-like syndrome; immune effector cell–associated neurotoxicity syndrome

DOI:  https://doi.org/10.1146/annurev-med-050224-120336
Biochim Biophys Acta Mol Cell Res. 2026 Jan 23. pii: S0167-4889(26)00011-X. [Epub ahead of print]1873(3): 120115

The role of cytokines in cytokine release syndrome (CRS) after CAR T cell therapy.

Kathrin Gabriel, Lucie Heinzerling, Louisa von Baumgarten, Marion Subklewe, Sebastian Kobold.

Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment landscape for hematological malignancies. However, cytokine release syndrome (CRS) remains a common and potentially severe toxicity, significantly affecting patient safety and requiring intensive clinical management. This review provides a focused synthesis on the role of cytokines in CRS after CAR T cell therapy, integrating recent mechanistic insights with clinical implications. We delineate the cellular and molecular pathways involving key cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6), interferon γ (IFN-γ), tumor necrosis factor α (TNF-α) and granulocyte-macrophage colony-stimulating factor (GM-CSF), describing their sources, downstream signaling events, and effects on target tissues. By bridging basic cytokine biology with clinical aspects and therapeutic strategies, this review aims to provide a comprehensive framework for understanding the role of cytokines in CRS pathophysiology, ultimately supporting the development of safer and more effective CAR T cell therapies.

DOI: https://doi.org/10.1016/j.bbamcr.2026.120115
Front Immunol. 2025 ;16 1691743

From innate-like to innate: the next wave of off-the-shelf CAR immunotherapies.

Ying Feng, Zhibo Yang, Yueru Zhou, Ying Liang, Hai Zhao.

  While autologous CAR T-cell therapies have revolutionized the treatment of hematologic malignancies, their widespread application is hindered by manufacturing complexities, high costs, and limited efficacy against solid tumors due to antigen heterogeneity and the TME. Moreover, the logistical burden of bespoke patient-specific manufacturing restricts global scalability. In response, the immunotherapy landscape is pivoting toward "off-the-shelf" allogeneic therapies derived from innate and innate-like effectors. This review provides a comprehensive analysis of four emerging platforms: CAR-NK cells, CAR-NKT cells, γδ T cells, and CAR-M. Unlike conventional αβ T cells, these lineages utilize MHC-independent mechanisms to recognize stress-induced ligands or lipid antigens, inherently minimizing the risk of GvHD while enabling standardized, batched manufacturing. We critically examine the diverse manufacturing paradigms, contrasting the scalability of iPSC-derived sources with the accessibility of umbilical cord blood products. Furthermore, we detail advanced engineering strategies designed to overcome the lineage-specific limitations revealed by early trials-specifically, "armoring" constructs with IL-15 to boost in vivo persistence and metabolic reprogramming to sustain function within the TME. Finally, we synthesize emerging clinical evidence which confirms the favorable safety profile of these allogeneic approaches but highlights persistent bottlenecks: limited durability of response, cryopreservation-induced loss of viability, and batch-to-batch variability. We conclude that unlocking the full potential of innate CAR therapies requires a dual focus on harmonizing manufacturing controls and developing next-generation engineering logic to ensure durable control of solid tumors.

Keywords:  CAR-NK; CAR-iNKT; CAR-macrophage; CAR-γδ T; IL-15 armoring; IPSC; Keywords: allogeneic; MAIT

DOI:  https://doi.org/10.3389/fimmu.2025.1691743
Front Oncol. 2025 ;15 1642022

Frontiers of cytokine engineering in CAR cell therapy for cancer.

Yinghan Wu, Yan-Ruide Li.

  Chimeric antigen receptor (CAR)-engineered T (CAR-T) cell therapy has revolutionized the treatment of hematologic malignancies, yet its efficacy in solid tumors remains limited by T cell exhaustion, restricted tumor infiltration, and an immunosuppressive tumor microenvironment (TME). Recent advances in cytokine engineering have introduced innovative strategies to overcome these barriers by modulating CAR cell survival, persistence, and cytotoxic function. This review provides a comprehensive analysis of emerging cytokine-augmented CAR platforms, highlighting mechanistic innovations such as IL-2 superkines that enhance selective CAR-T expansion, IL-15-armed CAR constructs that sustain in vivo persistence, and IL-12 and IL-18 co-expression systems that remodel the TME and recruit endogenous immune effectors. The roles of IL-7, IL-10, and IL-21 in preserving memory phenotypes, mitigating exhaustion, and improving metabolic fitness are also discussed in depth. Furthermore, the review explores synthetic and inducible cytokine circuits that enable spatial and temporal control of cytokine release, improving therapeutic precision and reducing systemic toxicity. Collectively, these innovations represent a paradigm shift toward next-generation, cytokine-engineered CAR therapies with enhanced efficacy, safety, and durability against both hematologic and solid tumors.

Keywords:  CAR-engineered T (CAR-T) cell therapy; antitumor capacity; cancer therapy; chimeric antigen receptor (CAR); cytokine; immunotherapy; in vivo persistence; invariant natural killer T (iNKT) cell

DOI:  https://doi.org/10.3389/fonc.2025.1642022
Front Immunol. 2025 ;16 1737013

The TCR and LCK: foundations for T-cell activation and therapeutic innovation.

Nadine M Woessner, Valeria Uleri, Ondrej Stepanek, Susana Minguet.

  The T cell receptor (TCR)-CD3 complex is crucial to adaptive immunity, driving antigen recognition and intracellular signaling cascades. CD3 subunits harbor key cytoplasmic motifs that recruit signaling proteins like LCK. While distal αβ TCR signaling is well-understood, gaps persist in our understanding of proximal signaling, particularly the roles of free versus co-receptor CD4 or CD8-associated LCK and their impact on antigen sensitivity and activation thresholds. In contrast to αβ T cells, γδ T cells recognize diverse antigens, often independently of MHC or MHC-like molecules. Despite their shared CD3 signaling components, the proximal signaling mechanisms of γδ T cells remain poorly characterized, raising important questions about their activation pathways and kinase dependencies. Addressing these gaps is essential to unlock the unique therapeutic potential of γδ T cells in cancer immunotherapy. Recent advances in engineered T-cell therapies demonstrate how proximal TCR signaling can be leveraged for therapeutic innovation. Chimeric antigen receptor (CAR) and chimeric-TCR designs that incorporate specific CD3 signaling motifs have shown improved anti-tumor activity, reduced exhaustion, and enhanced persistence, reflecting a shift beyond traditional ζ chain-dominated designs. In parallel, emerging small-molecule modulators targeting early TCR events offer new strategies to tune pathogenic T-cell responses in autoimmunity or to reset exhausted CAR T cells. This review explores the critical roles of CD3 motifs and LCK in TCR activation, with a focus on the underexplored γδ T cells. We also discuss how these insights could drive next-generation cancer immunotherapies and novel treatments for autoimmune diseases and immunopathologies.

Keywords:  Lck; T cells; TCR - T cell receptor; immunotherapy; signaling

DOI:  https://doi.org/10.3389/fimmu.2025.1737013
Nat Rev Drug Discov. 2026 Jan 26.

Roads and detours for CAR T cell therapy in autoimmune diseases.

Jérôme Avouac, Adi Barzel, Delma Caiati, Randall S Davis, Stephen Gottschalk, Ricardo Grieshaber-Bouyer, Xuming Mao, Eline T Luning Prak, Marko Radic, Marc Scherlinger, Yatin Suneja, Aimee Talleur, Amber L Thacker, Derya Unutmaz.

Chimeric antigen receptor (CAR) T cell therapy has been highly effective in eradicating malignant B cells in cancer, and this success has prompted an extension of the approach to areas beyond oncology. In pioneering studies, CAR T cells targeting the B cell marker CD19 demonstrated robust efficacy as treatment for the autoimmune disease systemic lupus erythematosus. Patients who received anti-CD19 CAR T cells experienced remission of most or all clinical manifestations and discontinued prior medications. These results have spurred intense interest in extending these observations to larger patient cohorts and other autoimmune conditions. More nuanced strategies for use of CARs in autoimmunity have also been developed. Here, we offer insight into the role of B cells in the pathophysiology of autoimmunity and present an overview of preclinical studies and clinical trials that use engineered cell therapy for autoimmune disorders. In discussing the prospects and challenges of this emerging field, a view emerges in which the promise of clinical efficacy invites careful consideration of potential pitfalls.

DOI: https://doi.org/10.1038/s41573-025-01349-4
Front Immunol. 2025 ;16 1723270

CAR-M therapy in the era of tumor immunotherapy: current research progress and engineering strategies.

Yi-Min Yang, Yu-Fan Ding, Yi-Yang Hu, Fan Fan, Jun-Long Zhao.

  Chimeric antigen receptor (CAR) cellular immunotherapy has emerged as a revolutionary modality in cancer treatment. CAR-T cell therapy has demonstrated remarkable efficacy against hematological malignancies; however, its application in solid tumors is significantly constrained by inadequate tumor infiltration, a profoundly immunosuppressive tumor microenvironment (TME), and pervasive antigen heterogeneity. Conversely, macrophages - innate immune cells inherently poised within tissues - exhibit superior tumor-tropic migration, potent phagocytic capability, and a unique capacity to remodel the TME, establishing CAR-engineered macrophages (CAR-M) as a highly promising next-generation therapeutic platform. Despite this considerable promise, the clinical translation of CAR-M faces several critical bottlenecks, including heterogeneity in cell sources, challenges in manufacturing standardization, risks of on-target/off-tumor toxicity, and the dynamic, immunosuppressive nature of the TME. This review offers a systematic and in-depth analysis of the current research landscape and engineering advances in CAR-M therapy. It comprehensively details the molecular evolution of CAR-M designs, spanning from early constructs to sophisticated logic-gated circuits and innovative in vivo generation strategies utilizing lipid nanoparticles (LNPs). We critically evaluate the applicability and limitations of various cellular sources, such as peripheral blood mononuclear cells (PBMCs), induced pluripotent stem cells (iPSCs), and the THP-1 cell line. Furthermore, the review elucidates the multimodal antitumor mechanisms of CAR-M, including the direct "phagocytosis-presentation-activation" cascade, synergistic potential with immune checkpoint blockade, and deep reprogramming of the immunosuppressive TME. By synthesizing the latest preclinical and emerging clinical evidence, this article underscores the distinctive advantages and delineates a translational roadmap for CAR-M development. It is intended to serve as an authoritative reference for the field, providing strategic insights into intelligent receptor design, precision biomanufacturing, and rational combination therapies aimed at overcoming the enduring barriers in solid tumor immunotherapy.

Keywords:  cancer immunotherapy; chimeric antigen receptor; logic gate; macrophage; synthetic biology

DOI:  https://doi.org/10.3389/fimmu.2025.1723270
Front Immunol. 2025 ;16 1697505

The broad spectrum of cancer and immunotherapy: achievements and limitations.

Arifa Aman, Belén Toledo, Aitor González-Titos, Manuel Picon-Ruiz, Pablo Hernández-Camarero.

  Cancer immunotherapy has revolutionized cancer treatment over the past decades, offering renewed hope to patients with previously untreatable malignancies. This therapeutic approach could be categorized into three primary strategies: immune checkpoint blockade, adoptive cell therapy, and cancer vaccines. Immune checkpoint inhibitors have been highly successful in boosting anti-tumour immune responses by blocking the immunosuppressive signals that cancer cells exploit to evade immune surveillance, mainly that exerted by cytotoxic T lymphocytes. Adoptive cell therapy, particularly chimeric antigen receptor (CAR)-T cell therapy, involves the infusion of genetically modified cytotoxic T cells to specifically target tumour cells, showing particular efficacy in hematological malignancies. Cancer vaccines have also emerged as a promising strategy, eliciting anti-tumour responses via the patient's own immune system. Despite these advancements, several challenges persist, particularly in the treatment of solid tumours. These include the development of tumour resistance, off-target effects that lead to adverse side effects, manufacturing complications, and variability in patient clinical outcomes. Overcoming these limitations will require further research and innovation to optimize the clinical translation of immunotherapy and broaden its application toward more personalized medicine. This review highlights the advancements and key challenges in the mentioned cancer immunotherapy strategies, with a special emphasis on the reinforcement of adaptive immune system against tumour cells. Additionally, some alternative approaches relying on the modulation of innate immune system are also summarized.

Keywords:  adoptive cell therapy; cancer immunotherapy; cancer vaccines; chimeric antigen receptor (CAR) cell; immune checkpoint inhibitors; immune resistance

DOI:  https://doi.org/10.3389/fimmu.2025.1697505
Cancer Immunol Immunother. 2026 Jan 27. 75(2): 40

Non-Genetically Modified Adoptive Cell Therapies for Solid Tumors: Current Landscape and Future Challenges.

Qinghuizi Luo, Wendi Jiang, Yiyang Xie, Zhe Dai, Jialong Zhu, Yuanyang Du, Xiaoyue Tao, Zengjie Lei, Xiaoyuan Chu, Bingji Wang, Gongbo Fu.

  Non-genetically modified adoptive cell therapies (ACTs) represent a rapidly advancing frontier in solid tumor immunotherapy, offering a safe and adaptable alternative to genetically engineered approaches by capitalizing on the intrinsic plasticity of immune cells. Genetic engineering strategies, including CAR-T cells, encounter significant obstacles in solid tumors, including on-target off-tumor toxicity, an immunosuppressive tumor microenvironment, and drug resistance. Although non-genetically modified ACTs-including tumor-infiltrating lymphocytes (TILs), cytokine-induced killer (CIK) cells, natural killer (NK) cells, and γδ T cells-offer unique advantages, their clinical application remains underexplored. This review consolidates the mechanistic basis, clinical progress, and limitations of non-genetically modified ACTs, proposing a paradigm shift toward combinatorial strategies. We systematically assessed how TILs overcome tumor microenvironment (TME) inhibition through lymphodepletion and cytokine assistance, compared the histocompatibility complex-unrestricted cytotoxicity of CIK cells with their functional diversity, and emphasized the innate flexibility of NK/γδ T cells against antigen-loss variants. By integrating preclinical and clinical data, we identify critical challenges: in vitro expansion inefficiency, absence of standardized protocols, and dynamic TME interactions. Furthermore, we advocated patient stratification by biomarkers, the addition of optimized cytokines, and rational combinations with checkpoint inhibitors or metabolic modulators to enhance efficacy. This review outlines the current landscape and proposes actionable solutions to reconcile the disparity between experimental potential and clinical applicability in non-genetically modified ACT.

Keywords:  Adoptive cell therapy; Non-genetically modified; Solid tumor treatment; Tumor microenvironment; Tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1007/s00262-025-04274-y
J Transl Med. 2026 Jan 27.

Adaptation of lentiviral vectors for viral gene therapy and their impact on host cell biology.

Catherine W Kaiser, Eric C Rouchka, Melissa L Smith.

   BACKGROUND: Lentiviral vectors (LVVs) are used as a viral gene therapeutic and were derived from human immunodeficiency virus subtype 1 (HIV-1). LVVs are used to deliver and induce the stable expression of transgenes through genome integration. Current clinical LVV delivery systems do not include HIV-1 major accessory genes; however, critical structural and non-structural HIV-1 proteins are encoded by the 4-plasmid combination that composes the 3rd generation LVV transduction systems. LVVs use HIV-1-like mechanisms for viral genome integration and both transgene delivery and expression. LVVs rely on host cell machinery to transcribe and translate transgenes for either knocking down disease-causing genes and/or supplying functional genes in a targeted disease. LVVs integrate into host intronic and intergenic regions due to genomic accessibility, but there are no known biases toward specific target integration motifs.
MAIN BODY: Investigation of LVV integration has uncovered the generation of chimeric LVV-host transcripts and altered host transcript splicing patterns. Several Food and Drug Administration (FDA)-approved LVV-derived therapies are used for treating diseases ranging from beta thalassemia to sickle cell anemia. An increasingly popular application of LVV is in the generation of chimeric antigen receptor (CAR) T cell therapies, which change and enhance T cell antigen specificity and effector function in liquid cancers. In November 2023, all CAR T cell therapies were placed under FDA investigation due to higher-than-expected rates of malignant transformation, hospitalization, and death in treated individuals. LVV integrations driving oncogene expression could be a cause for malignancy development. Current methods for resolving LVV integration patterns are technically limited by the sequencing approach applied allowing for only limited characterization of LVV integration profiles and altered host gene regulation.
CONCLUSIONS: A comprehensive understanding of LVV integration and its consequences is necessary for understanding how these events influence host cell gene regulation and splicing, possibly identifying tunable variables for enhanced positive clinical outcomes. Here, we review the development of LVV systems, what is known about LVV integration patterns, technologies used to characterize patterns of LVV integration, and what is understood about the subsequent impact on host cell gene regulation and its potential linkage to patient malignancies.

Keywords:  Chimeric antigen receptor (CAR) T cells; Gene therapy; Lentiviral vectors (LVVs); Viral integration

DOI:  https://doi.org/10.1186/s12967-025-07626-5
J Community Genet. 2026 Jan 26. 17(1): 23

The impacts of pricing and reimbursement policies on access to cell and gene therapies across Europe.

Yi Han, Mattia Andreoletti, Timo Minssen, Effy Vayena, Kelly E Ormond.



Keywords:  Gene therapy; Health technology assessment; Healthcare equality; Managed entry agreements; Patient access

DOI:  https://doi.org/10.1007/s12687-026-00860-4
Expert Opin Biol Ther. 2026 Jan 27.

Long-term outcomes and late toxicities of CAR T-cell therapy in large B-cell lymphoma.

Rafaella Litvin, Brian T Hill.

   INTRODUCTION: Chimeric antigen receptor (CAR) T-cell therapies have rapidly become an integral part of the treatment landscape for relapsed or refractory lymphomas. While early clinical trials demonstrated impressive response rates in patients with multiply relapsed disease and improved outcomes in those with disease refractory to first line treatments, subsequent longer follow-up has revealed the occurrence of both early and late relapses, as well as the emergence of delayed toxicities.
AREAS COVERED: Ten years after the initiation of the pivotal phase I/II trials that led to the approval of CD19-directed CAR T-cell therapies for large B-cell lymphoma (LBCL), extended follow-up data is now available. This review focuses on the long-term outcomes and toxicities of these therapies, as well as challenges to durable responses and future directions.
EXPERT OPINION: Long-term follow-up has confirmed the curative potential of CAR T-cell therapy in relapsed or refractory LBCL. Toxicities are generally manageable, and although infections remain an important cause of non-relapse mortality, standardized prophylactic approaches can mitigate risk. Advances in CAR T-cell engineering and administration are likely to enhance treatment effectiveness, expand indications, and improve patient outcomes.

Keywords:  CAR T cell; CAR T-cell therapy; DLBCL; Large B-cell lymphoma; chimeric antigen receptor; immunotherapy; long-term outcomes

DOI:  https://doi.org/10.1080/14712598.2026.2621889
Curr Issues Mol Biol. 2026 Jan 12. pii: 76. [Epub ahead of print]48(1):

Emerging Cell-Based Therapies for Systemic Sclerosis: From Stem Cells to CAR-T Cells.

Vitaly Chasov, Sabir Mukhametshin, Elvina Gilyazova, Damir Davletshin, Mariya Tikhomirova, Iuliia Topchu, Aygul Valiullina, Marcella Prete, Emil Bulatov.

  Systemic sclerosis (SSc) is a disease in which malfunctioning immune cells lead to the formation of autoantibodies that damage blood vessels and body tissues. Fibrosis then develops in the affected organs. Its complex pathogenesis involves multiple immune and stromal cell types, soluble mediators, and dysregulated tissue repair, resulting in heterogeneous clinical manifestations and poor prognosis. Current disease-modifying therapies provide only modest benefits, often slowing but rarely reversing disease progression, and are associated with considerable adverse effects. These limitations have spurred the development of cell-based therapeutic strategies aimed at restoring immune tolerance and promoting tissue repair. In this review, we summarize recent advances in hematopoietic stem cell transplantation, mesenchymal stem cell therapy, and adoptive regulatory T cell transfer and highlight the emerging role of chimeric antigen receptor (CAR)-T cell therapy as a transformative approach for SSc. Collectively, these evolving strategies hold the potential to improve survival, achieve durable remissions, and significantly enhance quality of life for patients with SSc.

Keywords:  CAR-T cell therapy; autoimmune diseases; cell-based therapies; hematopoietic stem cell transplantation; mesenchymal stem cells; systemic sclerosis

DOI:  https://doi.org/10.3390/cimb48010076
Vet Pathol. 2026 Jan 26. 3009858251411297

A comprehensive review of humanized mice applications in regulatory submissions for cell and gene therapy products.

Giovanni Pellegrini, Lucia Minoli, Sara Degl'Innocenti, Michela Gabaldo, Valeria Bertani, Alessandra Piersigilli, Francesca Sanvito, Patrizia Cristofori.

  The emergence of cell and gene therapies has transformed the therapeutic landscape, offering curative potential for a range of previously intractable diseases. However, their biological complexity and patient-specific mechanisms of action present significant challenges for preclinical evaluation, particularly in modeling human responses and predicting safety outcomes. Traditional animal models often lack translational fidelity, prompting the adoption of humanized immunodeficient mice, including those engrafted with human immune cells, as more predictive in vivo platforms. These models enable the assessment of pharmacodynamics, biodistribution, and immunotoxicity in a human-relevant context. This review critically explores the integration of humanized mice into regulatory submissions for cell and gene therapy products, highlighting their utility across proof-of-concept, pharmacokinetic, toxicology, and tumorigenicity studies. We also address key limitations of the different models, including variability in engraftment efficiency, immune reconstitution, and lifespan, as well as challenges in standardization and regulatory acceptance. Future directions include refining humanized mouse models to better mimic human physiology, incorporating pathological endpoints, and aligning with 3R principles and new methodological approaches. By enhancing the translational relevance of nonclinical data, humanized mice are poised to play an increasingly strategic role in early safety assessment and successful development of advanced therapies.

Keywords:  cell therapy; drug development; gene therapy; humanized mice; immunodeficient mice; preclinical studies; review

DOI:  https://doi.org/10.1177/03009858251411297
Front Bioeng Biotechnol. 2025 ;13 1694134

Scalable CAR-T production in a 2-litre perfusion stirred-tank bioreactor with automated harvesting and scale-down model characterisation.

Pierre Springuel, Pedro Silva Couto, Dale J Stibbs, Michal Szelwicki, Amanda Frangleton, Timo Schmidberger, Ajith George, Fern Slingsby, Nicola Bevan, Asma Ahmad, Rachel Legmann, Noushin Dianat, Rukmini Ladi, Julia Hengst, Qasim A Rafiq.

  The emergence of allogeneic, universal chimeric antigen receptor (CAR) T cell therapies requires intensified and scalable manufacturing workflows supported by representative scale-down models (SDMs) to enable efficient process development and future large-scale production of off-the-shelf therapies. Here, we present a 7-day CAR-T cell expansion process intensified via perfusion of serum-free medium in a 2 L Univessel® Single-Use stirred-tank bioreactor (STR), consistently achieving 30 × 106 cells/mL, corresponding to 113 ± 7 anti-CD19 CAR-T doses per batch. Parallel runs in 250 mL Ambr® 250 STRs conducted at equivalent volumetric power input (P/V) of ∼8.78 W/m3 demonstrated comparable process performance and final product quality, with univariate and multivariate analyses of cell growth, phenotype, cytotoxicity, and cytokine secretion validating the Ambr® 250 as a predictive SDM for the 2 L process. Integrating capacitance sensing in the 2 L STR enabled robust monitoring of viable cell concentrations in real-time, with strong correlation to offline measurements (R2 = 0.98). For downstream processing, the Ksep® 400 was used to automate CAR-T cell harvesting, concentration, and washing at the 2 L scale, achieving >90% product recovery and nine-fold volume reduction without impacting product quality attributes compared to manual methods. This study establishes a scalable CAR-T manufacturing workflow supported by a predictive SDM, providing an efficient platform for process development and scale-up to enable future large-scale production of allogeneic CAR-T cell therapies.

Keywords:  CAR-T cell; automated downstream processing; perfusion; scale-down model; scale-up; stirred-tank bioreactor

DOI:  https://doi.org/10.3389/fbioe.2025.1694134
Cancer Med. 2026 Feb;15(2): e71562

Bispecific Antibodies Versus Chimeric Antigen Receptor T-Cell Therapy in Relapsed/Refractory Diffuse Large B-Cell Lymphoma: A Comparative Narrative Review of Efficacy, Safety, and Accessibility.

Dana Sofian Abou, Husna Irfan Thalib, Fayza Akil, Samia Zuhair Sabbagh, Hala Sofian Abou, Mable Pereira, Fatma ElSayed Hassan.

   INTRODUCTION: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma, and despite advances in frontline therapies such as rituximab, cyclophosphamide, doxorubicin hydrochloride (hydroxydaunorubicin), vincristine sulfate (Oncovin), and prednisone, approximately 30%-40% of patients develop relapsed or refractory (rel/ref) disease. This subgroup has historically faced poor prognoses with limited treatment options, prompting the development of novel immunotherapeutic strategies. Chimeric antigen receptor T-cell (CAR T) therapy and bispecific antibodies (BsAbs) have emerged as transformative approaches in this setting.
METHODS: This narrative review compares these therapies across multiple domains, including mechanisms of action, clinical efficacy, safety profiles, logistics, cost, and accessibility.
RESULTS: CAR T therapies have demonstrated durable complete response rates (40%-60%) and extended progression-free survival (median 11-12.5 months), but they are limited by complex manufacturing, high cost, and potentially severe toxicities. In contrast, BsAbs offer immediate, off-the-shelf availability, with promising efficacy and a more favorable safety profile that enables outpatient administration, although long-term durability remains under investigation.
CONCLUSION: This review provides clinicians with a comprehensive comparison to support evidence-based treatment selection in rel/ref DLBCL.

Keywords:  CAR T cell therapy; accessibility; bispecific antibodies; efficacy; relapsed/refractory diffuse large B‐cell lymphoma; safety

DOI:  https://doi.org/10.1002/cam4.71562
Front Immunol. 2025 ;16 1674818

The role of immune checkpoint molecules in cancers.

Meilan Zhang, Junjie Xu, Zhaokuan Zheng, Zhiyun Guo, Hao Wang, Mingqing Zhou, Hailin Tang, Lewei Zhu.

  Immune checkpoint molecules play a central role in regulating T cell function, maintaining immune homeostasis, and facilitating tumor immune evasion, making them critical targets in cancer immunotherapy. This review provides a comprehensive overview of the structural characteristics and signaling mechanisms of key co-inhibitory and co-stimulatory molecules, and their immunoregulatory roles in both solid tumors and hematological malignancies. Recent advances in the clinical application of immune checkpoint inhibitors, combination therapy strategies, and mechanisms of resistance are discussed. Furthermore, the importance of multi-target combinatorial approaches and personalized immune modulation is emphasized, offering valuable insights and directions for optimizing cancer immunotherapy strategies.

Keywords:  T cell exhaustion; cancer; hematological malignancy; immune checkpoint; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1674818
Int J Technol Assess Health Care. 2026 Jan 28. 42(1): e8

Innovating HTA: a call for capacity building and standardization.

Diana M J Delnoij, Dalia M Dawoud, Jamie Elvidge, Zoltan Kaló, Saskia Knies, Bertalan Németh, Wim Goettsch.

   OBJECTIVES: New technologies are being developed in a context of scarcity. Health technology assessment (HTA) aims to support decision makers in providing equitable and affordable access to effective innovations. This study aims to summarize the policy-related findings of a Horizon2020 project on innovating HTA methods and discuss their implications for the governance of HTA in Europe.
METHODS: A thematic analysis of policy-oriented papers (n = 18) from the Next Generation Health Technology Assessment (HTx) project was carried out to summarize challenges and solutions. Subsequently, via an online survey and in a 2-day meeting, European and global stakeholders (n = 21) were invited to comment on these solutions and to prioritize future strategies.
RESULTS: Reported challenges included a lack of access to standardized data, differences in evidentiary needs, existing policy structures, and a lack of capacity and knowledge. Suggested solutions were capacity building, national and international dialogues, standardization, and increased European collaboration. Stakeholders had different expectations with respect to the likely success of these solutions.
CONCLUSION: Innovation of HTA requires alignment of evidentiary needs through dialogues, standardization through increased European collaboration, and capacity building. However, without additional investments in personnel capacity, HTA agencies must still prioritize some activities at the expense of others. Furthermore, although European collaboration is important, global alignment might be required to enforce standardization.

Keywords:  European collaboration; capacity building; health technology assessment; innovation; real-world evidence

DOI:  https://doi.org/10.1017/S0266462326103456
Pharmaceutics. 2025 Dec 22. pii: 11. [Epub ahead of print]18(1):

A Systematic Review of Advanced Drug Delivery Systems: Engineering Strategies, Barrier Penetration, and Clinical Progress (2016-April 2025).

Assem B Uzakova, Elmira M Yergaliyeva, Azamat Yerlanuly, Zhazira S Mukatayeva.

  Background/Objectives: Advanced drug delivery systems (DDSs) are essential for targeted delivery, controlled release, and reduced systemic toxicity, but their clinical adoption is limited by biological barriers, manufacturing complexities, and cost. The aim of this systematic review is to critically evaluate the quantitative relationships between platform design, overcoming biological barriers, and clinical translation outcomes for DDS developed between 2016 and 2025. Methods: A comprehensive literature search was conducted in PubMed/MEDLINE, Scopus, and Web of Science (January 2016-April 2025) in accordance with the PRISMA 2020 guidelines. Included studies focused on experimental or clinical data for nanocarrier platforms (liposomes, lipid nanoparticles, polymer systems, biomimetic carriers, extracellular vesicles). Data on platform characteristics, interactions with barriers, pharmacokinetics, manufacturing, and clinical outcomes were extracted and synthesized in narrative form due to the significant methodological heterogeneity. Results: An analysis of 77 included studies confirms that successful clinical translation depends on matching the physicochemical properties of the carrier (size, surface chemistry, material) to specific biological barriers. Liposomes and lipid nanoparticles (LNPs) remain the most clinically validated platforms, exploiting the EPR effect and liver tropism, respectively. Key engineering solutions include stealth coatings, ligand-mediated targeting, and stimulus-responsive materials to overcome barriers such as mononuclear phagocyte system clearance, the blood-brain barrier, and mucosal barriers. Microfluidic and continuous manufacturing processes enable reproducibility, but scalability, cost, and immunogenicity (e.g., anti-PEG responses) remain key translational challenges. Engineered extracellular vesicles, biomimetic carriers, and 3D/4D-printed systems combined with AI-driven design demonstrate the potential for personalized, adaptive delivery. Conclusions: Cutting-edge DDSs have validated their clinical value, but realizing their full potential requires a holistic, patient-centered design approach integrating barrier-specific engineering, scalable manufacturing, and rigorous safety assessment from the earliest stages of development. Further progress will depend on standardizing methods for new platforms (e.g., extracellular vesicles), implementing digital and AI tools, and ensuring translational feasibility as a fundamental principle.

Keywords:  AI-assisted design; biological barriers; drug delivery systems; lipid nanoparticles; liposomes; nanocarriers

DOI:  https://doi.org/10.3390/pharmaceutics18010011
Expert Rev Clin Immunol. 2026 Jan 27.

CAR-T cell immunotherapy of malignant melanoma.

Olha Kharasakhal, John Maher.

   INTRODUCTION: Management of inoperable and advanced malignant melanoma has been transformed in recent years by the advent of a number of approaches, including immune checkpoint blockade, small molecule inhibitors and adoptive immunotherapy with ex vivo expanded tumor-infiltrating lymphocytes.
AREAS COVERED: In this review, we describe efforts made to develop an alternative immunotherapeutic approach for this disease using chimeric antigen receptor (CAR) engineered T-cells. Literature was reviewed in the PubMed database and clinicaltrials.gov website (1998-2025).
EXPERT OPINION: CAR T-cell immunotherapy has proven transformative in the treatment of selected hematological malignancies. However, solid tumors such as melanoma remain much more challenging to treat using this emerging modality. Here we consider issues surrounding target selection, encompassing both tumor cells and accompanying stroma, in addition to armoring approaches that may potentiate delivery to or efficacy within the tumor microenvironment. We also consider a number of advanced CAR-based architectures to enable multi-antigen or universal antigen targeting and combination-based approaches.

Keywords:  CAR armoring; CAR combination therapies; CAR macrophages; CAR manufacture; Chimeric antigen receptor (CAR); NK cells; NKT-cells; cancer immunotherapy; dual targeting; gd T-cells; malignant melanoma; target selection; tumor microenvironment (TME); universal CAR

DOI:  https://doi.org/10.1080/1744666X.2026.2621811
Front Public Health. 2025 ;13 1729821

Orphan medical devices: addressing the regulatory and access gaps in the EU and US.

Sanae Akodad, Baptiste Haon, Lise Rochaix, Hilde Stevens.

   Background: Orphan medical devices remain the blind spot of rare disease policy. While the United States has recognized them since 1990 through the Humanitarian Use Device (HUD) and Humanitarian Device Exemption (HDE) framework, the European Union only introduced a non-binding definition in 2024 (MDCG 2024-10), revealing a deeper asymmetry: flexibility is codified in the US but interpreted in the EU.
Methods: We conducted a document-based policy analysis (1990-2025) and examined legislation, regulatory guidance, and academic literature to compare EU and US frameworks across evidentiary standards, access pathways, economic incentives, and reimbursement-post-market alignment. Three illustrative case studies (Berlin Heart EXCOR, Argus II, and the Medtronic Melody valve) were used to assess real-world consequences for access, sustainability, and patient continuity of care.
Results: The EU's Medical Devices Regulation 2017/745 lacks a legal orphan-device designation, dedicated incentives, or a harmonized HTA framework. Access remains fragmented, and recertification under the MDR threatens supply continuity. The US HUD/HDE pathway codifies flexibility through a "probable benefit" standard under IRB supervision and an annual distribution cap, though financial sustainability remains limited by profit restrictions and inconsistent reimbursement. Case comparisons reveal: (i) earlier EU access without post-market safeguards (Argus II); (ii) US capacity to transition from humanitarian to full approval when incentives align (Melody); and (iii) vulnerability of SMEs to compliance costs (EXCOR).
Conclusion: Addressing this policy vacuum requires an inflection point equivalent to the 1983 Orphan Drug Act, one that redefines how innovation for the few is valued. Five policy pillars emerge: a legal designation, adaptive evidentiary pathways, sustainable incentives (e.g., pooled procurement), integrated reimbursement mechanisms, and mandatory continuity-of-access or "exit-insurance" schemes. Without such reform, essential technologies for rare diseases will remain trapped between regulatory rigidity and market abandonment. This policy paper highlights structural regulatory gaps and proposes actionable reforms to ensure equitable access to orphan medical devices.

Keywords:  Berlin heart EXCOR; access pathways; adaptive evidentiary pathways; argus ii; economic incentives; evidentiary standards; exit-insurance schemes; harmonized HTA framework

DOI:  https://doi.org/10.3389/fpubh.2025.1729821
Biomol Biomed. 2026 Jan 28.

Advanced immunotherapy across diseases and the role of artificial intelligence: A review.

Ritika Sharma.

Immunotherapy, a therapeutic strategy aimed at modulating the host immune system, has undergone rapid evolution over recent decades, particularly in oncology. Advanced methodologies, including immune checkpoint inhibition, cytokine therapy, chimeric antigen receptor T-cell therapy (CAR-T), and tumor-infiltrating lymphocyte therapies, have significantly transformed cancer treatment. This review summarizes recent advancements in immunotherapy and examines its expanding applications across a range of diseases, such as autoimmune disorders, infectious diseases, transplant rejection, and allergic conditions. A structured literature search was conducted using PubMed and Google Scholar, prioritizing studies published from 2015 to 2026. The findings underscore the efficacy of monoclonal antibodies, adoptive cell therapies, cytokine modulation, and checkpoint-targeted strategies beyond oncology. However, challenges remain, including variable patient responses, immune-related adverse events, and treatment costs. This review also explores the emerging role of artificial intelligence (AI) in enhancing personalized immunotherapy through patient stratification, biomarker identification, and predictive modeling. The integration of multi-omics data with AI presents promising opportunities for improving treatment efficacy and safety, although issues related to data quality, interpretability, regulatory frameworks, and ethical considerations must be addressed. In conclusion, immunotherapy is rapidly extending beyond cancer, and AI-supported personalized approaches offer a promising pathway to safer, more effective, and broadly applicable treatments.

DOI: https://doi.org/10.17305/bb.2026.13199
Cancer Immunol Immunother. 2026 Jan 27. 75(2): 44

Dual targeting of CD155 augments the antitumor efficacy of ROR1-CAR-T cells in ovarian cancer.

Yingjun Ye, Tingwei Liu, Chao Cheng, Huajing Wang, Jiacheng Shen, Xiaowen He, Shaohua Xu.

   BACKGROUND: Exploring novel therapeutic targets and developing targeted therapies constitute an urgent clinical need for improving the prognosis of ovarian cancer (OC), particularly among patients with advanced stages. Currently, chimeric antigen receptor T (CAR-T) cell therapy has been demonstrated to have a remarkable therapeutic effect in hematological malignancies, while its application remains limited in OC due to the absence of appropriate target molecules and the complex immunosuppressive tumor microenvironment (TME). Poliovirus receptor (PVR, CD155) has been the subject of extensive research in the field of regulatory molecules within the immune microenvironment. However, there has been a paucity of research investigating its role in OC. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is barely expressed in normal tissues but widely expressed in tumor tissues, making it a promising target for CAR-T therapy. Nevertheless, the potential effectiveness of CAR-T cell targeting ROR1 in OC remains unknown. Therefore, the purpose of this study is twofold: The primary objective of this study is to investigate the potential efficacy of single-target ROR1-CAR-T cells on OC. The secondary objective is to examine the feasibility of CD155 as an immunotherapy target for OC and to determine whether combined targeting of CD155 can enhance the function of ROR1-CAR-T cells in OC.
METHOD: ROR1 and CD155 expression were detected via flow cytometry analysis. In vitro experiments were conducted to explore the regulatory effect of CD155 on OC proliferation, invasion, angiogenesis, and T cell function. ROR1-CAR, CD155-CAR, and ROR1/CD155 bispecific CAR constructs were designed and synthesized. Then, they were introduced into T cells using lentiviral particles to generate CAR-T cells. We subsequently validated the synergistic effects of CD155 in ROR1/CD155 bispecific CAR-T cells based on cytotoxic efficacy, activation, exhaustion, and differentiation status.
RESULTS: ROR1-CAR-T cells exhibited tumoricidal activity in OC, but elevated tonic signaling was observed, resulting in rapid depletion. CD155 constitutes an ideal therapeutic target in OC: firstly, ubiquitous CD155 expression in OC cell lines. Secondly, CD155 promotes tumor proliferation, migration, and angiogenesis in OC cell lines, acting as an oncogenic driver. Thirdly, CD155 impairs T cell function and accelerates their depletion, contributing to an immunosuppressive TME. The bispecific CAR-T combined targeting CD155 and ROR1 demonstrated superior cytotoxicity compared to single-target ROR1-CAR-T or CD155-CAR-T. Co-targeting CD155 significantly attenuated tonic signaling and delayed CAR-T cell exhaustion.
CONCLUSION: CD155 emerges as a promising therapeutic target for CAR-T therapy in OC. The bispecific CAR-T construct that co-targets CD155 and ROR1 demonstrates superior and durable tumoricidal activity, offering new perspectives on OC targeted therapy.

Keywords:  Bispecific CAR-T; CD155; Ovarian cancer; ROR1

DOI:  https://doi.org/10.1007/s00262-025-04283-x
Drug Deliv Transl Res. 2026 Jan 30.

The RNA delivery dilemma-lipid versus polymer nanoparticle platforms.

Cláudia Martins, Michael J Mitchell, Dan Peer, Yvonne Perrie, Daniel J Siegwart, María José Alonso, Juan Aparicio-Blanco.

  Since the first market authorization of RNA therapies, just eight years ago, the field has witnessed an extraordinary expansion, ranging from hepatic delivery for rare genetic diseases to global-scale vaccination during the COVID-19 pandemic, and now to cutting-edge cancer vaccines and gene editing strategies entering late-stage clinical trials. In parallel, the RNA therapeutics landscape has evolved rapidly, progressing from small interfering RNAs to next-generation and combinatorial RNA modalities. None of these breakthroughs would have been possible without the development of sophisticated RNA delivery technologies capable of navigating complex biological environments, enabling precise cellular targeting, and facilitating efficient intracellular trafficking. In this Editorial Note, we take a step back to reflect on key lessons learned throughout the RNA delivery journey. Featuring insights from leading and experienced voices in the field, this manuscript highlights critical milestones, persistent challenges, and the roles of lipid nanoparticles (LNPs) and polymer nanoparticles (PNPs) as RNA delivery platforms. These experts reflect on the features that have positioned LNPs as the current RNA delivery gold standard, while also exploring the untapped potential and distinctive advantages of polymer-based nanosystems. Collectively, these perspectives underscore a striking truth: we are only beginning to unlock the full therapeutic potential of RNA, and nanomedicine will certainly continue to shape the future clinical translation of RNA-based therapies.

Keywords:  Clinical translation; Extrahepatic delivery; Genetics; Manufacturing scalability; Nanomedicine; Regulatory readiness

DOI:  https://doi.org/10.1007/s13346-026-02044-6
Cureus. 2025 Dec;17(12): e100313

The Role of Salivary Diagnostics in Early Detection of Systemic and Oral Diseases: A Comprehensive Review.

Shalin D Shah, Sudarshan Gupta, Pramod Kumar Pamu, Jay Priteshkumar Shukla, Subash Nayak, Kumarjyoti Chatterjee.

  Early diagnosis of oral and systemic diseases remains a major challenge due to limitations in conventional invasive procedures. This review addresses the critical need for non-invasive, accessible diagnostics by examining the potential of saliva as an alternative diagnostic fluid. The main objective is to synthesize current knowledge on salivary biomarkers and technological innovations that enhance early detection capabilities. Methodologically, the review integrates evidence from proteomic, genomic, and metabolomic studies, as well as recent advances in microfluidic point-of-care devices. Key findings highlight that saliva contains a rich array of biomarkers, including cytokines, microRNAs, and extracellular vesicles, that can accurately reflect both local oral pathologies, such as dental caries and oral cancer, and systemic conditions, including diabetes, cardiovascular diseases, autoimmune disorders, and neurodegenerative diseases. The analysis further emphasizes that portable biosensors and lab-on-chip platforms are rapidly improving diagnostic sensitivity and enabling decentralized testing. Notwithstanding these encouraging advancements, issues with biological variability, standardization, and regulatory validation still exist. This review underscores the significance of interdisciplinary collaboration to overcome these barriers and fully integrate salivary diagnostics into routine healthcare. The implications are profound: widespread adoption could transform preventive medicine by providing patient-friendly, real-time monitoring tools that improve health outcomes globally.

Keywords:  biomarkers; early detection; point-of-care devices; precision health; salivary diagnostics; salivary proteomics

DOI:  https://doi.org/10.7759/cureus.100313
Nat Commun. 2026 Jan 26. 17(1): 101

CXCR4 induces memory formation over exhaustion in CAR-T cells to achieve durable leukemia targeting.

Ari Itoh-Nakadai, Minggao Liang, Michiho Shindo, Chen Bibi, Mariko Tomizawa-Murasawa, Saera Fujiki, Akiko Kaneko, Emi Kanamaru, Mari Hashimoto, Hiroshi Kajita, Yoshinari Ando, Miki Kojima, Jonathan Moody, Makoto Iwasaki, Shinsuke Takagi, Ryo Nakagawa, Saumya Agrawal, Hanae Amitani-Iijima, Kaori Sato, Yuriko Sorimachi, Nahoko Suzuki, Takehiro Fukami, Kazuharu Hanada, Satoshi Morita, Kazushige Katsura, Takehisa Matsumoto, Maiko Kobayashi, Masahiko Kato, Yasuyuki Negishi, Mikako Shirouzu, Yuho Najima, Keiyo Takubo, Chung Chau Hon, Naoyuki Uchida, Shuichi Taniguchi, Yukihide Momozawa, Piero Carninci, Leonard D Shultz, Yoriko Saito, Michiel de Hoon, Jay W Shin, Fumihiko Ishikawa.

Chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment of B-cell malignancies, but its success in acute myeloid leukemia (AML) remains limited. Durable responses depend on the formation of long-lived memory T cells, whereas T cell exhaustion contributes to non-response and relapse. In patients with AML who achieved remission after cord blood transplantation, we here first observe enrichment of memory T cells with high expression of the chemokine receptor CXCR4. Next, we show that engineering CAR-T cells to co-express CXCR4 enhances their persistence and anti-leukemic activity in patient-derived xenograft models. Using single-cell profiling and metabolic analysis, we find that CXCR4 promotes memory-associated transcriptional programs, reduces exhaustion, and supports oxidative metabolism. These effects are observed with CAR-T cells targeting CD25 or CD96 as AML-associated targets. Our results indicate that CXCR4 strengthens CAR-T cell memory and durability, offering a strategy to improve immunotherapy outcomes in AML and beyond.

DOI: https://doi.org/10.1038/s41467-025-67745-x
Protein Eng Des Sel. 2026 Jan 28. pii: gzag003. [Epub ahead of print]

VIF-Ig: A novel Fc framework for ADCC by incorporation of VHH unit.

Yaohui Li, Yichen Huang, Yingdan Duan, He Zhao, Shanshan Wang, Jiefu Li, Hua Jing, Kebing Yu, Chih-Chuan Chang, Feng Wang.

  Antibody-dependent cellular cytotoxicity is a key mechanism for antibody-based therapeutics, and current engineering strategies to enhance ADCC primarily rely on two approaches: Fc mutations to improve the antibody's intrinsic CD16a affinity, or the fusion of binding-modules targeting NK cell receptors. The former often compromises antibody stability and induces CD16a downregulation; the latter occupies sites critical for target association and limits the assembly of multi-specific therapeutics. Here, we introduce a novel Fc engineering approach wherein the CH2 domain of the Fc region is replaced with an anti-NKp46 VHH named VIF-Ig. It has been reported that NKp46 expression remains unaltered after NK cell activation across various tumor microenvironments, addressing a key limitation of CD16a-dependent strategies. The novel molecules exhibit potent ADCC, high thermal stability, and retain FcRn binding for favorable pharmacokinetic profiles. Furthermore, we demonstrate that VIF-Ig can accommodate VHHs to target various epitopes. Thus, this versatile modular platform is suitable for developing next-generation NK cell or even other cell engagers with enhanced efficacy and tunable specificity, especially for emerging multi-specific immune cell engagers.

Keywords:  ADCC; Anti-NKp46 VHH; CH2; NKCE; VHH-Incorporated Fc (VIF-Ig)

DOI:  https://doi.org/10.1093/protein/gzag003
Genome Biol. 2026 Jan 28.

Rational engineering of combinatorial bacterial therapies for cancer.

Paige Steppe, Katherine O'Connor, Jeff Hasty.

  Engineered bacteria are emerging as a transformative class of cancer therapeutics. Recent advances in synthetic biology have expanded the genetic circuit toolbox, enabling the programmable control of attenuation, payload release, and immunomodulation. These developments have transformed bacteria from simple, colonizing agents into a versatile chassis for complex therapeutic functions. In this review, we examine recent circuit-based strategies for enhancing tumor specificity, regulating therapeutic delivery and engaging the host immune system, with emphasis on programming spatiotemporal control and consortia behavior. We consider current barriers to clinical translational and discuss how rational engineering can guide the next generation of microbial therapeutics.

Keywords:  Bacteria; CAR-T; Cell therapy; Immunotherapy; Synthetic Biology; Tumor microenvironment

DOI:  https://doi.org/10.1186/s13059-026-03951-0
Hum Vaccin Immunother. 2026 Dec 31. 22(1): 2620889

CAR T therapy in adult DLBCL patients in Slovenia: Evaluation of predictive scores for outcomes and adverse events.

Lucija Sršen, Irena Auersperger, Larisa Janžič, Andreja N Kopitar, Katarina Reberšek, Barbara Jezeršek Novaković, Polona Novak, Karla Rener, Klara Šlajpah, Alojz Ihan, Samo Zver, Matjaž Sever.

  CAR T cell therapy is a promising immunotherapy for hematologic malignancies, yet early prediction of outcomes and adverse events remains difficult, especially in small real-world cohorts. We retrospectively analyzed 14 adult patients with diffuse large B-cell lymphoma (DLBCL) treated with CAR T cells in Slovenia, assessing IL-6 increase rates and established predictive metrics including EASIX-C, CAR-HEMATOTOX, and IBPS on Day -5 (pre-lymphodepletion) and Day 0 (infusion). Contrary to our expectation, an inverse correlation was observed between the increase rate of IL-6 and the occurrence of severe cytopenias, indicating higher IL-6 increase rate leads to less severe cytopenias. The EASIX-C score showed higher predictive values when calculated on Day 0, contrary to the CAR-HEMATOTOX score, whose higher predictive values were observed on Day -5. The IBPS predictive values showed mixed results when comparing Day -5 to Day 0. We observed 50% response rate and 29% remission rate. The results highlight the utility of predictive scores, with unexpected findings on IL-6 suggesting further study is necessary.

Keywords:  CAR T cell therapy; adverse events; diffuse large B-cell lymphoma; hematologic malignancies; predictive scores; therapeutic outcomes

DOI:  https://doi.org/10.1080/21645515.2026.2620889
J Leukoc Biol. 2026 Jan 28. pii: qiag015. [Epub ahead of print]

CD200R1 promotes the development of murine γδ17 T cells.

Holly Linley, Shafqat Jaigirdar, Lucy Buckingham, Joshua Cox, Megan Priestley, Anna Hains, Amy Saunders.

  γδ T cells are enriched at barrier sites such as skin, gut and lung, where they protect against cancer and infections, and promote healing. They detect diverse ligands in T cell receptor-dependent or independent manners, producing large quantities of pro-inflammatory cytokines. γδ T cells develop in foetal thymi in temporally controlled waves where, unlike αβ T cells, many γδ T cells adopt their effector fate, becoming either IFNγ or IL-17A-producers (γδ17 T cells). CD200R1 suppresses myeloid cell activity but has also been shown to promote innate lymphoid cell IL-17A production, enhancing psoriasis-like skin inflammation. γδ17 T cells are potent IL-17A producers in skin therefore, the effect of CD200R1 on IL-17A production by γδ17 T cells was investigated using CD200R1KO mice. CD200R1 was revealed to promote IL-17A production by γδ T cells in skin and lymphoid organs. Although CD200R1 is not expressed by adult γδ T cells, it is expressed by immature developing γδ T cells in foetal thymus where it supports the development of γδ17 T cells, enhancing IL-17-producing and RORγt+ γδ T cell numbers in foetal thymic organ cultures. This identifies CD200R1 as an important novel regulator of γδ17 T cell development in early life, a key process for ensuring immunity, particularly at barrier sites.

Keywords:  CD200R1; IL-17A; development; skin; γδ T cells

DOI:  https://doi.org/10.1093/jleuko/qiag015
Front Immunol. 2025 ;16 1709915

The immunobiology and therapeutic potential of regulatory T cells in autoimmune diseases and allergic diseases.

Wen-Wen Xie, Jian-Bin Huang, Yi-Chi Zhou, Jing-Yi Yuan, Jia-Xue Feng, Xiao-Hang Shi, Li Tian, Xian-Hai Zeng, Shu-Qi Qiu, Mei-Zhen Zhao, Bao-Hui Cheng, Hao-Tao Zeng.

  Autoimmune and allergic diseases represent two major categories of immune-mediated disorders that collectively impose a significant global health burden. Although driven by distinct triggers-aberrant responses against self-antigens in autoimmunity and hypersensitivity to innocuous environmental antigens in allergy-both classes of disease are fundamentally rooted in a failure of immunological tolerance. At the center of this regulatory failure lies the dysfunction of regulatory T cells (Tregs) which are the master orchestrators of peripheral tolerance, actively suppressing effector immune responses through the secretion of inhibitory cytokines and contact-dependent inhibition. In both autoimmune and allergic conditions, defects in Treg number, stability, or suppressive function permit the uncontrolled expansion of autoreactive lymphocytes in autoimmunity, while in allergic diseases, it fails to constrain the T helper 2 (Th2) cell-mediated pathways that drive pathology. Despite the well-established role of Tregs in each disease category, research often proceeds in parallel, leaving a critical knowledge gap regarding the convergent mechanisms of Treg failure across these interconnected pathologies. A unified understanding of how factors such as genetic predispositions and environmental influences cohesively impact Treg function remains underdeveloped. This review addresses this gap by providing a comprehensive synthesis of Treg immunobiology, with a specific emphasis on the convergent pathways that underpin their dysfunction in both autoimmune and allergic diseases. By elucidating the shared principles of Treg-mediated immune dysregulation, this review aims to provide a robust conceptual framework to accelerate the development of next-generation therapies capable of restoring tolerance across this broad spectrum of disorders.

Keywords:  Treg plasticity; allergic diseases; autoimmune diseases; epigenetics; immunetolerance; regulatory T cells (Tregs)

DOI:  https://doi.org/10.3389/fimmu.2025.1709915
J Pers Med. 2025 Dec 19. pii: 1. [Epub ahead of print]16(1):

Targeted Hepatic Delivery of Bioactive Molecules via Nanovesicles: Recent Developments and Emerging Directions.

Alessia Rita Canestrale, Sharad Kholia, Veronica Dimuccio, Maria Beatriz Herrera Sanchez.

  Liver diseases, including fibrosis, viral hepatitis, hepatocellular carcinoma, and monogenic genetic disorders, represent a major global health burden with limited therapeutic options and frequent systemic toxicity from conventional treatments. Nanovesicle-based drug and gene delivery systems offer targeted approaches that may improve therapeutic precision and reduce off-target effects. This review aims to evaluate the promise and comparative potential of three key nanovesicle platforms-lipid nanoparticles (LNPs), extracellular vesicles (EVs) and liposomes-for drug and gene delivery in liver disease therapy. A systematic search of peer-reviewed studies published in electronic databases was performed, focusing on preclinical and clinical research investigating the use of LNPs, EVs and liposomes for hepatic drug or gene delivery. Studies were analyzed for vesicle composition, targeting efficiency, payload capacity, therapeutic outcomes, and reported limitations. The analysis indicates that LNPs demonstrate strong efficiency in nucleic acid encapsulation and delivery, supported by growing clinical translation. EVs show promising biocompatibility and innate targeting to hepatic cells but face challenges in large-scale production and standardization. Liposomes remain versatile and well-characterized platforms capable of carrying diverse therapeutic molecules, though rapid clearance can limit their efficacy. Together, these nanovesicle systems hold considerable potential for advancing targeted drug and gene therapies in liver disease. Future work should focus on improving stability, manufacturing scalability, and cell-specific targeting to support clinical translation.

Keywords:  extracellular vesicles; lipid nanoparticles; liposomes; liver genetic diseases; mRNA delivery; nanobubbles; nanovesicles

DOI:  https://doi.org/10.3390/jpm16010001
Cancer Invest. 2026 Jan 27. 1-10

Dysphagia Outcomes Following Chimeric Antigen Receptor T-Cell (CAR-T) Treatment in Patients with Non-Hodgkin Lymphoma.

Nana-Hawwa Abdul-Rahman, Samantha K Sinacore, Tamara Wasserman-Wincko, Angela L Mazul, Katie M Carlson, Melanie Potiaumpai, Vasilii Bushunow, Andrew Zhang, Aaron Edwards Jackson, Kristen Stablein, Christine Baker, Ashur-Dee Brown, Sandra Stinnett.

   INTRODUCTION: Dysphagia is a well-established complication in cancer patients, often resulting from chemoradiation-induced inflammation, fibrosis, and neuromuscular dysfunction. However, little is known about the incidence and clinical impact of dysphagia in patients undergoing adoptive cellular therapies such as Chimeric Antigen Receptor T-cell (CAR-T) therapy.
AREAS COVERED: In this retrospective cohort study, we evaluated 116 patients with non-Hodgkin's lymphoma (NHL) who received CAR-T therapy between January 2017 and May 2023. The overall prevalence of dysphagia was 19.83%, with a median onset of 6 days and a median duration of 14 days. Dysphagia was significantly associated with cytokine release syndrome (CRS) (p = 0.002), immune effector cell-associated neurotoxicity syndrome (ICANS) (p < 0.001), advanced tumor stage (p = 0.02), ICU admission (p < 0.001), and prolonged ICU stay (median 7 days). The Kaplan Meier analysis revealed significantly reduced 6-month overall survival in patients with dysphagia (59.01%) compared to those without (86.36%) (p = 0.001).
EXPERT OPINION: Dysphagia is an underrecognized but clinically significant complication of CAR-T therapy. Its association with severe treatment-related toxicities and poorer survival suggests the need for routine dysphagia screening and multidisciplinary management in CAR-T treated patients. Early recognition may guide supportive interventions and improve patient outcomes and quality of life.

Keywords:  Adoptive cellular therapy; Chimeric Antigen receptor T-cell (CAR-T); Cytokine release syndrome (CRS); Dysphagia, Functional oral intake scale (FOIS); Immune effector cell-associated neurotoxicity syndrome (ICANS); Non-Hodgkin’s lymphoma (NHL)

DOI:  https://doi.org/10.1080/07357907.2026.2619564
Cureus. 2025 Dec;17(12): e100035

Cytomegalovirus Lymphadenitis After Anti-CD19 Chimeric Antigen Receptor T-cell (CAR-T): An Underappreciated Etiology of Hypermetabolic Lymphadenopathy in the Post-CAR-T Setting.

Daniel Rosas, Alissa Cox, Diana Martinez, Amneh Fares, Ihsane Ouansafi, Dante Melendez, Jose Sandoval-Sus.

  Chimeric antigen receptor T-cell (CAR-T) is a revolutionary type of immunotherapy that genetically engineers a patient's own immune T-cells to recognize and attack cancer cells. This type of therapy has transformed the treatment of relapsed/refractory large B-cell lymphoma (LBCL). However, profound immunosuppression may lead to opportunistic infections that could resemble relapse in rare situations. Cytomegalovirus (CMV) reactivation and clinical infection are well recognized after hematopoietic stem cell transplantation but are less studied in the post-CAR-T setting. We describe a 56-year-old woman with primary refractory stage IV diffuse LBCL, not otherwise specified, treated with axicabtagene ciloleucel. She initially achieved a complete remission (CR), but at six months s/p CAR-T, she developed constitutional symptoms and non-tender palpable lymphadenopathy. Positron emission tomography (PET) and computed tomography (CT) demonstrated hypermetabolic cervical and axillary lymph nodes, as well as focal uptake in the appendix. A biopsy did not show relapsed lymphoma but did reveal classic CMV inclusions, positive CMV immunohistochemistry, and high-level tissue CMV DNA despite negative plasma PCR, with a final diagnosis of CMV lymphadenitis. Symptoms resolved with a three-week course of valganciclovir, and follow-up imaging showed near-complete resolution of the disease. CMV lymphadenitis is a rare but important differential diagnosis of hypermetabolic lymphadenopathy in the post-CAR-T setting, which can mimic lymphoma relapse. Tissue biopsy remains essential for accurate diagnosis and to prevent unnecessary oncologic therapy. Clinicians should maintain vigilance for infectious etiologies in this setting, and future studies may clarify whether targeted CMV monitoring is warranted in high-risk patients.

Keywords:  allogeneic stem cell transplant recipients; cytomegalovirus (cmv); hemato-oncology; non-hodgkin's lymphoma; oncolog

DOI:  https://doi.org/10.7759/cureus.100035
Cureus. 2025 Dec;17(12): e100102

Artificial Intelligence in Radiology: Advancing Precision, Accuracy, and Early Detection in Cancer Diagnosis.

Pragati Gurjar, Saad Khan Mayana, Sravan Krishna Reddy Annadevula, Bhanupriya Singh, Kumar Sambhav, Sapana B Shah.

  Artificial intelligence (AI) is rapidly transforming oncologic radiology, enabling earlier detection, greater precision, and more personalized care. Yet much of the literature remains fragmented into disease-specific studies or narrow performance assessments. This review addresses that gap through a narrative thematic synthesis of research published between 2019 and 2025, identified from major biomedical and engineering databases and selected for clinical relevance, translational value, and policy significance. Unlike prior reviews that catalog isolated applications, it organizes evidence into cross-cutting frameworks that redefine radiology's role in cancer care. These include advances in precision imaging and early detection, the integration of multimodal data for richer disease characterization, and the use of AI in prognosis and treatment monitoring. Equally, the review highlights challenges of model explainability, federated learning, equity, and workforce adaptation as determinants of adoption. By situating these themes within Clinical Decision Support Systems (CDSS) and broader healthcare infrastructures, the analysis shows that AI's significance lies less in isolated accuracy gains than in its transparency, inclusivity, and adaptability across contexts. The review concludes that the decisive priority now is to build global collaborations, robust validation, and ethical frameworks that ensure AI evolves as an inclusive ecosystem capable of delivering equitable improvements in cancer care worldwide.

Keywords:  artificial intelligence; cancer diagnosis; clinical decision support systems; precision oncology; radiology

DOI:  https://doi.org/10.7759/cureus.100102
Intensive Care Med. 2026 Jan 26.

The next frontier in sepsis: connected ICU data for real-world clinical decision making.

Ricardo Simon Carbajo, Julia Palma, Ignacio Martin-Loeches.

   BACKGROUND: Fragmented and locally siloed data limit progress in critical care research and education. The European Health Data Space (EHDS) proposes a federated, privacy-preserving framework to connect intensive care units (ICUs) across Europe. Sepsis is an ideal model condition given its heterogeneity, high mortality, and persistent gaps in standardization and outcomes.
OBJECTIVES: This narrative review explores how federated and synthetic data can transform sepsis research, quality improvement, and education within the EHDS. It aims to outline both the opportunities and practical limitations of building a European-wide, learning ICU network.
METHODS: Recent literature, European policy documents, and federated data initiatives were reviewed to synthesize conceptual, technical, and ethical aspects of implementing federated learning in intensive care.
RESULTS: Federated infrastructures enable joint analysis of distributed ICU data without sharing patient-level information, supporting benchmarking and surveillance while maintaining privacy. Synthetic data add value for simulation, algorithm testing, and training but cannot replace real-world complexity. Major barriers include data harmonization, interoperability, and governance. Ongoing projects demonstrate that transparent, secure frameworks can make responsible data sharing feasible.
CONCLUSIONS: The EHDS offers a realistic foundation for connecting ICUs across Europe through ethically governed federated systems. Combining clinical, engineering, and data science expertise will be key to transforming fragmented ICU information into shared intelligence that supports sepsis research, education, and personalized critical care.

Keywords:  Artificial intelligence; Data governance; European Health Data Space; Federated data; Intensive care unit; Sepsis; Synthetic data

DOI:  https://doi.org/10.1007/s00134-025-08284-3