bims-carter 2026-01-25 papers

bims-carter

Biomed News

on CAR-T Therapies

Issue of 2026–01–25
37 papers selected by
Luca Bolliger, lxBio

CAR-engineered cell therapies: current understandings and future perspectives.
Beyond αβ T cells: unlocking the potential of diverse immune cells in CAR modification.
CAR-T therapy: Advances in respiratory diseases.
CAR-T cell therapy: A new dawn in the treatment of autoimmune disease.
It's time to reimagine reimbursement for CAR T-cell therapy.
Serial Killing Assay Using Longitudinal Impedance-Based Tumor Cell Viability Measurement - A Useful Method to Assess T Cell Performance.
Industrializing CAR-T cell therapy: impact of automation on cost and space efficiency of manufacturing facilities.
Regulatory landscape for CAR-T therapy development in the Brazilian context.
CAR-T/NK/M-based combination therapies in cancer: A comprehensive review.
Dextran-based T-cell expansion nanoparticles for manufacturing CAR T cells with augmented efficacy.
The gut microbiota-brain-CAR T cell axis: a systematic review of gut microbiome modulation and its impact on neurological complications and treatment responses in CAR T cell therapy.
Bispecific and multispecific T-cell engagers: advancing the future of immunotherapy.
Patient-Derived Three-Dimensional Tumor Organoid Model for In Vitro Chimeric Antigen Receptor T Cell Screening.
UniTope & TraCR: A Universal Tool to Tag, Enrich, and Track TCR-T Cells and Therapeutic Proteins.
Next generation CAR-T cells to tackle down solid tumors.
Strategies to eliminate native T cell receptors for adoptive T cell therapies.
Improving CRISPR-Cas9 Screens in CAR T Cells: A Refined Method for Library Preparation.
IL-7: a potential next-generation adjuvant for immune cell therapies.
CD2 costimulation bridges potent CAR-induced cytolysis and durable persistence.
Reproducible and Efficient Phenotyping for Cell Therapy Manufacturing Using the Accellix Automated Flow Cytometer Platform.
RO4, a high-affinity humanized antibody against the juxtamembrane region of mesothelin for targeted cancer therapy.
Engineering a fifth-generation CAR T cells to overcome PD-L1-mediated immunosuppression in lung cancer.
Health Technology Assessment in the Early Phases of Development of Medical Devices: A Catalyst for Sustainable Growth and Innovation.
m-EASIX (better than EASIX) predicts severe CAR T-cell toxicities, worse overall survival, and discriminates cytokine release syndrome from sepsis.
Therapeutic antibody delivery: vector tools to boost efficacy and affordability.
MHC one-two punch knocks out cancer.
Methionine restriction for cancer therapy: From preclinical studies to clinical trials.
Calculated INSIGHT: A New Way to Evaluate Health Care Technology Innovation.
Development of a Performance Measurement Framework for European Health Technology Assessment: Stakeholder-Centric Key Performance Indicators Identified in a Delphi Approach by the European Access Academy.
The Integrated Stress Response in Cancer: Paradox and Therapeutic Promise.
Viral vector-based gene therapies in the clinic: An update.
Frameworks for Guiding the Selection of Digital Data Collection Tools Used in Clinical Trials: Protocol for a Systematic Review.
Barriers and Strategies to Enhance CAR-T Cell Infiltration in Solid Tumours: A Systematic Review.
Research progress and application prospect of engineered small extracellular vesicles.
Mapping the regulatory landscape for environmental sustainability of medical device practices within the European Union.
Possibilities and challenges of next-generation therapeutics: solid lipid nanoparticles revolutionizing metabolic disorder treatment.
Cost-Effectiveness of Adjuvant Immunotherapy in Cancer Treatments: A Systematic Review.

Mol Biomed. 2026 Jan 21. 7(1): 7

CAR-engineered cell therapies: current understandings and future perspectives.

Mobina Bayat, Javid Sadri Nahand.

  Chimeric antigen receptor (CAR)-engineered cell therapies represent a significant breakthrough in immunotherapy, initially in cancer and now expanding into diverse clinical fields. While originally developed for oncology, these platforms are increasingly being adapted for non-malignant conditions such as autoimmune disorders, infectious diseases, fibrosis, ageing-related issues, and organ transplants. This review details the evolution and diversification of CAR modalities- including CAR-T, CAR-NK, CAR-macrophages, and CAR-NKT cells- as well as emerging next-generation designs. It describes the key aspects of CAR structure, signalling pathways, and manufacturing, emphasising their application in treating hematologic and solid tumours, while considering challenges such as the tumour microenvironment (TME). The review also discusses expanding uses beyond cancer- such as CD19/BCMA-targeted CAR-T cells achieving long-term remission in lupus and rheumatoid arthritis without ongoing immunosuppression, CAR-NK approaches targeting HIV, CAR-Tregs enhancing transplant tolerance, and senolytic CARs reducing tissue fibrosis. Up-to-date research through 2025 is summarised to evaluate efficacy, safety, and adverse events, noting that CAR therapies show lower cytokine release syndrome (CRS) in autoimmune diseases. Innovations like off-the-shelf allogeneic products and logic-gated CARS are highlighted, alongside ongoing challenges such as manufacturing complexity, high costs, and antigen escape. Trials like KYV-101 for multiple sclerosis demonstrate continued progress and the potential of these therapies to translate into clinical practice. Overall, CAR-engineered treatments enable precise, programmable immune modulation, paving the way for advanced therapies across an expanding array of diseases.

Keywords:  Autoimmune Diseases; Cancers; Chimeric Antigen Receptor (CAR) Therapy; Immunotherapy; Infectious Diseases

DOI:  https://doi.org/10.1186/s43556-025-00401-4
Clin Sci (Lond). 2026 Jan 21. pii: CS20256571. [Epub ahead of print]140(2):

Beyond αβ T cells: unlocking the potential of diverse immune cells in CAR modification.

Yangyang Gao, Feifei Guo, Min Li, Naifei Chen, Chao Niu, Jiuwei Cui.

  Chimeric antigen receptor (CAR) T cell therapy has emerged as a groundbreaking advancement in cancer immunotherapy, demonstrating remarkable success in treating hematologic malignancies. However, its application in solid tumors remains challenging. The complex manufacturing process and severe treatmentrelated toxicities further limit its broader clinical application. To address these challenges, researchers are investigating alternative CAR-engineered immune cells, including CAR-NK cells, CAR-γδ T cells, and CARmacrophages (CAR-M), which offer distinct advantages over conventional CAR-T therapy. Notably, CAR-NK and CAR-γδ T cells exhibit HLA-independent cytotoxicity, making them promising 'off-the-shelf' therapeutic options. Meanwhile, CAR-M not only phagocytose tumor cells and present antigens but also remodel the immunosuppressive tumor microenvironment. Despite their potential, these innovative therapies still face several challenges in clinical application. This review systematically summarizes recent advances in CAR-T cells, CAR-NK cells, CAR-γδ T cells, and CAR-M for cancer treatment, providing a comprehensive analysis of their respective strengths, limitations, and future optimization strategies to support the clinical translation of next-generation CAR-based immunotherapies.

Keywords:  NK cells; chimeric antigen receptor; gamma delta T cells; immunotherapy; macrophages

DOI:  https://doi.org/10.1042/CS20256571
Chin Med J Pulm Crit Care Med. 2025 Dec;3(4): 289-299

CAR-T therapy: Advances in respiratory diseases.

Hui Han, Yongxian Hu.

  Chimeric antigen receptor (CAR) T cell (CAR-T) therapy is a form of adoptive immunotherapy based on the genetic engineering of T lymphocytes. The expression of CARs on T cells facilitates precise, efficient immune responses by enabling direct binding to target cell-specific surface antigens, circumventing the need for major histocompatibility complex-restricted antigen presentation. Having achieved clinical success in treating refractory hematologic malignancies, research efforts have been increasingly directed toward expanding the application of CAR-T therapy, as there is growing interest in investigating its therapeutic potential for a range of respiratory diseases. This review systematically explores the expanding utilization of CAR-T therapy in treating respiratory diseases such as respiratory malignancies, severe asthma, infectious diseases, idiopathic pulmonary fibrosis, and autoimmune disorders with significant pulmonary involvement, providing a comprehensive summary of the current preclinical and clinical advancements. Despite encouraging outcomes, the clinical translation of CAR-T therapy for respiratory diseases is impeded by several persistent challenges, including the limited availability of tumor-specific antigens because of heterogeneous expression of target antigens, the impairment of CAR-T functionality by the immunosuppressive microenvironment of solid tumors, and considerable manufacturing and logistical hurdles. To address these obstacles, this review highlights emerging combinatorial strategies aimed at enhancing therapeutic efficacy and safety. With ongoing advancements, CAR-T therapy holds promise as a versatile and effective treatment, potentially achieving durable remissions and establishing a novel therapeutic paradigm for patients with otherwise refractory respiratory diseases.

Keywords:  Asthma; Autoimmune disease; Chimeric antigen receptor T cell; Idiopathic pulmonary fibrosis; Infectious disease; Respiratory malignancies

DOI:  https://doi.org/10.1016/j.pccm.2025.11.001
Cell Transplant. 2026 Jan-Dec;35:35 9636897251414211

CAR-T cell therapy: A new dawn in the treatment of autoimmune disease.

Sijia Yan, Xiaojian Zhu, Yi Xiao.

  Autoimmune diseases (AIDs) are a class of diseases caused by autoimmune intolerance, which can be divided into systemic and organ-specific diseases. AIDs affect approximately 10% of the global population and rank among the leading causes of disability and mortality. At present, immunosuppressive agents are the first choice for the treatment of AIDs. B-cell-targeted therapies-particularly CD20 monoclonal antibodies-have brought new hope for systemic AIDs, yet a subset of patients still respond poorly. As a rapidly developing cellular immunotherapy technology, Chimeric antigen receptor T cell (CAR-T) plays an important role in the treatment of hematological malignancies. CAR-T targeting B-cell-specific antigens can rapidly deplete circulating B cells, thereby reducing the formation of autoantibodies, which has become the basis for research on CAR-T in the treatment of autoimmune diseases. Currently, many studies are underway, and CAR-T and its derivative therapies bring new hope for the treatment of autoimmune diseases.

Keywords:  Autoimmune Disease; CAR-NK; CAR-T; CARR-T; CD19; Myasthenia agravis; systemic lupus erythematosus

DOI:  https://doi.org/10.1177/09636897251414211
Am J Manag Care. 2025 Dec;31(Spec. No. 13): SP922-SP929

It's time to reimagine reimbursement for CAR T-cell therapy.

Anna Sureda, Meagan O'Neill, Brian O'Rourke.

Members of the CAR T Vision Steering Committee outline key issues around US and EU reimbursement and discuss potential solutions.

DOI: https://doi.org/10.37765/ajmc.2025.89878
J Vis Exp. 2025 Dec 30.

Serial Killing Assay Using Longitudinal Impedance-Based Tumor Cell Viability Measurement - A Useful Method to Assess T Cell Performance.

Tengis Tschaidse, Marcel P Trefny, Emanuele Carlini, David Andreu-Sanz, Stefanos Michaelides, Ngoc Thien Thu Nguyen, Sebastian Kobold.

Chimeric antigen receptor (CAR) cell therapy has revolutionized the treatment of specific hematologic malignancies. However, a significant portion of patients experience relapse because of antigen loss, antigen downregulation, or T cell exhaustion. These challenges highlight the need for functional assays that can evaluate the killing capacity and persistence of CAR T cells under chronic antigen stimulation. Serial killing assays, which measure the ability of CAR T cells to repeatedly eliminate tumor targets, offer valuable insights into the durability and potency of CAR T cell responses. Here, we present an impedance-based assay using the Real-Time Cell Analysis (RTCA) system to quantify CAR T cell-mediated serial killing in vitro. Tumor cells are repeatedly seeded and allowed to adhere to assay-specific E-plates before the addition of CAR T cells at defined effector-to-target (E:T) ratios. The platform continuously monitors tumor cell viability without labels, capturing dynamic cytotoxicity with high temporal resolution. Core readouts include Cell Index (CI) kinetics, tumor-cell killing rate, and time-to-target clearance. The progressive decline in killing capacity observed upon repeated tumor-target engagements serves as a marker of acquired CAR T cell dysfunction, often termed T cell exhaustion. Together, these metrics allow precise evaluation of CAR T cell function at various E:T ratios and enable direct comparison among different CAR T cell constructs or co-treatments over time. To enhance cost efficiency, we developed a plate-washing procedure that enables the reuse of assay E-plates without compromising assay performance or data integrity. The optimized workflow reduces assay cost while preserving analytical robustness. This approach enables affordable and scalable preclinical assessment of CAR T cell function, facilitating improvements in cell-therapy design.

DOI: https://doi.org/10.3791/69623
Front Bioeng Biotechnol. 2025 ;13 1612248

Industrializing CAR-T cell therapy: impact of automation on cost and space efficiency of manufacturing facilities.

Anna Louisa Weltin, Ysanne De Graaf, Amir Goudarzi, Mirko Müller, Laura Herbst, Bastian Nießing, Hubertus J M Vrijhoef, Robert H Schmitt.

  The A-Cell Case Study published by the "Alliance of Regenerative Medicine" illustrates how Quality-by Design can be applied to the manufacturing of Advanced Therapeutical Medicinal Products (ATMPs), using Chimeric Antigen Receptor (CAR)-T cell therapy as a 'model' process. However, no emphasis is given to different degrees of automation in this study. CAR-T cell therapies have been developed for various forms of leukemia, such as Acute Lymphoblastic Leukemia (ALL) or Non Hodgkin-Lymphoma (NHL). As more CAR-T cell therapies reach market approval and are being considered as first- or second line treatments, the economic efficiency and scalability of the chosen production modality become increasingly critical. Currently, academic and industrial manufacturers employ a range of approaches, from fully manual and open processing to closed and automated systems. New technologies, investments and cleanroom space requirements must be considered to assess economic and spatial efficiency in cell therapy manufacturing. This study analyses the costs and space requirements of different production modalities for autologous CAR-T cell production. The analysis shows that a higher degree of automation can reduce manufacturing costs by lowering personnel costs, cleanroom grade requirements and spatial footprint. It emphasizes the importance of maximizing cleanroom efficiency to support the scalable production of cell therapies as clinical demand grows. These results underscore the need for both industry and academia to consider automated production as a strategic approach to optimize resource use in CAR-T cell manufacturing.

Keywords:  automation; chimeric antigen; humans receptors; leukemia; t-lymphocytes; technology

DOI:  https://doi.org/10.3389/fbioe.2025.1612248
Expert Rev Anticancer Ther. 2026 Jan 21. 1-18

Regulatory landscape for CAR-T therapy development in the Brazilian context.

Felipe Pantoja Mesquita, Marília Silveira Maia, Pedro Filho Noronha Souza, Luany Elvira Mesquita Carvalho, Luciana Maria de Barros Carlos, Fernando Barroso Duarte.

   INTRODUCTION: Chimeric antigen receptor T (CAR-T) therapy represents a significant advance in the treatment of hematologic malignancies, yet its global implementation remains limited by regulatory, logistical, and manufacturing challenges. Understanding differences among international regulatory frameworks is essential for expanding safe and equitable access, particularly in emerging academic programs.
AREAS COVERED: This review examines the regulatory pathways, manufacturing requirements, and quality standards governing CAR-T therapies in Brazil, comparing them with those in the United States and the European Union. A focused literature search encompassed peer-reviewed articles, institutional guidelines, and regulatory documents from 2016 to 2025. Key elements assessed include GMP expectations, analytical method validation, biosafety considerations, and infrastructure requirements. The analysis also explores expanded-access mechanisms and summarizes clinical experiences that have used these pathways in the real world.
EXPERT OPINION: Despite structural differences, all jurisdictions converge on core principles emphasizing product quality, long-term safety, and traceability. However, Brazil faces unique multi-agency coordination requirements and infrastructural constraints that may delay national deployment. Global evidence indicates that strengthening GMP facilities, analytical validation strategies, and harmonized regulatory processes, particularly for academic and point-of-care manufacturing, will be crucial to broaden access and sustain innovation in CAR-T therapies.

Keywords:  CAR-T; Cancer; advanced therapy; cancer therapies; regulation

DOI:  https://doi.org/10.1080/14737140.2026.2617956
Curr Probl Cancer. 2026 Jan 20. pii: S0147-0272(26)00003-6. [Epub ahead of print]61 101269

CAR-T/NK/M-based combination therapies in cancer: A comprehensive review.

Shivani Vaja, Shubhi Khandelwal, Chaitali Vora, Abdul Arif Khan, Syed Wajeed, M Hassan Sk, Mirza S Baig.

  Chimeric Antigen Receptor T (CAR-T) cell therapy, in combination with other treatments or medications, presents a groundbreaking development in cancer immunotherapy. CAR-T immunotherapy has shown remarkable progress, with multiple therapies approved by the US FDA for hematological malignancies. Studies indicate that CAR-NK and CAR-M therapies are more effective against solid tumors than CAR-T-based therapy. The synergistic potential of combining CAR-based therapies with immunomodulatory agents, cytokines, oncolytic viruses, and immune checkpoint inhibitors presents a promising strategy for treating various cancers. This comprehensive review examines the current status and application of CAR-T, CAR-NK, and CAR-M therapies, particularly their integration with immunomodulatory agents and other molecules for treating solid tumors, including glioblastoma, pancreatic, gastric, liver, ovarian, lung, and breast cancers.

Keywords:  CAR-M; CAR-NK; CAR-T; Cancer; Immunomodulatory agents; Immunotherapy

DOI:  https://doi.org/10.1016/j.currproblcancer.2026.101269
Nat Commun. 2026 Jan 20.

Dextran-based T-cell expansion nanoparticles for manufacturing CAR T cells with augmented efficacy.

Tao Zheng, Keerthana Ramanathan, Maria Ormhøj, Mikkel Rasmus Hansen, Hólmfridur Rósa Halldórsdóttir, Hanxi Li, Kamilla Kjærgaard Munk, Carlos Rodriguez-Pardo, Rasmus Ulslev Wegener Friis, Islam Seder, Peter M H Heegaard, Klaus Qvortrup, Hinrich Abken, Yi Sun, Sine Reker Hadrup.

Adoptive T cell therapy using chimeric antigen receptor (CAR) engineered T cells is currently being explored in multiple cancer types beyond leukemia/lymphoma. A key step in CAR-T cell manufacturing is the activation and expansion of T cells, which facilitates viral transduction, however, may hamper T cell fitness and reduce in vivo persistence. "T-Expand" is developed for T cell activation and expansion, comprising dextran-based nanoparticles conjugated with anti-CD3 and anti-CD28 antibodies. The nanoparticles trigger robust polyclonal expansion of human T cells with efficiency in the range of commercial microbeads (Dynabeads™). Engineered in the presence of T-Expand, CD19 CAR T cells display enhanced proliferative capacity, cytotoxicity and persistence in vitro, and furthermore, exhibit potent anti-lymphoma activity in mouse models, resulting in complete tumor clearance at one fourth of the CAR T cell dose. Importantly, T-Expand is biocompatible with no observed toxicity, circumventing removal steps after T cell expansion compared to DynabeadsTM. As a biocompatible T cell expansion platform, T-Expand simplifies the manufacturing process while enhancing T cell persistence and functionality, and thereby holds promise for increasing clinical efficacy of CAR T cell therapy.

DOI: https://doi.org/10.1038/s41467-025-67868-1
Front Immunol. 2025 ;16 1703146

The gut microbiota-brain-CAR T cell axis: a systematic review of gut microbiome modulation and its impact on neurological complications and treatment responses in CAR T cell therapy.

Ashvath Arumugam Pillai, Sai K Reddy Pasya, Gaurav Kansal, Aishwarya Jaikrishnan, Anchit Chauhan, Arghadip Das, Korat Parth Manojbhai, V Deepak Prabu, Muhammad Mahdi Nashatizadeh.

   Background: CAR T-cell therapy represents a substantial advance for relapsed/refractory hematologic cancers, but toxicities still limit its benefits. A particular concern is immune effector cell-associated neurotoxicity syndrome (ICANS), whose mechanisms remain only partly resolved. In parallel, work across immunology and neurogastroenterology shows that gut microbial communities can shape systemic inflammation and show correlations with brain function. Together, these strands suggest-without yet proving-that microbiome features could bear on both CAR T efficacy and ICANS risk.
Objectives: We examined human clinical evidence at three touchpoints: how CAR T and the gut microbiota interact; how gut profiles relate to brain function; and which signals accompany CAR T-related neurotoxicity. The aim was to locate areas of overlap, not to claim a single causal chain.
Methods: Following PRISMA, PubMed, Scopus, and Embase were searched from 2015 to 11 April 2025. We included randomized trials, prospective cohorts, and retrospective series reporting gut microbial composition, inflammatory or neurobiological markers, CAR T outcomes, or ICANS. Study quality was appraised with the Newcastle-Ottawa Scale and certainty graded with GRADE.
Results: Twenty-five studies were included (four CAR T-gut, eleven gut-brain, ten CAR T-neuro). Recurrent signals were (i) reduced microbial diversity, (ii) loss of short-chain fatty-acid producers, and (iii) prior antibiotic exposure-each linked to poorer clinical outcomes and higher or more severe ICANS. Candidate markers (e.g., C-reactive protein, interleukin-6, neurofilament light chain) and imaging findings, including PET abnormalities, were reported but remain exploratory and variably measured. Included studies are small and methodologically varied, and results should be interpreted with caution.
Conclusion: Taken together, the data support a convergence model: the gut microbiota may correlate with both treatment efficacy and neurotoxicity in CAR T recipients. The signal is consistent yet preliminary. Microbiome interventions such as probiotics and FMT are investigational and not yet recommended for CAR T recipients. Prospective, mechanism-rich studies-ideally pairing longitudinal stool profiling with inflammatory panels and neuroimaging-are needed before clinical translation.
Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42024548645.

Keywords:  CAR T-cell therapy; ICANS; brain–immune axis; cytokines; gut microbiota; immunotherapy; microbiome; neurotoxicity

DOI:  https://doi.org/10.3389/fimmu.2025.1703146
Antib Ther. 2026 Jan;9(1): 58-69

Bispecific and multispecific T-cell engagers: advancing the future of immunotherapy.

Xiaoqiang Kang, Yue Zhao, Hong Ling, Xiao Huang.

  T-cell engagers (TCEs) represent an emerging class of immunotherapies that harness T cells' cytotoxic power to eliminate diseased cells-a transformative future therapeutic strategy. TCEs form immunological synapses to trigger potent immune responses, with proven efficacy in blood cancers; research expands their use to solid tumors via innovative molecular design and improved safety profiles. Beyond oncology, TCEs hold promise in autoimmune disorders by eliminating autoreactive cells, offering novel avenues for diseases like lupus. However, achieving optimal outcomes without disrupting immune homeostasis remains a challenge. Key obstacles-on-target off-tumor toxicity, cytokine release syndrome, tumor antigen loss, and T cell exhaustion-limit broader adoption. Current research addresses these via enhanced specificity, optimized design, improved druggability, and synergistic combinations. This review analyzes TCEs' mechanisms, challenges, innovations and applications, highlights our pipeline advances, and advocates sustained innovation to broaden TCE use across diseases.

Keywords:  CD3; T cell engagers; autoimmune diseases; bi- or trispecific antibodies; cancer immunotherapy

DOI:  https://doi.org/10.1093/abt/tbaf026
J Vis Exp. 2025 Dec 30.

Patient-Derived Three-Dimensional Tumor Organoid Model for In Vitro Chimeric Antigen Receptor T Cell Screening.

Linjun Liang, Yue Shi, Minzhu Ji, Yang Xu, Ru Zhang, Yong Cui, Liang Li.

Chimeric antigen receptor T (CAR-T) cell therapy has achieved exciting clinical efficacy in hematological malignancies, but CAR-T cell therapy for solid tumors still requires further development. Patient-derived tumor organoids are in vitro disease models that retain patient heterogeneity and have been used to test the efficacy and safety of chemotherapy and targeted drugs. This method describes an in vitro efficacy testing model of co-culturing tumor organoids with CAR-T cells. Colorectal cancer samples from patients are constructed into tumor organoids with a three-dimensional (3D) structure in a basement membrane matrix. The tumor organoids can grow stably and be passaged continuously. Mature tumor organoids are separated from the matrix by washing and centrifugation, and CAR-T cells are added at different effector-to-target (E:T) ratios to form an immune-organoid co-culture system. After 6-24 h, the morphology and intercellular structures of the organoids are observed by bright-field imaging. This experiment further performs dead cell staining in the co-culture system, which can reflect the viability of the organoids and evaluate the cytotoxic effect of CAR-T cells on tumor organoids. This experiment can effectively observe the interaction between CAR-T cells and 3D tumor organoids, and the results can be used to assess the tumor-killing activity of CAR-T cells.

DOI: https://doi.org/10.3791/69113
Med Sci (Basel). 2025 Dec 31. pii: 18. [Epub ahead of print]14(1):

UniTope & TraCR: A Universal Tool to Tag, Enrich, and Track TCR-T Cells and Therapeutic Proteins.

Kanuj Mishra, Barbara Lösch, Dolores J Schendel.

   BACKGROUND: Adoptive cell therapy using genetically engineered recombinant T cell receptors (rTCRs) expressed in T cells (TCR-T cell therapy) provides precision targeting of cancer cells expressing tumor-associated or tumor-specific antigens recognized by the rTCRs. Standardized analytical tools are lacking to easily quantify receptor expression.
METHODS: To overcome this hindrance, a universal tagging system (UniTope & TraCR) was designed consisting of a minimal peptide epitope (UniTope) inserted into the constant region of the rTCR α or β chain and a high-affinity monoclonal antibody (TraCR) specific to this tag. Detailed biophysical, biochemical, and functional assays were performed to evaluate rTCR expression, folding, pairing, and antigen recognition, as well as antibody performance, using the UniTope & TraCR System.
RESULTS: Tagged rTCRs were stably expressed in human T cells with surface densities comparable to untagged rTCRs. The TraCR antibody bound UniTope with nanomolar affinity and no detectable cross-reactivity was observed for endogenous proteins expressed by human cells of diverse origin, importantly, including T cells of the natural T cell repertoires of multiple human donors. Functional assays confirmed that UniTope-tagged rTCRs preserved their antigen-specific cytokine secretion and cytolytic activity upon antigen-specific stimulation. The UniTope & TraCR System enabled robust detection of rTCR-expressing T cells by flow cytometry, and rTCR protein expression by Western blot or immunoprecipitation, supporting the quantitative assessment of receptor copy number and structural integrity.
CONCLUSIONS: The UniTope & TraCR System provides a modular, construct-agnostic platform for monitoring engineered rTCRs, integrated into TCR-T cell therapies currently in development.

Keywords:  T cell receptor; adoptive cell therapy; epitope tag; immunotherapy analytics; quality control; universal antibody

DOI:  https://doi.org/10.3390/medsci14010018
J Control Release. 2026 Jan 20. pii: S0168-3659(26)00051-9. [Epub ahead of print] 114650

Next generation CAR-T cells to tackle down solid tumors.

Teresa Abreu, Ana Godinho-Santos, Ana Teresa Amaral, Artur Paiva, João N Moreira, Joao Goncalves.

  The genetic modification of human T cells to express chimeric antigen receptors (CAR-T cells) has revolutionized cancer immunotherapy by redirecting their cytotoxicity towards specific tumor antigens. While CAR-T cell therapies have demonstrated remarkable success in hematological malignancies, their translation to solid tumors remains limited by several challenges. These include the lack of exclusive tumor antigens and intrinsic tumor heterogeneity, which contribute to suboptimal targeting and increase the risk of on-target, off-tumor effects. Additionally, solid tumors present a complex and hostile tumor microenvironment (TME), characterized by multiple physical barriers and immunosuppressive mechanisms that severely hinder CAR-T cells trafficking, persistence, and anti-tumor activity. A deeper understanding of these obstacles has fueled the development of next-generation CAR designs equipped with advanced synthetic biology approaches.. Improved antigen specificity with logic-gated systems, multiple-input CAR designs, co-expression of cytokine receptors, armored CARs, and engineered resistance to immunosuppressive cues in the form of chimeric switch or dominant negative receptors have emerged in response. In this context, this review provides a stepwise and comparative overview of the major biological and structural challenges limiting CAR T-cells efficacy in solid tumors. It critically discusses the innovative CAR constructs developed to overcome each of these obstacles - from antigen selection to trafficking and TME remodeling - offering a forward-looking framework to guide future research and accelerate the translation of CAR-T therapies beyond blood cancers.

Keywords:  Immunosuppression; Next-generation CAR-T cells; Solid tumors; Tumor heterogeneity; Tumor microenvironment; Tumor trafficking

DOI:  https://doi.org/10.1016/j.jconrel.2026.114650
Mol Ther. 2026 Jan 20. pii: S1525-0016(26)00018-3. [Epub ahead of print]

Strategies to eliminate native T cell receptors for adoptive T cell therapies.

Donovan Flumens, Diana Campillo-Davo, Florian Van Oers, Philip Anthony Gilbert Shaw, Eva Lion.

Adoptive T cell therapy has revolutionized modern medicine by harnessing and engineering T cells to selectively target disease-specific antigens. While scientists have developed numerous innovative methods to enhance T cell therapies, strategies to eliminate the native T cell receptor (TCR) have particularly accelerated the field. In TCR T cell therapy, mispairing between native and introduced TCR chains and competition for CD3 binding can compromise therapeutic efficacy and safety. In the context of allogeneic T cell therapies, residual TCR expression can lead to graft-versus-host disease (GvHD), a life-threatening complication. Effective elimination of native TCRs is therefore essential for improving both safety and efficacy of adoptive T cell therapies. Multiple strategies targeting the TCR at the genomic, transcriptomic, or proteomic level have been developed to achieve effective TCR disruption, each characterized by its own advantages and limitations. This review provides a comprehensive overview of current strategies to eliminate the native TCR in human T cells, highlighting the strengths and weaknesses of each method.

DOI: https://doi.org/10.1016/j.ymthe.2026.01.017
J Vis Exp. 2026 Jan 02.

Improving CRISPR-Cas9 Screens in CAR T Cells: A Refined Method for Library Preparation.

Maider Garnica, Patxi San Martin-Uriz, Paula Rodriguez-Marquez, Maria E Calleja-Cervantes, Saray Rodriguez-Diaz, Rebeca Martinez-Turrillas, Mikel Hernaez, Felipe Prosper, Juan R Rodriguez-Madoz.

Chimeric antigen receptor (CAR) T cell therapies have demonstrated remarkable efficacy in several hematological malignancies, yet their success has not been fully replicated in solid tumors. Moreover, even in hematological cancers, relapse after CAR T cell infusion continues to compromise long-term outcomes. These challenges highlight the urgent need to develop strategies that enhance CAR T cell efficacy, persistence, overcoming tumor and microenvironment-mediated resistance. Clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9-based screening platforms provide a powerful approach to systematically identify genes that regulate CAR T cell function. By linking genetic perturbations to phenotypic outcomes, these assays enable the discovery of pathways controlling activation, proliferation, memory formation, and cytotoxicity. Standard workflows involve transduction of substantial numbers of cells with a single guide RNA (sgRNA) library, Cas9-mediated editing, selection of edited cells, and PCR amplification of sgRNA cassettes from genomic DNA (gDNA) prior to sequencing. However, PCR amplification using large amounts of gDNA poses significant challenges and often fails to selectively amplify and retrieve sgRNAs. Here, we describe an optimized CRISPR-Cas9 knockout screening protocol, which we have tested on primary human CAR T cells. The method here incorporates an intermediate step during sgRNA library preparation that reduces gDNA carryover through enzymatic digestion and selective pulldown of the sgRNA cassette, thereby increasing the efficiency of the first PCR amplification. This modification allowed us to retrieve sgRNA information across our CAR T cell screens, which had remained elusive in our previous attempts using traditional 1 and 2-step PCR amplification protocols. In conclusion, this optimized workflow facilitates CRISPR screening library preparation in challenging samples and enables the identification of key genetic determinants that can be targeted to improve therapeutic efficacy.

DOI: https://doi.org/10.3791/69721
Front Immunol. 2025 ;16 1736931

IL-7: a potential next-generation adjuvant for immune cell therapies.

Richard S Hotchkiss, John F DiPersio, Cassian Yee, Russell K Pachynski, Marcel R M Van Den Brink.

  Cell-based immune therapies ranging from CAR-T cells to tumor infiltrating lymphocytes (TILs) and endogenous T-cell products, have produced unprecedented clinical responses in hematologic malignancies and are currently under active investigation for solid tumors. Nevertheless, several key challenges continue to limit the durability and breadth of clinical benefit. IL-7 is a pleiotropic cytokine that increases both the number and function of lymphocytes. Although not yet clinically approved, IL-7 has been used in over 620 adult and pediatric patients for a variety of reasons including, for example, to hasten bone marrow recovery after allogenic stem cell transplantation, to reverse lymphopenia due to HIV and idiopathic etiologies, to treat patients with various malignancies, and to boost vaccine responses. IL-7 is generally well-tolerated and effective in producing a durable increase in the number and function of CD4 and CD8 T cells. Recently, IL-7 has been used clinically in multiple myeloma patients receiving CAR-T cell therapy, in patients with urothelial cancer who are receiving checkpoint inhibitors, in patients undergoing endogenous lymphocyte cell therapy, and in critically-ill lymphopenic patients with COVID-19. The authors, all of whom have used IL-7 clinically, discuss how IL-7 effectively addresses all the major problems currently limiting adoptive cell therapies. Peering into the future, we believe that IL-7 will be a major advance as an adjuvant treatment in many cell therapies and hope that this commentary will expedite IL-7's testing in multiple clinical settings.

Keywords:  IL-7; TIL (tumor infiltrating lymphocytes); cancer therapy; car-t; chimeric antigen receptor T-cell immunotherapy; immunotherapy

DOI:  https://doi.org/10.3389/fimmu.2025.1736931
J Immunother Cancer. 2026 Jan 22. pii: e013208. [Epub ahead of print]14(1):

CD2 costimulation bridges potent CAR-induced cytolysis and durable persistence.

Fang Liu, John T Keane, Hyeon S Lewis, Tiffany R King-Peoples, Carl H June, Avery D Posey.

   BACKGROUND: Current second-generation CAR T cell products rely on CD28 or 4-1BB costimulatory domains, additions that respectively favor rapid cytolysis or long-term persistence, but rarely both. Preclinical modeling and retrospective analysis have linked CD2-CD58 engagement to superior preclinical and clinical responses, yet the direct contribution of CD2 intracellular signaling remains undefined.
METHODS: We replaced the costimulatory domain of anti-mesothelin (SS1) and anti-TnMUC1 (5E5) CARs with the human CD2 cytoplasmic tail (CD2z) and benchmarked them against 28z and BBz formats. Transient mRNA expression was used to profile proximal Ca2+ flux and degranulation free of tonic viral signals; durable functional assays employed lentiviral CARs. Cytokine release, genome-wide transcriptional programs, and anti-tumor activity were assessed in vitro and in NSG xenograft models.
RESULTS: CD2z CAR T cells degranulated as efficiently as other z-containing CARs and generated a Ca2+ flux signal intermediate to 28z and BBz CARs. Lentiviral CD2z CARs released a Th1-skewed cytokine panel and matched 28z cytolysis despite a lower acute cytokine release. Transcriptomic analysis characterized CD2z cells in an early effector-memory state: glycolytic, mTORC1, and TNFa-NF-κB hallmarks were upregulated, whereas exhaustion-up signatures were selectively depleted vs 28z. In vivo, a single CD2z infusion induced deep and durable tumor regressions over the 60-day observation period in subcutaneous mesothelin-positive mesothelioma and orthotopic TnMUC1-positive pancreatic tumor models, achieving tumor control comparable to 28z and more rapid early tumor clearance than BBz, while supporting peripheral T cell persistence similar to BBz.
CONCLUSIONS: The CD2 cytoplasmic tail, in combination with CD3z, delivers balanced costimulation that couples brisk tumor debulking to T cell persistence. CD2z therefore may provide a simple, versatile alternative to canonical CD28 and 4-1BB modules for next-generation CAR T therapies.

Keywords:  Adoptive cell therapy - ACT; Chimeric antigen receptor - CAR; Immunotherapy; co-stimulatory molecules

DOI:  https://doi.org/10.1136/jitc-2025-013208
PDA J Pharm Sci Technol. 2026 Jan 18. pii: pdajpst.2025-000035.1. [Epub ahead of print]

Reproducible and Efficient Phenotyping for Cell Therapy Manufacturing Using the Accellix Automated Flow Cytometer Platform.

Jacob Van Vloten, Seungmi Yoo, Gurleen Sandhu, Leah Teschner, Dinh Nguyen, Elaine Than, Rey Mali, Donna Rill, Chris Ayers, Felix A Montero Julian.

  Measuring cellular quality attributes of cell therapy products is crucial because it ensures their safety, purity, potency, identity, and stability. These attributes help determine whether the therapy is effective and consistent across batches. Since cell therapy products are biologically complex, assessing their quality helps maintain lot-to-lot consistency, supports clinical data generation, and ensures compliance with regulatory standards. Additionally, critical quality attributes (CQAs) are essential for monitoring process control and validating the therapyâs effectiveness. Many of these cellular quality attributes are assessed using flow cytometry; however, beyond well-established clinical immunophenotyping assays, the technology remains insufficiently standardized, complicating alignment with Good Manufacturing Practice (GMP) and regulatory expectations. The work outlined here assesses the feasibility of the Accellix Platform for automated cellular sample analysis by analyzing repeatability and reproducibility across sites, operators, and dedicated instruments. The data presented demonstrates the potential of combining cytometry automation with advanced T cell engineering techniques to achieve robust and compliant manufacturing processes for innovative cellular therapies.

Keywords:  Accellix; Cell therapy; Good Manufacturing Practices; Triumvira; flow cytometry

DOI:  https://doi.org/10.5731/pdajpst.2025-000035.1
Antib Ther. 2026 Jan;9(1): 1-12

RO4, a high-affinity humanized antibody against the juxtamembrane region of mesothelin for targeted cancer therapy.

Masanori Onda, Xiufen Liu, Wenlong Liu, Jingyu Zhan, Carolyn A Maslanka, Di Xia, Mitchell Ho, Ira Pastan.

   Background: Mesothelin (MSLN) is a surface antigen highly expressed in several solid tumors, including mesothelioma, ovarian, and pancreatic cancers. However, therapeutic efficacy of MSLN-targeted agents is often compromised by shed MSLN (SM), which acts as a soluble decoy and accumulates in tumor microenvironments, reducing antibody engagement at the tumor surface.
Methods: To overcome this barrier, we generated antibodies targeting the membrane-proximal, non-shed region of MSLN using a peptide encompassing major cleavage sites for rabbit immunization. From 200 B-cell clones, 14 antibodies specific to the juxtamembrane region of MSLN were identified. The lead candidate, RO4, underwent detailed characterization and humanization to improve clinical applicability.
Results: Humanized RO4 (hRO4) exhibited enhanced binding affinity to MSLN and specifically recognized tumor-associated, non-shed epitopes. Structural analysis confirmed precise epitope engagement near the cleavage site. hRO4 effectively inhibited mesothelin shedding in vitro and enabled potent tumor eradication when expressed in chimeric antigen receptor (CAR) T cells in NOD scid gamma mouse models.
Conclusions: Targeting a non-shed epitope of MSLN with hRO4 overcomes a critical limitation of conventional MSLN-directed therapies. By avoiding decoy interference and enhancing tumor-specific targeting, hRO4-based therapeutics offer promising clinical potential for improving outcomes in MSLN-positive cancers.

Keywords:  CAR T-cell therapy; antibody; cancer; immunotherapy; structure

DOI:  https://doi.org/10.1093/abt/tbaf022
Biomed Pharmacother. 2026 Jan 17. pii: S0753-3322(25)01161-8. [Epub ahead of print]195 118967

Engineering a fifth-generation CAR T cells to overcome PD-L1-mediated immunosuppression in lung cancer.

Yupanun Wutti-In, Piriya Luangwattananun, Nunghathai Sawasdee, Preeyanat Vongchan, Pa-Thai Yenchitsomanus, Aussara Panya.

  The tumor microenvironment (TME) significantly hinders chimeric antigen receptor (CAR) T cell therapy in solid tumors, despite its success in hematological malignancies. This disparity is attributable to immunosuppressive factors, such as program death ligand 1 (PD-L1) upregulation in non-small-cell-lung cancer (NSCLC). This study aims to create and assess anti-FRα-CAR5, a novel anti-folate receptor alpha (FRα) CAR T cell designed to secrete a PD-L1 blocking single chain variable fragment (scFv). Human T lymphocytes were engineered with a lentiviral vector to express anti-FRα-CAR5, which incorporates a fourth-generation CAR backbone (CD28, 4-1BB, CD27, and CD3 zeta) augmented by a secreted anti-PD-L1 scFv derived from atezolizumab. Transfected HEK293T cells were used to evaluate surface expression of anti-FRα-CAR. The secreted anti-PD-L1 scFv was tested for binding ability on lung adenocarcinoma cell lines. Furthermore, the secreted anti-PD-L1 scFv demonstrated over 80 % inhibitory activity against PD-L1 monoclonal antibody. Importantly, anti-FRα-CAR5 T cells enhanced expansion and cytotoxicity against FRα and PD-L1 expressing lung cancer cell lines in vitro compared to an anti-FRα-CAR4 lacking the secreted anti-PD-L1 scFv. This fifth-generation CAR offers a promising strategy to enhance CAR T cell therapy efficacy in PD-L1-mediated immunosuppressive TMEs. These findings suggest that anti-FRα-CAR5 T cells therapy warrants further preclinical validation as a potential treatment strategy for NSCLC patients.

Keywords:  CAR T cell; Chimeric antigen receptor; FRα; Folate receptor alpha; Immune checkpoint blockade; Non-small cell lung cancer; PD-L1; Secreting anti-PD-L1 scFv

DOI:  https://doi.org/10.1016/j.biopha.2025.118967
Indian J Community Med. 2025 Dec;50(Suppl 3): S305-S309

Health Technology Assessment in the Early Phases of Development of Medical Devices: A Catalyst for Sustainable Growth and Innovation.

Navneet Kaur, Shankar Prinja.

  India's medical device sector is experiencing growth and technological advancements, driven by increased interest and government support in research and development. To promote innovation, significant amount of time and resources are spent on research and development before realization of a final product. To optimize the judicious allocation of these limited resources, the implementation of Health Technology Assessment (HTA) during the early phases of product development and testing should be adopted. Conducting early HTA enables an innovator to make well-informed decisions, demonstrate value to stakeholders, and improve market access by determining an appropriate price for the device which represents its value. The health economic models can be used throughout the life cycle of the innovation to inform decision making; however, the challenge lies in the lack of awareness regarding early HTA. It is thus imperative to increase knowledge and build capacity of the researchers, and foster collaboration between innovators and government organizations to realize the true potential of early HTA.

Keywords:  Early HTA; HTA; economic evaluation; health technology assessment; medical device

DOI:  https://doi.org/10.4103/ijcm.ijcm_182_24
Front Immunol. 2025 ;16 1664788

m-EASIX (better than EASIX) predicts severe CAR T-cell toxicities, worse overall survival, and discriminates cytokine release syndrome from sepsis.

Ana Belén Moreno-Castaño, Sara Fernández, Helena Brillembourg, Gontzal Iraola, David F Moreno, Helena Ventosa-Capell, Julia Martinez-Sanchez, Blanca De Moner, Patricia Molina, Alex Ramos, Marta Palomo, Pilar Gómez-Ramírez, Valentín Ortiz-Maldonado, Nuria Martínez-Cibrián, Julio Delgado, Aina Oliver-Caldés, Carlos Fernández de Larrea, María Queralt Salas, Álvaro Urbano, Adrián Téllez, José María Nicolás, Manel Juan, Azucena González-Navarro, Olaf Penack, Gines Escolar, Enric Carreras, Francesc Fernández-Avilés, Pedro Castro, Maribel Diaz-Ricart.

   Background: Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) are life-threatening complications that often arise after CAR T-cell immunotherapy. Endothelial dysfunction is believed to play a central role in their development, leading to the interest in biomarker-based tools for diagnosis and differentiating these toxicities from sepsis. This study aimed to evaluate the Endothelial Activation Stress Index (EASIX) and its modified version (m-EASIX, which replaces creatinine with C-reactive protein [CRP] (mg/dL)) as early predictors of severe CRS and ICANS, as well as tools to distinguish CRS from sepsis.
Methods: One hundred and nineteen patients treated with CAR T-cell therapy for CD19-positive hematologic malignancies (n=94) or multiple myeloma (n=23) were included. EASIX and m-EASIX scores were measured at various time points: before CAR T-cell infusion, 24-48 hours post-infusion, at CRS or ICANS onset, and after treatment for each toxicity. A comparator group of 129 sepsis patients, including 86 with hematologic malignancies, was also analyzed.
Results: Both EASIX and m-EASIX correlated with biomarkers of endotheliopathy, with m-EASIX showing stronger predictive power for severe toxicities and ICU admission. Higher EASIX and m-EASIX values at early time points were associated with worse overall survival (OS). Furthermore, m-EASIX accurately distinguished CRS from sepsis at symptom onset.
Conclusions: m-EASIX is a practical and accessible tool for the early prediction of severe CAR T-cell-related toxicities, risk stratification, and differential diagnosis from sepsis, offering potential to guide clinical decision-making and early intervention.

Keywords:  CAR T-cells; EASIX; biomarkers; endotheliopathy; m-EASIX; sepsis; toxicities

DOI:  https://doi.org/10.3389/fimmu.2025.1664788
Front Immunol. 2025 ;16 1714390

Therapeutic antibody delivery: vector tools to boost efficacy and affordability.

Abhishek Chiyyeadu, Bushra Khan, Katrin Ehrhardt, Hildegard Büning, Michael Morgan, Axel Schambach.

  Antibody (Ab)-based therapeutics have become powerful tools across diverse disease areas, with advances in bioengineering giving rise to next-generation molecules designed to outperform conventional Abs. Yet, large-scale production and purification of such complex proteins remain costly and can restrict patient access. A promising alternative is to improve in vivo expression capabilities, which will reduce manufacturing burdens and improve safety and tolerability. Multiple gene delivery platforms - ranging from mRNA and viral vectors to engineered cell therapies - have matured considerably, as a direct result of years of clinical experience and growing regulatory confidence. The rapid deployment of mRNA vaccines against SARS-CoV-2, the clinical success of adeno-associated virus (AAV)- and lentiviral-based interventions, and the approval of chimeric antigen receptor (CAR)-T cell therapies highlight the potential of these technologies to transform how we deliver Ab therapeutics. While these approaches hold the promise to treat genetic aberrations in patients, they may also contribute considerably to advancing conventional Ab therapeutics against viral infections and other diseases through local persistence of the proteins. Looking forward, in situ expression may confer even more benefits for engineered Ab-like molecules, thereby compensating for possibly shorter half-lives and overcoming challenges in in vitro production and purification. Therefore, in this review, we critically evaluate how these established and emerging gene therapy platforms can be harnessed to expand access, and discuss possibilities to improve in situ availability through the choice of transient or stable expression systems to increase the efficacy of Abs and other therapeutic proteins. Furthermore, we explore the current landscape of technological advancements, identify key translational challenges, and project future directions for optimizing these approaches towards widely applicable clinical interventions.

Keywords:  AAV vectors; antibody delivery; infectious diseases; lentiviral vectors; mRNA-LNP; plasma cell therapy

DOI:  https://doi.org/10.3389/fimmu.2025.1714390
J Exp Med. 2026 Feb 02. pii: e20252203. [Epub ahead of print]223(2):

MHC one-two punch knocks out cancer.

Amir Ghorbani, Jonathan W Yewdell.

In this issue of JEM, Zhang et al. (https://doi.org/10.1084/jem.20250025) describe complete T cell antigens (CTAs), comprised of class I and class II immunogenic peptides fused in a single polypeptide that greatly increase the effectiveness of cancer immunotherapy, even when the CTA antigens are not expressed in tumor cells.

DOI: https://doi.org/10.1084/jem.20252203
Cancer Pathog Ther. 2026 Mar;4(2): 124-135

Methionine restriction for cancer therapy: From preclinical studies to clinical trials.

Nagaraju Bandaru, Shaik Mohammad Noor, Maha Lakshmi Kammili, Mohan Gandhi Bonthu, Alluri Pavani Gayatri, Perli Kranti Kumar.

  Methionine restriction (MR) has shown significant promise in cancer therapy because it targets the unique methionine dependency of many tumors. However, despite extensive research on MR, a clear synthesis of preclinical findings and their translation into clinical settings is lacking. This review aims to address this gap by consolidating existing evidence, identifying challenges, and highlighting opportunities for advancing MR as a viable cancer treatment strategy. Preclinical studies have revealed that MR effectively hinders cancer cell proliferation, triggers cell cycle arrest, and enhances the effectiveness of standard treatments, including chemotherapy and radiotherapy. Mechanistically, MR disrupts critical cancer pathways by influencing epigenetic regulation, redox balance, and autophagy. Moreover, animal models have demonstrated notable tumor suppression and extended survival, underscoring the therapeutic potential of MR. Early-phase clinical trials are now examining MR in combination with established therapies, reporting positive preliminary results regarding safety and tolerability, and investigating biomarkers for predicting patient responsiveness. These findings suggest the utility of MR as a complementary treatment strategy, particularly for tumors resistant to conventional therapies. The outcomes of this study underscore the importance of further research to refine MR protocols, understand long-term effects, and identify optimal patient groups. Furthermore, combining MR with immunotherapies, targeted treatments, and advanced modalities such as chimeric antigen receptor (CAR)-T cell therapy may offer new therapeutic pathways. Additionally, the development of MR-mimetic drugs and targeted supplements can improve patient compliance and broaden the therapeutic applicability of MR. Large-scale clinical trials are essential to evaluate the efficacy of MR across diverse cancer types, focusing on sustainability and safety over extended periods. If successful, MR can transform cancer therapy by exploiting metabolic vulnerabilities in cancer cells, providing a novel and less toxic treatment option for challenging malignancies.

Keywords:  Cancer treatment; Clinical studies; Methionine metabolism; Preclinical studies

DOI:  https://doi.org/10.1016/j.cpt.2025.01.002
Comput Inform Nurs. 2026 Jan 20.

Calculated INSIGHT: A New Way to Evaluate Health Care Technology Innovation.

Nelita Iuppa, Darren Batara, Anna Schoenbaum, Chad Carroll, Angela Ross, Hiyam Nadel, Olga Kagan, Kathleen McGrow.

  As health care innovation accelerates, evaluating the full potential and impact of emerging technologies is challenging. Understanding the justification of selected automations often brings up questions. Upfront costs, legacy systems, limited resources, and misaligned priorities also complicate technology selection and adoption. Nurses hold critical understanding of clinical workflows, patient impact, and operational transformation. Recognizing this central role, the HIMSS Nursing Innovation Advisory Workgroup used essential nursing practices of clinical assessment and evidence-based design to address this problem. This team developed INSIGHT, the Innovation Scoring and Impact Guide for Healthcare Technologies, a dynamic, evidence-informed evaluation tool. INSIGHT applies weighted scoring to industry-validated criteria, generating both numeric and narrative impressions across 3 themes: value and culture, risks and rewards, and complexity. It supports clinicians, operational and technical leaders, executives, and academia in comparing solutions, building business cases, informing investments, and general understanding of key factors influencing successful technology adoption. By translating nursing clinical judgment and strategic evaluation into a structured framework, INSIGHT equips any stakeholder to substantiate technology solutions with data, elevating their perspectives with evidence and confidence. INSIGHT promotes alignment with organizational capacity and priorities, introduces transparency, consistency, and objectivity, advancing more inclusive, informed, and effective technology solutions in health care.

Keywords:  Clinical systems; Innovation calculator; Technology decisions; Technology evaluation; care technology

DOI:  https://doi.org/10.1097/CIN.0000000000001460
J Mark Access Health Policy. 2026 Mar;14(1): 5

Development of a Performance Measurement Framework for European Health Technology Assessment: Stakeholder-Centric Key Performance Indicators Identified in a Delphi Approach by the European Access Academy.

Elaine Julian, Nicolas S H Xander, Konstantina Boumaki, Maria João Garcia, Evelina Jahimovica, Joséphine Mosset-Keane, Monica Hildegard Otto, Mira Pavlovic, Giovanna Scroccaro, Valentina Strammiello, Renato Bernardini, Stefano Capri, Ruben Casado-Arroyo, Thomas Desmet, Walter Van Dyck, Frank-Ulrich Fricke, Fabrizio Gianfrate, Oriol Solà-Morales, Jürgen Wasem, Bernhard J Wörmann, Jörg Ruof.

   BACKGROUND: The objective of this work was to support the implementation of the European Health Technology Assessment Regulation (EU HTAR) and optimize performance of the evolving EU HTA system. Therefore, an inclusive multi-stakeholder framework of key performance indicators (KPI) for success measurement was developed.
METHODS: A modified Delphi-procedure was applied as follows: (1) development of a generic KPI pool at the Fall Convention 2024 of the European Access Academy (EAA); (2) review of initial pool and identification of additional KPIs; (3) development of prioritized KPIs covering patient, clinician, Health Technology Developer (HTD), and System/Member State (MS) perspectives, and (4) consolidation of the stakeholder-centric KPIs after EAA's Spring Convention 2025.
RESULTS: Steps 1 and 2 of the Delphi procedure revealed 14 generic KPI domains. Steps 3 and 4 resulted in four prioritized KPIs for patients (patient input; utilization of patient-centric outcome measures; time to access; equity); six for clinicians (population/intervention/comparator/outcomes (PICO); addressing uncertainty; clinician involvement; transparency; equity and time to access); four for HTDs (PICO; joint scientific consultation (JSC) process; joint clinical assessment (JCA) process; time to national decision making); five from a system/MS perspective (PICO; learning and training the health system; reducing duplication; equity and time to access). The scope of, e.g., the PICO-related KPI, differed between stakeholder groups. Also, several KPIs intentionally reached beyond the remit of EU HTA as they are also dependent on MS-specific factors including national health systems and budgets.
DISCUSSION AND CONCLUSIONS: The KPI framework developed here presents a step towards the generation of systematic multi-stakeholder evidence to support a successful implementation of the EU HTAR. The relevance of the identified stakeholder-centric KPIs is confirmed by their alignment with the Health System Goals suggested in the context of "Performance measurement for health improvement" by the World Health Organisation. Implementation of the framework, i.e., measurement of KPIs, is envisioned to provide evidence to inform the 2028 revision of the EU HTAR.

Keywords:  EUHTA; European access academy; PICO; health policy; health technology assessment; key performance indicators

DOI:  https://doi.org/10.3390/jmahp14010005
Compr Physiol. 2026 Feb;16(1): e70105

The Integrated Stress Response in Cancer: Paradox and Therapeutic Promise.

Chenliang Zhang, Ting Zhang, Qiulin Tang, Yu Zeng, Dan Cao.

  The integrated stress response (ISR) is an evolutionarily conserved signaling pathway that converges diverse cellular stresses onto the eIF2α-ATF4 axis, thereby orchestrating a fundamental decision between adaptive survival and cell death. In cancer, malignant cells exploit the ISR to cope with microenvironmental pressure, yet strong or persistent ISR activation can also trigger apoptosis, highlighting its therapeutic potential. However, this duality complicates the targeting of the ISR for cancer therapy. In this review, we systematically outline the upstream regulators and downstream effector networks of the ISR, analyze its context-dependent functions, encompassing both tumor-promoting and tumor-suppressing activities, in tumorigenesis, immune modulation, and therapy resistance, and evaluate the rationale for targeting the ISR under defined conditions. We also comprehensively summarize and discuss recent advances in ISR-targeting agents, including both inhibitors and activators, under preclinical and clinical development, assessing their potential and current constraints. Although numerous challenges remain in therapeutically harnessing the ISR, we conclude that a deeper mechanistic understanding of how the ISR governs cell fate will further establish the ISR as a promising and actionable target for future cancer therapeutics.

Keywords:  ATF4; apoptosis; drug resistance; eIF2α; integrated stress response; tumor immunotherapy; tumor therapy

DOI:  https://doi.org/10.1002/cph4.70105
Bioeng Transl Med. 2026 Jan;11(1): e70106

Viral vector-based gene therapies in the clinic: An update.

Kyung Soo Park, Yong In Cho, Samir Mitragotri, Zongmin Zhao.

  Gene therapy has advanced considerably in recent years, driven by innovations in vector engineering and a more advanced understanding of virology for clinical translation. Since 2021, the U.S. Food and Drug Administration (FDA) has approved seven new viral vector-based gene therapies, five of which use adeno-associated virus (AAV) vectors, reinforcing their status as the leading platform for in vivo gene delivery. These approvals encompassed hematologic, neuromuscular, dermatologic, and neurogenetic diseases, using diverse serotypes and delivery routes tailored to the therapeutic context. Disease-specific patterns of capsid usage reveal advancement in tailored capsid engineering based on anatomical targeting needs. Beyond AAV, non-AAV vectors, such as herpes simplex virus (HSV) and adenovirus, are actively explored in cancer trials, while lentiviral vectors support applications in oncology and immune-related disorders. This review provides an updated analysis of the clinical landscape of viral vector-based gene therapies, highlighting new FDA-approved products and ongoing clinical trials by vector type, disease indication, and clinical phase since our original review in 2021. Our analysis highlights advances in viral vector technologies that reflect a maturing field, transitioning from proof-of-concept studies to precision platforms increasingly capable of addressing rare monogenic disorders and more prevalent, complex diseases.

Keywords:  adenovirus; adeno‐associated virus; clinical translation; clinical trials; gene; gene therapy; herpes simplex virus; viral vector

DOI:  https://doi.org/10.1002/btm2.70106
JMIR Res Protoc. 2026 Jan 22. 15 e78529

Frameworks for Guiding the Selection of Digital Data Collection Tools Used in Clinical Trials: Protocol for a Systematic Review.

Bavatharani Ananthesayanan, Kayode Philip Fadahunsi, Huanhuan Xiong, John O'Donoghue.

   Background: Data collection is an essential aspect of clinical trials because it forms the basis of the scientific analysis that evaluates the performance and safety of interventions. With the wide variety of digital data collection tools available, decision-makers responsible for choosing the appropriate tools for clinical trials must exercise caution. There are numerous challenges that could impact data collection, and a careful selection of tools is necessary to ensure that they effectively support the trial. Therefore, an evidence-based framework is needed to support the selection of an appropriate digital data collection tool in clinical trials.
Objective: This systematic review aims to develop an evidence-based framework for the selection of digital data collection tools for clinical trials.
Methods: Bibliographic databases including IEEE Xplore, eAIS, PubMed, CINAHL, MEDLINE, Embase, ClinicalTrials.gov, Scopus, and Web of Science will be searched for published articles. Additionally, searches will be performed for publicly available gray literature from reputable institutions such as the United States Food and Drug Administration and World Health Organization. Studies should include a framework that is relevant to selecting digital data collection tools for clinical trials. Two reviewers will independently use Covidence to screen and review the articles to be included. Data related to the selection of digital data collection tools will be extracted. Thematic synthesis will be conducted to develop a new evidence-based framework to select digital data collection tools for clinical trials.
Results: The review started in May 2025 and is expected to be completed in December 2025. The searches yielded 9151 studies, which were reduced to 4333 after the removal of duplicates using Covidence.
Conclusions: There is a dearth of established frameworks to guide the selection of digital data collection tools for clinical trials. This review aims to develop an evidence-based framework to support technology decision-makers in identifying and selecting tools that are fit-for-purpose, ensuring they meet the specific needs of clinical research settings.

Keywords:  clinical trials; data collection tool; digital data collection; digital health technology; framework; health technology selection

DOI:  https://doi.org/10.2196/78529
Immunology. 2026 Jan 19.

Barriers and Strategies to Enhance CAR-T Cell Infiltration in Solid Tumours: A Systematic Review.

Yan Zhang, Huihui Sun, Lianfeng Zhao, Ningning Zhao, Zhengliang Chen, Lingfeng He, Zhigang Guo, Jun Yu.

  Chimeric antigen receptor T (CAR-T) cell therapy has revolutionised the treatment of hematologic malignancies, achieving durable and robust responses. However, the application of CAR-T cells in solid tumours remains limited by a complex network of barriers, most notably poor tumour infiltration. The key obstacles include mismatch between chemokines and receptors, abnormal tumour vasculature, immunosuppressive cellular populations (such as myeloid-derived suppressor cells, tumour-associated macrophages and regulatory T cells), dense network of cancer-associated fibroblasts and extracellular matrix, T cell dysfunction and exhaustion, metabolic limitations within the tumour microenvironment, tumour heterogeneity and transport limitations related to tumour location. By integrating mechanistic insights with innovative bioengineering and combination approaches, this review systematically elaborates on the factors that limit the infiltration of CAR-T cells and emphasises transformation strategies for improving the efficacy, durability and invasiveness of treating solid tumours.

Keywords:  CAR‐T cell therapy; tumour infiltration; tumour microenvironment

DOI:  https://doi.org/10.1111/imm.70094
Cell Transplant. 2026 Jan-Dec;35:35 9636897251409473

Research progress and application prospect of engineered small extracellular vesicles.

Haoyu Zhang, Jian Chen, Xijie Tang, Xiangzhong Liu, Zhanghua Li.

  Extracellular vesicles (Evs) act as a natural intercellular message transmitter, Evs can carry proteins, ribonucleic acid (RNA) and other bioactive substances, and have rich biological regulatory functions. Because of its low immunogenicity and high biocompatibility, it has become a popular research object in drug delivery. These remarkable properties also create new opportunities for modern therapy. However, due to the complex preparation process, there are challenges in terms of targeting accuracy, load release controllability, and pharmacokinetic optimization, and many problems may be encountered in reality. Based on real-life biomedical experiments, this paper summarizes the methods and types of Evs loading drugs, membrane modification methods, and the use of biological materials to improve the release efficiency, so as to provide reference for future research on engineered Evs.

Keywords:  Ev engineering; Ev therapy; Evs; drug delivery; exosome

DOI:  https://doi.org/10.1177/09636897251409473
Eur J Public Health. 2026 Jan 12. pii: ckaf262. [Epub ahead of print]

Mapping the regulatory landscape for environmental sustainability of medical device practices within the European Union.

Marianna Zarro, Alessia Ferranti, Giulia Garagozzo, Giuseppe Fico, Leandro Pecchia.

Regulatory frameworks that integrate environmental sustainability into the lifecycle of medical devices (MDs) are essential to ensure quality, safety, and effectiveness for patients while minimizing environmental impact. The Medical Device Regulation 2017/745/EC (MDR) establishes the core framework for MDs, but additional EU legislation addresses Ecodesign, sustainable packaging, financial incentives, and waste management. Although sustainability is not explicitly included in the MDR, understanding how complementary EU regulations contribute to the European Green Deal agenda is crucial to inform decisionmakers and guide future integration of sustainability principles into medical device governance. We employed a validated policy mapping methodology, derived from the scoping review approach and adapted to systematically identify and analyse regulatory documents from policy repositories rather than academic databases. This method has been previously applied in diverse policy domains, including health, education, and digital innovation. Findings were reported according to the PRISMA-ScR. Eight binding regulations that are either directly applicable or transferable to MDs in the European Union were identified. Together, they introduce requirements on Ecodesign, packaging, financial incentives, and waste management. These complement the MDR framework by embedding sustainability principles into various stages of the MD lifecycle, even though they are not explicitly mandated within the MDR itself. While environmental sustainability provisions remain absent from the MDR, complementary EU regulations create an emerging framework that supports systemic economic transformation in line with the European Green Deal. Future research should examine enforcement and practical implementation of this framework across Member States to assess its impact on medical device regulation and environmental performance.

DOI: https://doi.org/10.1093/eurpub/ckaf262
J Diabetes Metab Disord. 2026 Jun;25(1): 37

Possibilities and challenges of next-generation therapeutics: solid lipid nanoparticles revolutionizing metabolic disorder treatment.

Sameer Iqbal, Hammad Ahmed, Faiza Rafique, Muhammad Farooq, Sharjeel Adnan.

   Purpose: Metabolic disorders (obesity, diabetes mellitus, hyperlipidemia) represent a major and escalating global health burden. Conventional pharmacological therapies face limitations, including poor bioavailability, systemic side effects, and reduced patient compliance. This review explores the potential of solid lipid nanoparticles (SLNs) as an advanced drug delivery system to overcome these limitations and improve the management of metabolic disorders.
Methods: The approach involves utilizing SLNs, leveraging their unique physicochemical properties (nanoscale size, biocompatibility, encapsulation capability for both hydrophilic and lipophilic drugs). This enables improved drug solubility, controlled/sustained release, and targeted delivery to specific tissues. SLNs are investigated for delivering agents like antidiabetics, antihyperlipidemics, and anti-obesity drugs, with a focus on overcoming biological barriers (e.g., gastrointestinal tract, blood-brain barrier).
Results: SLNs demonstrate significant promise for metabolic disorder therapeutics. Key outcomes include enhanced pharmacokinetics and pharmacodynamics of encapsulated drugs, improved solubility, controlled and sustained release profiles, targeted delivery reducing systemic toxicity, and improved ability to penetrate critical biological barriers, thereby expanding treatment options and potentially enhancing therapeutic efficacy.
Conclusion: SLN represents scientific research in the therapeutic approach to obesity, diabetes, and hyperlipidemia. The recent advances offer a highly promising strategy to address the limitations of conventional therapies for metabolic disorders, enhancing drug delivery and targeting while minimizing adverse effects. Despite challenges in drug loading capacity, long-term stability, scalable production, and regulatory pathways, ongoing advancements in nanotechnology. While the path to clinical widespread adoption requires overcoming manufacturing and regulatory obstacles, the continued evolution of SLN technology is poised to play a central role in building the next generation of targeted, effective, and patient-personalized treatment strategies.

Keywords:  Adipokine signaling; Metabolic disorders; Nanostructured lipid carriers; Nanotechnology; Obesity; Oral insulin delivery; PPARγ; Receptor-mediated endocytosis; Therapeutic outcomes

DOI:  https://doi.org/10.1007/s40200-025-01827-x
JAMA Oncol. 2026 Jan 22.

Cost-Effectiveness of Adjuvant Immunotherapy in Cancer Treatments: A Systematic Review.

Rashidul Alam Mahumud, Yifu Chen, Md Shahjalal, Padam Kanta Dahal, Khorshed Alam.

Importance: Adjuvant immunotherapy is increasingly integrated into cancer care to reduce recurrence and improve survival. However, its high cost raises critical concerns regarding affordability and economic value across diverse health system contexts.
Objective: To synthesize published economic evaluations of adjuvant immunotherapy and assess cost-effectiveness outcomes, quality-adjusted life-year (QALY)/life-year (LY) gains, and methodologic approaches.
Evidence Review: A systematic search was conducted of PubMed, Scopus, Embase, and Web of Science for full economic evaluations published between January 1, 2015, and January 31, 2025. Eligible studies included cost-effectiveness or cost-utility analyses of adjuvant immunotherapy across any cancer type. Data were extracted on cancer type, treatment strategy (single vs combination therapy), treatment line, model structure, health utility instruments, funding sources, and cost-effectiveness outcomes. Methodologic quality was appraised using the Criteria for Health Economic Quality Evaluation 2023. Due to heterogeneity of health systems, findings were narratively synthesized.
Findings: The analysis included 69 studies covering a range of cancer types, most frequently non-small cell lung cancer and melanoma. Of these, 46 (67%) evaluated first-line therapy with single-agent checkpoint inhibitors. Higher QALY/LY gains were consistently reported among the adjuvant immunotherapy group (63 [91%]), particularly for non-small cell lung cancer, industry-funded studies, and combination regimens. More than half of the evaluations (40 [58%]) concluded that adjuvant immunotherapy was cost-effective, although results varied by cancer type, model assumptions, drug pricing, funding organizations, and country-specific thresholds. Markov modeling was the dominant analytic approach (46 [67%]) and EuroQol 5 Dimensions was the most commonly used health utility instrument (56 [81%]).
Conclusions and Relevance: This systematic review found that adjuvant immunotherapy was frequently associated with meaningful QALY/LY improvements and was often considered cost-effective in high-risk or first-line settings. However, economic value remains context-specific, shaped by treatment strategy, drug costs, and modeling assumptions. These findings support the selective, value-based adoption of adjuvant immunotherapy and underscore the need for transparent, standardized economic evaluations to guide reimbursement and policy decisions.

DOI: https://doi.org/10.1001/jamaoncol.2025.6080