bims-carter 2026-05-10 papers

bims-carter

Biomed News

on CAR-T Therapies

Issue of 2026–05–10
forty papers selected by
Luca Bolliger, lxBio

PSCA CAR Vδ1 T cells: a safer off-the-shelf CAR T therapy for pancreatic cancer?
Adapter-based allogeneic CAR T cells to overcome antigen escape in solid tumors.
CAR-engineering of innate and innate-like immune cells: a new horizon in adoptive cell therapy for solid tumors.
Overcoming T cell exhaustion and senescence in CAR T cell therapy for solid tumors.
CAR T cell therapy shows promise for treatment of stiff person syndrome.
When tumor contact reshapes CAR-T cells.
Regulatory T cell therapies: biological foundations, engineering strategies, and clinical translation.
Advances in cell therapy for solid tumours: European perspective and future directions.
Genetic Code Expanded T Cell for Controllable Immunotherapy.
Nanotechnology-enhanced CAR-T therapy strategies in cancer, aging, and autoimmune diseases.
Lipid nanoparticle mRNA delivery preserves CAR T cell cytotoxicity and limits exhaustion compared to electroporation.
Editorial: Novel chimeric antigen receptor (CAR) designs in engineering NK cells for cancer.
Targeting CAR-T cell exhaustion in non-Hodgkin lymphoma: mechanistic insights and emerging clinical strategies.
Non-viral in vivo cell and gene therapies: A change journey for CMC science and scientists.
Trust and trade: patient perspectives on the ethics of real-world data monetisation.
Competencies for Health Technology Assessment Professionals: A Scoping Review and Content Analysis.
Advances in Cell Therapy for Chronic Graft-versus-Host Disease: Prophylactic and Therapeutic Perspectives.
Next-generation cancer immunotherapy: the promise of CAR T-Cell therapy.
Precision Immunotherapy: Revolutionizing Cancer Treatment With Targeted Innovations.
Digital health reimbursement: A scoping review of global lessons and policy implications.
Editorial: Community Series in Engineered Immune Cells in Cancer Immunotherapy (EICCI), volume II.
Payer and Manufacturer Agreements for High-Cost Therapy: A Narrative Review.
A call for action to strengthen stakeholder readiness for ICF data exchange in European health data space: a structured narrative review.
Rewiring the immune response in lung cancer: current progress in bispecific antibodies, CAR-T therapy, and the rise of in vivo CAR-T platforms.
Modulation of Gut Microbiota Through Dietary Fibers to Enhance Regulatory T Cell-Based Immunotherapy in GVHD Following Hematopoietic Stem Cell Transplantation.
2025 Advancing Cell and Gene Therapies for Cancer post-meeting report.
Advancing hepatocyte-based therapies: A translational perspective.
BCMA-directed CAR-T cell therapy in relapsed/refractory multiple myeloma: efficacy, safety, survival, and future directions - A systematic review and meta-analysis.
Recent advances in chemokine-directed strategies to improve CAR-T cell infiltration into solid tumors.
Antigen spreading mediates heterogeneous solid tumor eradication by DNA demethylating agent-programmed CAR T cells.
Dual CAR-T cell therapy targeting CD19 and BCMA as a novel opportunity for immune reset in systemic lupus erythematosus.
High-throughput screening to engineer optimal T cell therapies: current knowledge and future prospects.
Remodeling memory T cells with chemotherapy and immune checkpoint inhibitors as host pre-conditioning to empower in vivo CAR-T therapy.
Fully Anonymized Digital Health Data Acquisition in a Research Partnership Using a Blinded Deidentification Proxy in the HerzFit App: Implementation Study.
Longitudinal real-world surveillance of infection outcomes in CAR-T and bispecific therapy recipients: the CLARITY study protocol.
NeoTCRseek: an integrated platform for high-sensitivity identification of neoantigen-specific TCR clonotypes to track clinical T-cell dynamics.
A retrospective pharmacovigilance analysis based on the FAERS database reveals sex-associated differences in toxicities of CAR T-cell therapy.
Evolution of bispecific and multispecific antibodies in cancer therapy.
HLA incompatibility mitigation strategies in off-the-shelf cancer immunotherapies: clinical implications and a practical framework for strategy selection and combination.
B-cell Maturation Antigen Targeted Chimeric Antigen Receptor T-cell Therapy for Refractory Systemic Lupus Erythematosus and Systemic Sclerosis.

J Immunother Cancer. 2026 May 08. pii: e014088. [Epub ahead of print]14(5):

PSCA CAR Vδ1 T cells: a safer off-the-shelf CAR T therapy for pancreatic cancer?

Joseph A Fraietta, Jason J Lohmueller.

  Pancreatic cancer remains among the deadliest malignancies, with a 5-year survival of ~13%. Chimeric antigen receptor (CAR) T -cell therapy offers hope, but conventional αβ T cells can trigger severe toxicities, including graft-versus-host disease (GvHD) when used for allogeneic therapy. By contrast, γδ T cells recognize tumors without MHCmajor histocompatibility complex restriction and are unlikely to cause GvHD, making them attractive candidates for "off-the-shelf" immunotherapy. Li et al engineered the Vδ1 subset of γδ T cells with a CAR targeting prostate stem cell antigen (PSCA) and compared these cells to CAR-engineered Vδ2 γδ and conventional αβ T cells in preclinical pancreatic cancer models. All three groups showed comparable tumor killing efficacy, but the CAR Vδ1 T cells induced none of the GvHD or systemic toxicity seen with CAR αβ T cells. They also displayed lower exhaustion than CAR Vδ2 cells, suggesting potential for greater persistence. Vδ1 CAR T cells could be expanded robustly ex vivo and remained highly potent even after cryopreservation, a key "off-the-shelf" requirement. These findings position CAR Vδ1 T cells as a safer alternative to traditional CAR T cells. Future rigorous clinical evaluation will be needed to confirm superior safety and efficacy of this promising approach in patients.

Keywords:  Chimeric antigen receptor - CAR; Gastrointestinal Cancer; Graft versus host disease - GVHD; Immunotherapy; T cell

DOI:  https://doi.org/10.1136/jitc-2025-014088
Front Immunol. 2026 ;17 1822583

Adapter-based allogeneic CAR T cells to overcome antigen escape in solid tumors.

Phuc Q Pham, Quaovi H Sodji.

  Monospecific Chimeric Antigen Receptor (CAR) T cell therapy against hematological malignancies targeting specific tumor-associated antigen (TAA) has gained clinical success in recent years. Despite their clinical outcomes, challenges including antigen escape, time and labor-intensive manufacturing process, and diminished efficacy especially against solid tumors persist. While allogeneic monospecific "off-the-shelf" CAR T cell therapy from healthy donors with knockout of alloreactive genes using gene editing tools such as CRISPR/Cas9 or TALEN has been evaluated to overcome manufacturing challenges, these allogeneic CAR T cells still face antigen escape. As such, adapter-based CAR T cells that can be redirected by small-molecule adapters to target multiple TAAs have emerged as an alternative therapeutic platform to overcome antigen escape. However, autologous adapter-based CAR T cell manufacturing remains time and labor intensive and scales poorly. Furthermore, chemotherapy-induced T cell dysfunction may compromise both manufacturing and efficacy of autologous CAR T cells. In this comprehensive review, we highlight advantages and limitations of the adapter-based CAR T platform and discuss how allogeneic manufacturing can be applied to adapter-based CAR T as a potential "off-the-shelf" therapeutic for treating multiple cancer types and overcome antigen escape.

Keywords:  CAR T cell therapy; CRISPR/Cas9; T cell receptor; allogeneic cell therapy; antigen escape; tumor-associated antigen

DOI:  https://doi.org/10.3389/fimmu.2026.1822583
J Immunother Cancer. 2026 May 04. pii: e014592. [Epub ahead of print]14(5):

CAR-engineering of innate and innate-like immune cells: a new horizon in adoptive cell therapy for solid tumors.

Giuseppe Nardo, Francesca Putti, Alice Indini, Michele Del Vecchio, Filippo De Braud, Massimo Di Nicola, Francesca De Santis.

   BACKGROUND: Chimeric antigen receptor (CAR) therapies have revolutionized cancer immunotherapy, particularly in hematologic malignancies, but their efficacy in solid tumors remains limited. Key barriers include tumor antigen heterogeneity, on-target/off-tumor toxicity, impaired trafficking, and an immunosuppressive tumor microenvironment.
METHODS: We conducted a narrative review of preclinical and clinical studies investigating CAR-engineered innate and innate-like immune cells, including CAR-natural killer, CAR-γδ T, CAR-natural killer T (NKT), and CAR-macrophages, focusing on their biological features, therapeutic potential, and current clinical development in solid tumors.
RESULTS: These alternative platforms exhibit distinct advantages over conventional CAR-T cells, including reduced risk of severe toxicities, improved trafficking, overcoming antigen loss, and higher allogeneic potential. Emerging clinical data suggest favorable safety profiles, although limited persistence and variable efficacy remain key challenges. Advances in cell engineering, such as cytokine armoring and non-viral gene transfer, are further enhancing their therapeutic potential.
CONCLUSIONS: CAR-engineered innate and innate-like immune cells represent a promising next-generation strategy to overcome the limitations of conventional CAR-T therapies in solid tumors. Among these, CAR-NKT and CAR-γδ T cells may offer particular advantages for clinical translation, warranting further investigation in future trials.

Keywords:  Adoptive cell therapy - ACT; Chimeric antigen receptor - CAR; Macrophage; NKT Cells; Natural killer - NK

DOI:  https://doi.org/10.1136/jitc-2025-014592
Clin Transl Oncol. 2026 May 07.

Overcoming T cell exhaustion and senescence in CAR T cell therapy for solid tumors.

Ignacio Pérez-Criado, Mariona Figols, Ainhoa Moya-Sevilla, Ana Bautista, Daniela Gómez-Díaz, Albert Font, Juan Martin-Liberal, Vicenç Ruiz de Porras.

  Chimeric antigen receptor (CAR) T cell therapies have demonstrated remarkable efficacy in hematologic malignancies; however, their clinical benefit in solid tumors remains limited. A major barrier is T cell dysfunction, particularly exhaustion and senescence, which impair persistence, effector function, and durable tumor control. Targeting these dysfunctional states is therefore essential in order to improve CAR T cell efficacy in solid tumors.This review summarizes recent preclinical strategies aimed at preventing or reversing CAR T cell exhaustion and senescence in solid malignancies. While both exhaustion and senescence are relevant dysfunctional states, the preclinical evidence summarized in this review is currently more extensive for modulation of exhaustion-associated programs than for direct reversal of canonical T cell senescence. Approaches are organized according to their primary mechanistic focus, including gene editing, metabolic modulation, receptor redesign, and remodeling of the tumor microenvironment.Across these mechanistic categories, reported benefits include enhanced CAR T cell persistence, reduced expression of inhibitory receptors, such as PD-1, LAG-3, and TIM-3, preservation or restoration of memory-like phenotypes, and improved antitumor cytotoxicity. Notably, combinatorial strategies targeting multiple dysfunction pathways consistently demonstrate superior efficacy in preclinical models. Despite these advances, important translational challenges remain, including the limited predictive value of current preclinical systems, potential safety concerns, and the manufacturing complexity associated with increasingly engineered cell products.Collectively, preclinical evidence supports the rational integration of complementary approaches to generate next-generation CAR T cells capable of resisting dysfunction and maintaining activity within immunosuppressive solid tumor microenvironments. Further validation in clinically relevant models will be critical to facilitate translation into safe and durable cancer immunotherapies.

Keywords:  CAR T cell therapy; Senescence; Solid tumors; T cell exhaustion

DOI:  https://doi.org/10.1007/s12094-026-04383-9
Nat Rev Neurol. 2026 May 06.

CAR T cell therapy shows promise for treatment of stiff person syndrome.

Heather Wood.

DOI: https://doi.org/10.1038/s41582-026-01220-z
J Exp Med. 2026 Jun 01. pii: e20260645. [Epub ahead of print]223(6):

When tumor contact reshapes CAR-T cells.

Sangwoo Park, Marcela V Maus.

Repeated tumor contact leaves more behind than simple CAR-T exhaustion. This study by Gu et al. (https://doi.org/10.1084/jem.20252564) shows that chronic antigen exposure impairs a Rab5-dependent endocytic program, allowing trogocytosed antigen to accumulate, functional CAR to decline, and fratricide to increase.

DOI: https://doi.org/10.1084/jem.20260645
Front Immunol. 2026 ;17 1797186

Regulatory T cell therapies: biological foundations, engineering strategies, and clinical translation.

Charleen Plaisse, Séverine Bézie, Carole Guillonneau.

  Regulatory T cell (Treg) therapy has emerged as a promising strategy to control pathological immune responses in autoimmunity, graft-versus-host disease, and solid organ transplantation. Most clinical studies to date have relied on autologous Tregs expanded ex vivo, an approach that has demonstrated safety and feasibility but remains limited by variable cell quality, restricted scalability, and complex manufacturing requirements. To address these constraints, multiple alternative strategies are being developed, including the induction of regulatory phenotypes in conventional T cells, the engineering of antigen-specific Tregs, and the generation of allogeneic "off-the-shelf" regulatory cell products. In parallel, induced pluripotent stem cells (iPSCs) offer a renewable and standardized source for regulatory T cell generation, enabling extensive genetic engineering and batch consistency. Early-phase clinical trials with CD4+ Tregs have established an excellent safety profile, and initial clinical evaluation of CD8+ Tregs is now underway. This review provides a comprehensive and comparative analysis of the biological principles, engineering strategies, and translational challenges that shape the development of regulatory T cell-based immunotherapies.

Keywords:  CD4+ and CD8+ T cells; allogeneic immunotherapy; cell engineering; cell therapy; immune tolerance; induced pluripotent stem cells; regulatory T cells

DOI:  https://doi.org/10.3389/fimmu.2026.1797186
Lancet Reg Health Eur. 2026 May;64 101590

Advances in cell therapy for solid tumours: European perspective and future directions.

Victor Moreno, Fiona Thistlethwaite, Ramón Yarza, Willemijn S Tak, Kok Haw Jonathan Lim, John B A G Haanen.

  Cell therapy has revolutionised the landscape of cancer treatment, with therapies such as Chimeric Antigen Receptor T cells (CAR-T cells), showing remarkable efficacy in haematological malignancies, and approaches such as Tumour Infiltrating Lymphocytes (TILs) and T-cell receptor-engineered T cells (TCR-T) showing increasing promise in solid tumours. The recent US FDA approvals of lifileucel (a TIL therapy for advanced melanoma) and afamitresgene autoleucel (a TCR therapy targeting MAGE-A4 in synovial sarcoma) mark the first regulatory recognition of cell therapies for solid tumours and signal a new era for oncology. Europe has played a central role in these advances, leading pivotal phase 3 trials and pioneering hospital-exemption-based manufacturing programmes. However, the continent still faces major challenges, including fragmented regulatory frameworks, high manufacturing costs, and inequitable patient access across member states. Emerging innovations such as gene-edited, allogeneic, and iPSC-derived cell products promise to address current limitations by improving scalability, safety, and time-to-treatment. This Series paper examines the latest advancements in cell therapy, focussing on the European experience, while comparing global trends. We discuss challenges specific to Europe, such as regulatory frameworks, manufacturing scalability, and disparities in access. Emphasis is placed on emerging innovations like gene-edited and allogeneic therapies, as well as future directions for integrating cell therapies into mainstream oncology. We conclude with recommendations for overcoming barriers related to cost, toxicity management, and equitable access across Europe.

Keywords:  Advanced therapy medicinal products (ATMPs); Cell therapy; Chimeric antigen receptor T cells (CAR-T); European Medicines Agency (EMA); Gene; Immunotherapy; Solid tumors; T-cell receptor therapy (TCR-T); Tumor infiltrating lymphocytes (TILs)

DOI:  https://doi.org/10.1016/j.lanepe.2026.101590
Adv Sci (Weinh). 2026 May 04. e75501

Genetic Code Expanded T Cell for Controllable Immunotherapy.

Xue Wang, Yingao Gao, Yeyu Su, Yong Wang, Tao Liu.

  Chimeric antigen receptor (CAR)-T cell therapy has demonstrated curative potential against hematologic malignancies, but its clinical application remains constrained by the risk of uncontrolled immune activation. To address this, we engineered a translational control system for CAR expression based on Genetic Code Expansion (GCE), enabling tight, dose-dependent, and function-preserving regulation through nonsense codon suppression via noncanonical amino acids (ncAAs). By introducing amber stop codons into CAR constructs and engineered aminoacyl-tRNA synthetase and tRNA pair, we developed a leak-free regulatory module applicable in both Jurkat and primary human T cells. NcAA-treated GCE-CAR-T cells exhibited antigen-specific cytotoxicity and cytokine secretion comparable to wild-type CAR-T cells. In a xenograft mouse model, tumor-specific immune responses were observed only upon ncAA administration, with untreated controls showing no therapeutic effect. This work establishes a stringent, fast-acting translational switch that enables precise modulation of CAR-T cell function without compromising efficacy, offering a promising platform for next-generation programmable cell therapies.

Keywords:  T cells; chimeric antigen receptors (CARs); genetic code expansion (GCE); immunotherapies; noncanonical amino acids (ncAAs)

DOI:  https://doi.org/10.1002/advs.75501
J Hematol Oncol. 2026 May 08.

Nanotechnology-enhanced CAR-T therapy strategies in cancer, aging, and autoimmune diseases.

Hongjia Li, Jinxin Li, Xiting Liu, Xueju Wei, Xin Zeng, Qiwei Wang, Yingli Han, He Huang, Pengxu Qian.

  Chimeric antigen receptor T-cell (CAR-T) therapy has emerged as a transformative immunotherapy, which achieves remarkable success in hematological malignancies. However, broader application of CAR-T therapy is hindered by multiple challenges, including limited efficacy in solid tumors, antigen escape, severe toxicities, and complex, costly manufacturing. Recent studies have emerged that nanotechnology offers innovative solutions to overcome barriers. In this review, we summarized how nanotechnology enhances CAR-T therapy across six dimensions: CAR design, transfection, expansion, modification, monitoring, and combination with other therapies. We discussed the applications of various nanomaterials to improve CAR-T cell function, including lipid nanoparticles, nanogels, and nanobodies. Specifically, we recapitulate that nanotechnology facilitates the generation of CAR-T cells in vivo, enables spatiotemporal control of T cells, remodels the immunosuppressive microenvironment in solid tumors, and enables dual-targeting strategies to mitigate antigen escape. Finally, we outlined the clinical application of nanotechnology in hematological malignancies and solid tumors, as well as non-malignant senescence and autoimmune diseases. Collectively, we believe the integration of nanotechnology enhances the safety and efficacy and broadens therapeutic scope, which will open a new era of precision medicine.

Keywords:  Autoimmune diseases; CAR-T; In vivo CAR-T; Nanotechnology; Solid tumors

DOI:  https://doi.org/10.1186/s13045-026-01805-7
Mol Ther Nucleic Acids. 2026 Jun 16. 37(2): 102929

Lipid nanoparticle mRNA delivery preserves CAR T cell cytotoxicity and limits exhaustion compared to electroporation.

Samira Picht, Martí Farrera-Sal, Anna L Hiller, Sophia Brumhard, Antonia M Klaas, Sarah Schulenberg, Rebecca Friedrich, Cedric Scholz, Lisa Hemmerling, David N Simon, Gerhard Krönke, Chantal Pichon, Leif E Sander, Hans-Dieter Volk, Manfred Gossen, Michael Schmueck-Henneresse, Norman M Drzeniek.

  Chimeric antigen receptor (CAR) T cells offer a promising strategy for the treatment of autoimmune diseases. However, clinical translation is limited by the high cost, complexity, and poor scalability of current manufacturing, restricting broad patient access and persisting safety concerns including insertional mutagenesis risk from integrating vectors and uncontrolled long-term CAR T cell persistence. In-vitro-transcribed (IVT) mRNA enables transient, non-integrating CAR expression with improved safety and scalability, making it particularly suited for non-malignant indications where prolonged persistence may not be required. Here, we systematically compare two IVT mRNA delivery platforms, electroporation and lipid nanoparticles (LNPs), for transient CAR T cell engineering in primary human T cells using single-cell transcriptomics and functional cell assays. We show that electroporation yields higher transfection efficiency and more sustained CAR surface expression, whereas LNP delivery reduces stress- and senescence-related transcriptional signatures as well as exhaustion marker expression, while enhancing antigen-driven activation, chemotactic responses, and cytotoxic function. Our comparative analysis highlights that the mode of mRNA delivery is associated with distinct transcriptional signatures and functional properties of CAR T cells, providing a framework to guide future development of mRNA-based approaches. These insights support LNP-mediated delivery as a functionally favorable strategy for transient CAR T cell engineering in autoimmune disease and beyond.

Keywords:  CAR t cells; MT: delivery strategies; autoimmune disease; chemotaxis; exhaustion markers; lipid nanoparticles; mRNA electroporation; multiplexed engineering; transient gene expression

DOI:  https://doi.org/10.1016/j.omtn.2026.102929
Front Immunol. 2026 ;17 1823184

Editorial: Novel chimeric antigen receptor (CAR) designs in engineering NK cells for cancer.

Wing Keung Chan.



Keywords:  CAR-NK cell therapy; CAR-iNKT cells; CAR-macrophage; NK cell; NKG2D (Natural killer group 2 member D); car-t; immunotherapy; tumor micro environment (TME)

DOI:  https://doi.org/10.3389/fimmu.2026.1823184
Front Immunol. 2026 ;17 1727926

Targeting CAR-T cell exhaustion in non-Hodgkin lymphoma: mechanistic insights and emerging clinical strategies.

Anirudh Rao, Christina Darwish, Kerry S Campbell, Rashmi Khanal, Henry Fung, Anthony Stack.

  Although the response rates to chimeric antigen receptor T (CAR-T) therapy in patients with treatment-resistant lymphoma are high, the majority of patients relapse. CAR-T cell exhaustion, characterized by the progressive loss of T-cell effector functions due to several molecular and epigenetic pathways, is a major mediator of CAR-T cell failure. Strategies to prevent CAR-T cell exhaustion, including modifications to the CAR structure, addition of adjunctive agents, and alternative product manufacturing strategies have shown promise. In this review, we discuss the mechanisms of CAR-T cell exhaustion and describe strategies for its mitigation, with the aim of supporting further research in this critical area.

Keywords:  B-cell malignancies; CAR-T; T-cell exhaustion (Tex); immunotherapy; non-Hodgkin lymphoma

DOI:  https://doi.org/10.3389/fimmu.2026.1727926
J Pharm Sci. 2026 May 01. pii: S0022-3549(26)00161-9. [Epub ahead of print] 104312

Non-viral in vivo cell and gene therapies: A change journey for CMC science and scientists.

Annette Bak, Marianne Ashford.

  The CMC (Chemistry Manufacturing and Controls) landscape is rapidly evolving as pharmaceutical science shifts from traditional small molecules and peptides towards non-viral in vivo cell and gene therapies. The article highlights the skills required including hybrid scientific roles spanning chemistry, biology, drug delivery, formulation and analytical development. They are essential to deliver clinical non-viral in vivo cell and gene therapy products. In addition, organizational structures that are best suited for these new therapies are discussed. To frame the discussion on skills, we briefly start out by summarizing the increased modality complexity in terms of multicomponent LNPs (lipid nanoparticles), including novel excipients, new product manufacturing methods, complex analytical requirements, and a regulatory framework that is still developing. Finally, it is highlighted how non-viral in vivo cell and gene therapies will have clinical and patient access advantages. We hope to provide inspiration for scientists on a similar journey and demonstrate that expanding your skills, knowledge and science is a worthwhile undertaking to aid in developing the differentiated medicines of the future.

Keywords:  Cell and Gene Therapies; Chemistry Manufacturing and Controls; In Vivo

DOI:  https://doi.org/10.1016/j.xphs.2026.104312
Front Health Serv. 2026 ;6 1771744

Trust and trade: patient perspectives on the ethics of real-world data monetisation.

Alexandros Sagkriotis.

  Real-world data (RWD) and real-world evidence (RWE) are increasingly used to inform regulatory decisions, health technology assessment, and health system planning. However, patients whose data underpin these activities often experience limited transparency or benefit when their information is monetised. While regulatory and HTA frameworks emphasise methodological rigor and analytical transparency, they provide limited guidance on fairness, reciprocity, and legitimacy from a patient perspective. This Policy Brief examines this governance gap and argues that evidence integrity must extend beyond technical standards to include ethical stewardship and public trust. Drawing on policy contexts from UK, EU, and North America, it proposes five pragmatic safeguards to strengthen transparency, accountability, and patient-centred governance in secondary data use, supporting the sustainability and legitimacy of RWE infrastructures as data initiatives expand.

Keywords:  consent; data monetisation; ethics; evidence integrity; governance; patient trust; real-world data (RWD); real-world evidence (RWE)

DOI:  https://doi.org/10.3389/frhs.2026.1771744
Int J Technol Assess Health Care. 2026 May 07. 1-21

Competencies for Health Technology Assessment Professionals: A Scoping Review and Content Analysis.

Liza van Mun, Wietske Kievit, Wija Oortwijn.

DOI: https://doi.org/10.1017/S0266462326103808
Clin Exp Med. 2026 May 05.

Advances in Cell Therapy for Chronic Graft-versus-Host Disease: Prophylactic and Therapeutic Perspectives.

Zahra Taghinejad, Nahid Moradi, Athar Talebi, Leila Jafari, Hadis Soleimanzadeh, Amir Ali Hamidieh.

  Chronic graft-versus-host disease (cGvHD) can affect about 70% of people who undergo allogeneic hematopoietic stem cell transplantation (allo-HSCT). This condition is characterized by a complex immune dysregulation that leads to persistent inflammation and fibrosis. These complications can lead to long-term health issues that significantly affect the quality of life after HSCT. Conventional therapies such as corticosteroids and broad immunosuppressants are partially effective and have significant toxicity. They also fail to reverse established fibrotic damage. Advances in targeted pharmacological agents, including Bruton's tyrosine kinase inhibitors and JAK inhibitors, show improved outcomes for steroid-refractory cGvHD. However, their high costs and variable responses highlight the unmet need for more effective approaches. Cell-based therapies have emerged as promising strategies to modulate pathogenic immune responses and prevent or even treat cGvHD. Mesenchymal stromal cells (MSCs), regulatory T cells (Tregs), natural killer (NK) cells, and chimeric antigen receptor (CAR) T cells are being investigated for their immunoregulatory potential in preclinical and clinical trials, and they are considered a safer, more effective, and targeted approach to managing cGvHD. MSC-derived cytokines and exosomes can suppress Th17 cells and promote the generation of IL-10-expressing Tregs. This dual action helps reduce inflammation and tissue fibrosis associated with the cGvHD. Tregs and NK cells also help rebalance immune responses and suppress alloreactivity through different mechanisms. This review highlights underlying mechanisms, clinical efficacy, and challenges in translating these therapies into routine clinical practice. Additionally, it suggests that future trials should incorporate patient stratification based on cGvHD phases and phase-relevant biomarkers for managing disease progression more precisely.

Keywords:  Cell-based Therapy; Chronic GvHD; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Mesenchymal Stromal Cells; Regulatory T-Lymphocytes

DOI:  https://doi.org/10.1007/s10238-026-02120-8
Immunotherapy. 2026 May 04. 1-22

Next-generation cancer immunotherapy: the promise of CAR T-Cell therapy.

Harshad S Kapare, Rutuja Jadhav, Pawan N Karwa, Ritesh P Bhole, Sonali Labhade.

  Chimeric antigen receptor (CAR) T-cell treatment has developed among major substantial improvements for modern cancer treatment, providing sustained responses in patients with otherwise resistant blood cancers. This method comprises of patients reprogramming or donor's T lymphocytes to interpret tumor associated antigens self-sufficiently of major histocompatibility multifaceted presentation, thereby circumventing a key limitation of natural immune surveillance. The approval of CD19- and BCMA-targeted therapies demonstrated remarkable clinical impact and validated the approach. Over successive generations, CAR constructs have been refined with additional costimulatory elements, cytokine support, and multifunctional signaling domains, improving both their persistence and therapeutic activity. Despite such progress, important challenges remain, including risks of relapse, toxicity including neurotoxicity and cytokine release syndrome with limited efficacy in solid tumors. Current research is focused on strategies, such as armored CARs, gene editing, and combination therapies to expand clinical benefit. A comprehensive literature search was conducted using PubMed, Scopus, and Web of Science databases, covering publications from 2000 to 2026 till date. Relevant peer-reviewed articles were selected based on their relevance to CAR T-cell therapy, including preclinical and clinical studies. Detailed search strategy, inclusion criteria, and screening methods are described in the main manuscript. This review explores the evolution, applications, and future outlook of CAR T-cell rehabilitation.

Keywords:  Chimeric antigen receptor (CAR) T-cell therapy; antigen escape; cancer immunotherapy; clinical trials; cytokine release syndrome (CRS); hematologic malignancies

DOI:  https://doi.org/10.1080/1750743X.2026.2668205
Am Soc Clin Oncol Educ Book. 2026 Jun;46(3): e517508

Precision Immunotherapy: Revolutionizing Cancer Treatment With Targeted Innovations.

Myung-Ju Ahn, Bernadett Szabados, Will Ince, Jinyong Kim, Bo Mi Ku, Bridget P Keenan.

While immune checkpoint inhibitors have transformed treatment for many cancers, their benefit remains limited across all tumor types and is constrained by immune-related toxicity. Targeted immunotherapies, including T-cell engagers (TCEs), offer a more selective strategy by directing immune activity toward tumor-associated antigens. TCEs have achieved major success in hematologic malignancies and now show promise in selected solid tumors, with the approvals of tebentafusp and tarlatamab in uveal melanoma and small cell lung cancer, respectively, establishing proof of concept that durable benefit is possible. However, TCE efficacy is balanced by class-specific toxicities such as cytokine release syndrome and neurotoxicity, as well as on-target off-tumor effects. Antibody-drug conjugates (ADCs) can also enhance the specificity of cancer treatment by directing cytotoxic activity toward tumor cells via specific targets. ADC-checkpoint inhibitor combinations are similarly reshaping solid tumor therapy, most notably in urothelial carcinoma, where enfortumab vedotin plus pembrolizumab has demonstrated substantial survival gains. Across both strategies, efficacy may be influenced by antigen density, tumor heterogeneity, microenvironmental suppression, and treatment sequencing. Emerging drug engineering approaches and biomarker-driven patient selection aim to improve efficacy while limiting toxicity. Together, these advances support a new era of precision immuno-oncology, but broader success will require improved biomarkers, rational combinations, and an understanding of resistance mechanisms.

DOI: https://doi.org/10.1200/EDBK-26-517508
Digit Health. 2026 Jan-Dec;12:12 20552076261432044

Digital health reimbursement: A scoping review of global lessons and policy implications.

Reza Rabiei, Sohrab Almasi.

   Background: Digital health technologies have expanded access to healthcare services by improving disease management and reducing unnecessary hospitalizations. A major challenge, however, is designing appropriate reimbursement mechanisms for these technologies. Ensuring such mechanisms not only leverages their benefits but also maintains the financial sustainability of health systems.
Objective: This study aimed to identify reimbursement processes, classification methods, assessment frameworks and criteria used, pricing mechanisms, organizations involved in the digital health reimbursement process, and the technologies covered by health insurance in selected countries from each continent (Europe, North America, and Asia).
Methods: This study followed the Joanna Briggs Institute (JBI) framework. A systematic search was conducted in Web of Science, Scopus, PubMed, and grey literature sources (e.g. government reports and health organization websites), with no language restrictions, from 1 January 2000 to 9 February 2025. Data extraction focused on reimbursement processes, classification approaches, evaluation criteria, pricing mechanisms, key stakeholders, and insured digital health technologies.
Conclusion: Developing transparent reimbursement frameworks, coordinating stakeholders, and integrating digital technologies into insurance systems are essential. Learning from successful frameworks-such as Germany's DiGA, telemedicine in the USA and Canada, and China's digital health policies-can enhance equitable access and financial sustainability. Establishing digital health technology assessment (DHTA) guidelines, investing in digital health literacy and infrastructure, and implementing supportive regulatory policies are critical prerequisites.

Keywords:  Reimbursement; digital health; scoping review; telehealth; telemedicine

DOI:  https://doi.org/10.1177/20552076261432044
Front Immunol. 2026 ;17 1833581

Editorial: Community Series in Engineered Immune Cells in Cancer Immunotherapy (EICCI), volume II.

Axel Schambach, Francisco Martin, Cristina Maccalli.



Keywords:  adoptive cell therapy (ACT); allogeneic cell therapies; chimeric antigen receptor; gene editing; tumor-associated antigens

DOI:  https://doi.org/10.3389/fimmu.2026.1833581
J Pharm Pract. 2026 May 05. 8971900261450720

Payer and Manufacturer Agreements for High-Cost Therapy: A Narrative Review.

Vishwanauth Persaud, Albert Wertheimer.

  Between 2022 and 2025, several ultra-high-cost, one-time therapies were approved in the United States, offering potentially curative options for conditions such as spinal muscular atrophy, hemophilia, and sickle cell disease. Despite their clinical value, upfront costs often exceeding $2-4 million create major challenges for payers, especially Medicaid programs with fixed budgets. Traditional reimbursement models, designed for chronic therapies, may not align with the long-term benefits and financial risks of these treatments. This has led to growing interest in alternative payment models, including outcomes-based agreements, installment payments, and risk-sharing contracts. However, adoption remains inconsistent due to regulatory barriers, administrative complexity, and limited long-term data. A narrative literature review was conducted to evaluate U.S. pricing strategies and manufacturer-payer payment models for ultra-high-cost, one-time therapies. Peer-reviewed and grey literature were identified through searches of PubMed, Embase, and Google Scholar, along with policy and regulatory sources. Publications from 2010 to 2025 were included and synthesized to categorize payment models and identify implementation challenges. Manufacturers used diverse pricing approaches rather than a single model. Outcomes-based agreements were more common when clinical endpoints were measurable, while other therapies relied on lump-sum payments with support programs. Adoption varied based on therapy characteristics and payer preferences, with limited standardization across stakeholders. These therapies are financed through a mix of traditional and alternative models, but regulatory and operational barriers continue to limit widespread adoption.

Keywords:  cell and gene therapy; market access; value-based payment

DOI:  https://doi.org/10.1177/08971900261450720
Front Public Health. 2026 ;14 1786004

A call for action to strengthen stakeholder readiness for ICF data exchange in European health data space: a structured narrative review.

Linda Nieminen, Heidi Anttila, Harri Ketamo, Mauro Zampolini, Andrea Martinuzzi, Vincenzo Della Mea.

   Background: The European Health Data Space (EHDS) regulation introduces a transformative framework for the exchange of health data among EU stakeholders. Among its interoperability measures is the inclusion of the International Classification of Functioning, Disability and Health (ICF) as a standard for documenting functioning in patient summaries and discharge reports. While ICF offers a biopsychosocial lens to complement disease-centric classifications, the availability of interoperable ICF data remains uneven.
Objective: This structured narrative review examines the readiness of EU stakeholders to exchange and utilize ICF data within EHDS. It explores current practices from the data availability and technical infrastructure perspectives, discusses influencing factors such as legislative frameworks and socio-ethical conditions, identifies gaps, and proposes actionable recommendations for the future.
Methods: Given the limited data available on this topic, a structured narrative review was performed, including a structured literature search from five databases. Additionally, targeted searches were performed in policy repositories and institutional sources. The search included documents written in English, Finnish, and Italian, and the study objective defined the scope for the literature search. Documents were analyzed to synthesize contextual information across stakeholders, identify gaps, and gain strategic insights.
Results: In total, 78 studies and gray literature references are discussed in the synthesis. The available evidence on ICF data infrastructures across EU stakeholders reveals significant disparities. Many countries lack standardized EHR support for structured ICF data storage. There is a need to include and map the ICF to international key terminologies and health informatics frameworks to ensure semantic interoperability. Low professional awareness further hinders data availability. Unequal digital literacy and limited citizen empowerment compromise efficient use of ICF. To address these gaps, a three-phase roadmap is proposed: (1) promoting ICF awareness and structured documentation, (2) advancing technical integration through FHIR and ontology development, and (3) aligning policy and governance to support scaling.
Conclusion: Integrating the ICF into EHDS is not merely a technical task; it redefines how health is conceived and measured. By addressing readiness across data, technical, legal, and socio-ethical dimensions, the EU can unlock the full potential of functioning data to improve the well-being of its citizens.

Keywords:  health information systems; health policy; information dissemination; international classification of functioning, disability, and health; interoperability

DOI:  https://doi.org/10.3389/fpubh.2026.1786004
Front Immunol. 2026 ;17 1772428

Rewiring the immune response in lung cancer: current progress in bispecific antibodies, CAR-T therapy, and the rise of in vivo CAR-T platforms.

Lei He, Yi Sun, Bowen Ma, Guojun Lang, Jianguo Wen, George R Blumenschein, Hong Ma.

  Lung cancer remains the leading cause of cancer mortality worldwide and continues to impose a major clinical burden, particularly in advanced non-small cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). Although targeted therapies, antiangiogenic agents, immune checkpoint inhibitors, and antibody-drug conjugates have improved outcomes in selected patients, durable responses remain limited by primary and acquired resistance. Here, we comprehensively review recent progress in immunologically oriented therapeutic strategies for lung cancer, focusing on bispecific antibodies, chimeric antigen receptor (CAR) T-cell therapy, and emerging in vivo CAR-engineering modalities. We further elaborate on the clinical rationale, latest translational and early clinical evidence, and key challenges, including on-target, off-tumor toxicity, cytokine release syndrome, limited T-cell persistence, insufficient tumor trafficking, and immunosuppression within the tumor microenvironment. Taken together, we find that while bispecific antibodies currently show favorable efficacy and safety in lung cancer; advances in CAR design and in vivo delivery may broaden the applicability of CAR-T therapy in this setting.

Keywords:  CAR T-cell therapy; bispecific antibody; in vivo CAR programming; lung cancer; mRNA; non–small cell lung cancer; small cell lung cancer

DOI:  https://doi.org/10.3389/fimmu.2026.1772428
Nutrients. 2026 Apr 12. pii: 1216. [Epub ahead of print]18(8):

Modulation of Gut Microbiota Through Dietary Fibers to Enhance Regulatory T Cell-Based Immunotherapy in GVHD Following Hematopoietic Stem Cell Transplantation.

Melika Asayesh, Ata Nazarzadeh, Sanaz Jamshidi, Shayan Keramat, Ireneusz Ryszkiel, Agata Stanek.

  Graft-versus-host disease (GVHD) is one of the principal complications seen in the recipients of allogenic hematopoietic stem cell transplantation (allo-HSCT), and persists as a leading cause of post-transplant morbidity and mortality. Increasing evidence highlights the crucial influence of the gut microbiome (GM) on transplant outcomes. Microbial dysbiosis, characterized by reduced bacterial diversity and pathogenic overgrowth, is strongly associated with higher rates of complications and mortality. Patients with lower microbial diversity exhibit poorer overall survival (OS) and an increased incidence of acute GVHD (aGVHD). Conversely, restoration of beneficial commensal communities has been shown to enhance immune homeostasis, mitigate GVHD severity, and decrease infection risk. Emerging therapeutic strategies now focus on modulating the intestinal microbiome through dietary interventions, probiotics, prebiotics, and fecal microbiota transplantation (FMT). It has been demonstrated that bacterial metabolites, such as short-chain fatty acids (SCFAs) from the diet, especially a diet rich in fibers, reduce the occurrence/severity of GVHD by inducing regulatory T cells (Tregs), which release anti-inflammatory cytokines and regulate the host immune system. Hence, the implementation of dietary fibers (DFs) could increase beneficial commensals, Treg induction, and improve outcomes such as GVHD and OS in recipients of allo-HCT. Hereupon, this review addresses how a fiber-rich diet modulates GM composition, reinforces epithelial barrier integrity, and improves the efficacy of Treg-based immunotherapy by stabilizing their regulatory phenotype and increasing their functional persistence, ultimately leading to a reduction in GI complications associated with GVHD. Unlike prior reviews that primarily cover the microbiome-GVHD axis or Treg therapies in isolation, this review emphasizes fermentable dietary fibers as a mechanistically grounded, clinically actionable strategy to support Treg stability and persistence via microbiota-derived metabolites. We integrate mechanistic evidence with emerging clinical feasibility data and ongoing trials of prebiotic supplementation in allogeneic HSCT.

Keywords:  allogenic hematopoietic stem cell transplantation; dietary fiber; graft-versus-host disease; intestinal microbiota; regulatory T cells; short-chain fatty acids

DOI:  https://doi.org/10.3390/nu18081216
Mol Ther. 2026 May 06. pii: S1525-0016(26)00283-2. [Epub ahead of print]34(5): 2524-2526

2025 Advancing Cell and Gene Therapies for Cancer post-meeting report.

Paola Grandi, Maria G Castro, Evanthia Galanis, Michael C Milone, Saad Kenderian.

DOI: https://doi.org/10.1016/j.ymthe.2026.04.017
Cell Stem Cell. 2026 May 07. pii: S1934-5909(26)00147-5. [Epub ahead of print]33(5): 726-746

Advancing hepatocyte-based therapies: A translational perspective.

Zhen Sun, Ludi Zhang, Lijian Hui.

  Hepatocyte-based therapies represent a promising alternative to liver transplantation, yet their clinical translation is constrained by the limited availability of functional cells and inefficient engraftment. Here, we review progress in the field from a translational perspective, focusing on strategies to overcome these core challenges. We analyze emerging cell sources derived from stem cell technologies and assess their therapeutic potential. These translational efforts are organized around two clinical paradigms: hepatocyte replacement for long-term functional correction and temporary hepatocyte support for liver failure. Beyond hepatocytes, we also discuss preclinical and translational advances involving other liver cell types. To conclude, we outline critical gaps that need to be addressed for clinical translation, including scalable good manufacturing practice (GMP)-compliant manufacturing, efficient preconditioning regimens, long-term immune compatibility with non-invasive graft monitoring, and patient stratification for optimal clinical outcomes. We also discuss how hepatocyte-based therapies can complement gene/RNA therapies and xenotransplantation to broaden treatment options for liver diseases.

Keywords:  hepatocyte production; hepatocyte-based cell therapies; liver regenerative medicine; translational perspective

DOI:  https://doi.org/10.1016/j.stem.2026.04.007
Curr Probl Cancer. 2026 May 01. pii: S0147-0272(26)00035-8. [Epub ahead of print] 101301

BCMA-directed CAR-T cell therapy in relapsed/refractory multiple myeloma: efficacy, safety, survival, and future directions - A systematic review and meta-analysis.

Muhammad Shaheer Mannan, Adeena Musheer, Muhammad Waqas Khan, Hur Abbas, Sheikh Abdul Qadir Jillani, Ali Shan Hafeez.

   BACKGROUND: Multiple myeloma is an incurable hematologic malignancy, although therapeutic advances have improved survival. BCMA-directed CAR-T cell therapy has shown high response rates in relapsed or refractory multiple myeloma (RRMM), but efficacy and toxicity vary across trials. A rigorous synthesis of current evidence is needed to better define these outcomes.
METHODS: We performed a systematic review and meta-analysis of prospective interventional trials published from inception to January 2026 evaluating BCMA-targeted CAR-T therapies in adults with RRMM. Trials reporting efficacy or safety outcomes were included. Pooled estimates with 95% confidence intervals (CI) were calculated in R. Heterogeneity was assessed using the I² statistic, publication bias with Egger's regression, and stability with leave-one-out sensitivity analysis.
RESULTS: Fourteen clinical trials including 1,278 patients with RRMM and a median of 3 to 8 prior lines of therapy were included1-4. The pooled overall response rate (ORR) was 86% (95% CI: 80-90%; I² = 75.9%). Grade ≥ 3 immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 3% of patients (95% CI: 2-4%; I² = 0%). Discontinuation due to toxicity occurred in 4% (95% CI: 1-9%; I² = 68.2%), and treatment-related mortality in 5% (95% CI: 3-9%; I² = 64%). Additional efficacy and safety outcomes, including disease control rate and grade ≥ 3 hematologic toxicities, were also assessed.
CONCLUSION: BCMA-directed CAR-T cell therapy demonstrates high efficacy in RRMM with a low incidence of severe neurotoxicity. However, severe hematologic toxicities are frequent and treatment-related mortality remains clinically relevant, highlighting the need for optimized patient selection and toxicity mitigation.

Keywords:  Anti-BCMA CAR-T therapy; B-cell maturation antigen; CAR-T therapy; Cellular therapy; Multiple myeloma

DOI:  https://doi.org/10.1016/j.currproblcancer.2026.101301
Int Immunopharmacol. 2026 May 04. pii: S1567-5769(26)00629-6. [Epub ahead of print]181 116783

Recent advances in chemokine-directed strategies to improve CAR-T cell infiltration into solid tumors.

Jinhui Hu.

  Limited infiltration of CAR-T cells into solid tumors remains a major obstacle to their therapeutic efficacy. Strategies to enhance tumor penetration-such as stromal matrix degradation, induction of tissue-resident memory CAR-T cells, and intratumoral delivery-have shown potential, yet achieving CAR-T cells infiltration comparable to that of conventional T cells may offer the greatest promise. Chemokine-receptor interactions are central to this process, but their expression is often dysregulated within tumors, leading to mismatched signaling and impaired CAR-T trafficking. Recent studies targeting chemokine and receptor pathways in either CAR-T cells or the tumor microenvironment have demonstrated encouraging results in preclinical and early clinical settings. Although existing reviews touch on these approaches but often do briefly or incompletely as part of broader discussions of CAR-T therapy. Here, we provided a specifically focused review about chemokine/receptor modulation to enhance CAR-T cells infiltration and antitumor activity, structured according to chemokine classification based on structural characteristics. Multiple chemokine-receptor axes could improve CAR-T cell infiltration and anti-tumor activity. The strategies to establish chemokine-receptor gradient include engineering chemokines or receptors directly into CAR constructs, modulating chemokines or receptors expression through culture additives, co-infusing chemokine-secreting antigen-presenting cells, stimulating chemokines production via physical or pharmacologic agents, and delivering directly chemokines or receptors into tumor microenvironment using oncolytic viruses, etc. This review outlines key advances and offers insight into the rational design of next-generation CAR-T therapies targeting solid tumors.

Keywords:  Adoptive cell transfer; CAR-T; Chemokine; Chemokine receptor; Immune cell infiltration; Solid tumor

DOI:  https://doi.org/10.1016/j.intimp.2026.116783
Sci Adv. 2026 May 08. 12(19): eadz4088

Antigen spreading mediates heterogeneous solid tumor eradication by DNA demethylating agent-programmed CAR T cells.

Yelei Guo, Chuan Tong, Jianshu Wei, Zhiqiang Wu, Yuting Lu, Fuxin Han, Yipeng Zhang, Chunmeng Wang, Jinhong Shi, Fengxia Shi, Yao Wang, Weidong Han.

Antigen heterogeneity substantially limits the efficacy of chimeric antigen receptor-modified T (CAR T) cell therapy against solid tumors. Our study highlights the potent antitumor activity of low-dose decitabine-primed CAR T (dCAR T) cells in solid tumor models, a benefit previously confirmed in hematologic malignancies. Notably, dCAR T cell infusion in immunocompetent mice led to substantial elimination of mixed tumor masses containing both antigen-positive and antigen-negative cells, without the need for prior lymphodepletion. Our analysis showed notable proinflammatory remodeling of the tumor immunosuppressive microenvironment. Crucially, antigen-activated dCAR T cells sustained high levels of interferon-γ production, which induced immunogenic cell death in tumor cells and activated conventional dendritic cells. This, in turn, stimulated endogenous CD8+ T cells, enhancing their antigen-spreading capacity and aiding in the clearance of abscopal antigen-negative tumors. These findings reveal the robust antigen-spreading capability of dCAR T cells, underscoring their clinical potential in addressing solid tumors with inherent antigen heterogeneity.

DOI: https://doi.org/10.1126/sciadv.adz4088
Cell Mol Immunol. 2026 May 06.

Dual CAR-T cell therapy targeting CD19 and BCMA as a novel opportunity for immune reset in systemic lupus erythematosus.

Sascha Haubner, Michel Sadelain.

DOI: https://doi.org/10.1038/s41423-026-01403-0
Front Oncol. 2026 ;16 1787786

High-throughput screening to engineer optimal T cell therapies: current knowledge and future prospects.

Lei Liu, Saisai Chen, Meng Ding, Yuqing Duan, Lingling Pu, Liang Li, Hui Peng, Qingsheng Yu.

  Adoptive T cell therapy (ACT) is a potent strategy in cancer immunotherapy, but its clinical efficacy is often limited by primary resistance. To overcome this challenge, high-throughput screening technologies have emerged as essential tools for optimizing ACT. By enabling the identification of biologically significant targets and substances from vast libraries, these technologies have accelerated the development of advanced ACT strategies. This review delves into the latest advancements in high-throughput screening, highlighting its applications in genetic screening of T cells and tumor cells, as well as non-genetic screening for small molecules and targeted delivery systems. These insights provide valuable guidance for future research and clinical applications of ACT.

Keywords:  CRISPR screening; TCR-T cells; adoptive T cell therapies; cells; genetic screening; high-throughput screening; non-genetic screening

DOI:  https://doi.org/10.3389/fonc.2026.1787786
Synth Syst Biotechnol. 2026 Dec;14 155-170

Remodeling memory T cells with chemotherapy and immune checkpoint inhibitors as host pre-conditioning to empower in vivo CAR-T therapy.

Ding-Ya Sun, Jia-Lu Wang, Xin Li, Shan Wang.

  Chemotherapy and immune checkpoint inhibitors (ICIs) are widely utilized in cancer treatment, exerting not only direct cytotoxic effects on tumor cells but also significantly reshaping the systemic immune status of patients, particularly the composition and function of the T cell repertoire. This review begins with the analysis of the widespread depletion and dysfunction of early T cell subsets in cancer patients, particularly naïve T cells (Tn) and stem-like memory T cells (Tscm). Afterward, it details how chemotherapy and ICIs differentially regulate T cell homeostasis, including their ability to induce T cell exhaustion and differentiation skewing, as well as their ability to stimulate immunity and remodel the tumor microenvironment. On this basis, it is shown that the quality of T cell memory phenotypes is central in determining the in vivo expansion and persistence of chimeric antigen receptor T (CAR-T) cells. To overcome the challenges of classical autologous CAR-T therapy, which stems from raw material quality and in vitro manufacturing bottlenecks, we focus on transforming chemotherapy and ICIs from traditional treatment modalities into beneficial "host preconditioning" regimens aimed at optimizing the baseline state of the endogenous T cell repertoire. All in all, this transformation of traditional therapies into host preconditioning strategies, along with recent advances in in vivo CAR-T approaches, provides theoretical grounds and translatable clues to develop next-generation cellular immunotherapy.

Keywords:  Cancer; Chemotherapy; Immune checkpoint inhibitor; In vivo CAR-T; Memory T cell

DOI:  https://doi.org/10.1016/j.synbio.2026.04.012
JMIR Form Res. 2026 May 07. 10 e77983

Fully Anonymized Digital Health Data Acquisition in a Research Partnership Using a Blinded Deidentification Proxy in the HerzFit App: Implementation Study.

Lara Marie Reimer, Leon Nissen, Fabian Starnecker, Olga Stepanova, Florent Dufour, Ruth Ney, Sinann Al Najem, Heribert Schunkert, Stephan M Jonas.

   BACKGROUND: The European General Data Protection Regulation (GDPR) strictly regulates the processing of personal and health-related data, posing challenges for digital health research, especially when data are collected using participants' own devices. Although scientific data can theoretically be anonymized, standard internet communication protocols inevitably expose transmission metadata, preventing true anonymization. Existing solutions, including virtual private networks, reverse proxies, and trust centers, improve confidentiality but do not technically or legally enable fully anonymized data collection. Consequently, large-scale digital health research often requires extensive organizational measures, complex consent procedures, and high regulatory overhead.
OBJECTIVE: This study aimed to develop a GDPR-compliant concept for fully anonymized scientific data collection, ensuring that no entity has simultaneous access to identifying information and donated data. We also implemented and evaluated this concept in a real-world public-private partnership.
METHODS: We designed a data donation architecture based on a blinded deidentification proxy that decouples identifying transmission metadata from encrypted user data at the time of donation. The concept combines symmetric (Advanced Encryption Standard-128 in Cipher Block Chaining) and asymmetric (Rivest-Shamir-Adleman with Optimal Asymmetric Encryption Padding) encryption, enabling end-to-end encrypted and anonymized data transfer without persistent identifiers. The system was integrated into the HerzFit app, a mobile lifestyle coach for cardiovascular disease prevention available in German-speaking countries, and evaluated for adoption, technical feasibility, and performance. Performance overhead was assessed using round-trip time benchmarks. Duplicate donations were identified and merged to estimate unique data donors.
RESULTS: The solution was integrated and tested in the HerzFit app with more than 200,000 downloads between April 2022 and December 2025. Since the introduction of the data donation feature, more than 13,000 donations have been received, translating to more than 9000 individual users contributing anonymized datasets. Proxy-based transmission resulted in an average round-trip time of 143 ms, compared to 58 ms for direct transfer, representing a modest overhead while maintaining usability. The operator of the donation database did not gain access to identifying information at any stage, demonstrating full technical anonymization. The approach can be operated reliably at scale with minimal server resources due to the stateless proxy design.
CONCLUSIONS: This work introduces a novel system architecture enabling fully anonymized, GDPR-compliant data donation directly from participants' devices. By decoupling identifying metadata from encrypted health data, the concept minimizes regulatory effort, strengthens privacy protection, and provides a practical framework for large-scale digital health research in research partnerships, for example, between a private company and a research institution. The real-world deployment in HerzFit demonstrates the feasibility, scalability, and scientific utility of this approach. The concept is broadly transferable to other mobile health apps and has the potential to substantially expand ethically and legally compliant data acquisition.

Keywords:  GDPR; cardiovascular disease; data anonymization; digital health; mHealth; primary prevention

DOI:  https://doi.org/10.2196/77983
BMJ Open. 2026 May 07. 16(5): e111194

Longitudinal real-world surveillance of infection outcomes in CAR-T and bispecific therapy recipients: the CLARITY study protocol.

Gemma K Reynolds, Mary Ann Anderson, Karin Thursky, Benjamin W Teh, Monica A Slavin.

   INTRODUCTION: Infections are a leading cause of non-relapse mortality following chimeric antigen receptor T-cell therapy (CAR-T) and bispecific antibody (BsAb) therapies. However, infection data from clinical trials are often incomplete, lack pathogen-level detail and rarely capture late infectious complications. This CAR-T treatment in Lymphoma: Analysis of Risk of Infection following Therapy (CLARITY) study aims to generate real-world, longitudinal infection data with extended follow-up to characterise infection timing, including late events and inform risk prediction in patients with lymphoma and myeloma receiving novel immunotherapies.
METHODS AND ANALYSIS: CLARITY is a multicentre observational cohort study across six Australian centres enrolling adults treated with CAR-T or BsAb therapies. A co-designed REDCap (Research Electronic Data Capture) instrument captures infections classified as microbiologically defined, clinically defined or fever of unknown origin, using internationally standardised definitions. Patients were enrolled between 2019 and 2023, with at least 2 years follow-up per patient, allowing time-updated data on immunosuppressive exposures, haematological recovery and prophylaxis. Multivariable regression and landmark analyses will estimate infection incidence and identify dynamic risk factors over time. Incidence rate ratios will assess prophylaxis effectiveness. Data integrity is supported by central adjudication and site-level audits.
ETHICS AND DISSEMINATION: The study has received a waiver of consent (HREC/PMCC/89002) and was co-designed by haematology and infectious diseases investigators. Findings will be disseminated through peer-reviewed publications, scientific meetings and national guideline committees to inform infection prevention and late effects surveillance in immunotherapy-treated populations.

Keywords:  Epidemiology; HAEMATOLOGY; Infection control; Lymphoma

DOI:  https://doi.org/10.1136/bmjopen-2025-111194
Front Immunol. 2026 ;17 1674427

NeoTCRseek: an integrated platform for high-sensitivity identification of neoantigen-specific TCR clonotypes to track clinical T-cell dynamics.

Bin Song, Geng Liu, Bo Li, Yong Hou, Leo J Lee.

   Introduction: Identifying neoantigen-specific T-cell receptor (neoTCR) clonotypes is crucial for tracking clinical T-cell dynamics in personalized cancer immunotherapy. Despite advances in experimental and computational approaches for identifying antigen-specific TCR (asTCR) clonotypes, the identification of neoTCR clonotypes remains challenging due to their low frequencies and the limited sensitivity of current methods.
Methods: We introduce NeoTCRseek, an integrated platform that combines extended T-cell culture, deep TCR sequencing, and advanced TCR-clustering tools to enhance neoTCR clonotype identification. NeoTCRseek was developed using a model cytomegalovirus (CMV) antigen and subsequently validated under two neoantigen setups: a single neoantigen and a neoantigen pool representing a multi-antigen context. For each antigen setup, we used three cell sorting-based methods to detect enriched clonotypes and built a validation dataset for asTCR clonotype characterization and NeoTCRseek performance evaluation.
Results: NeoTCR clonotypes exhibited a significantly higher proportion of low-frequency clonotypes (0.01%-0.1%) than CMV-specific ones (70.3% vs. 33.3%). Nonetheless, NeoTCRseek achieved a detection limit of 0.01% and high accuracy in both single- and multi-antigen contexts by integrating expanded clonotype detection with co-clustering-based TCR prediction. Compared with the benchmark, NeoTCRseek improved the mean F1 score across the two neoantigen setups from 0.21 to 0.41.
Conclusion: NeoTCRseek achieves high analytical sensitivity and accuracy in neoTCR clonotype identification and supports multi-antigen analysis, providing an integrated platform for neoTCR clonotype characterization and for tracking clinical T-cell dynamics in personalized cancer immunotherapy.

Keywords:  TCR clustering; TCR sequencing; longitudinal T-cell tracking; low-frequency clonotypes; neoantigen-specific TCR clonotypes; personalized cancer immunotherapy

DOI:  https://doi.org/10.3389/fimmu.2026.1674427
Nat Commun. 2026 May 05.

A retrospective pharmacovigilance analysis based on the FAERS database reveals sex-associated differences in toxicities of CAR T-cell therapy.

Yuan Liu, Jingwen Yang, Madiha Iqbal, Mehmet Uyanik, Mei Luo, Liqi Yang, Yanyan Lou, Lixia Diao, Olalekan O Oluwole, Javid J Moslehi, Douglas B Johnson, Leng Han.

Chimeric antigen receptor (CAR) T-cell therapy has significantly advanced treatment outcomes for hematological malignancies; however, therapy-associated toxicities are often severe and sex-related differences in toxicity remain under-investigated. Here, we extract data from FDA Adverse Event Reporting System (FAERS) to evaluate sex-associated differences in CAR T-cell therapy toxicities. Among 7700 cases, females show higher reporting odds of cytokine release syndrome (CRS), with a reporting odds ratio (ROR) of 1.10 and a confidence interval (CI) of [1.00, 1.20], as well as leukemias (ROR = 1.34; CI [1.05, 1.70]). Elevated reporting odds in females are observed across multiple organ systems. Comparisons across cancer treatments indicate that sex-associated reporting patterns in CAR T-cell therapy cannot be attributed to baseline sex differences across cancer therapies. Stratified analyses further identify heterogeneity by cancer type and CAR T product. These results highlight distinct sex-associated toxicity patterns and may support incorporating sex into toxicity management.

DOI: https://doi.org/10.1038/s41467-026-72816-8
Lancet Reg Health Eur. 2026 May;64 101599

Evolution of bispecific and multispecific antibodies in cancer therapy.

Elisa Fontana, Rafael Grochot, Nuria Kotecki, Bernard Doger, Simon Nannini, María de Miguel.

  Antibody-based cancer therapy has rapidly evolved from monoclonal antibodies to bispecific and multispecific constructs that combine distinct binding specificities and mechanisms. These agents are seeing increasing clinical adoption, with European Medicines Agency approvals in haematological malignancies and selected solid tumours such as uveal melanoma and EGFR-mutant non-small-cell lung cancer. However, they are often still discussed as a single drug class, which does not capture the complexity of current formats and mechanisms, ranging from IgG-like to fragment-based architectures and from immune-cell redirection to dual immune modulation or oncogenic pathway blockade. This Series paper provides an integrated classification framework based on mechanism and format, relating key design features to pharmacology, efficacy, and safety. It synthesizes clinical evidence and ongoing development, discusses practical strategies to mitigate hallmark toxicities, and reviews emerging resistance mechanisms and rational combination approaches. It also outlines next generation directions, including higher order multispecific constructs, conditionally active antibodies, and payload conjugated multispecific formats. To consolidate these agents as an established therapeutic modality in oncology, priority should be given to rigorous understanding of mechanisms of action and toxicity, alongside rational optimisation of construct design and dosing, supported by robust prospective translational programmes.

Keywords:  Antibody; Antigen; Bispecific; CD3; Clinical Trial Phase II; Clinical Trial Phase III; Drug development; Multispecific; Oncology; Phase I Clinical Trial; Target

DOI:  https://doi.org/10.1016/j.lanepe.2026.101599
Front Immunol. 2026 ;17 1803331

HLA incompatibility mitigation strategies in off-the-shelf cancer immunotherapies: clinical implications and a practical framework for strategy selection and combination.

Rajdeep Das, Medhat Askar.



Keywords:  HLA incompatibility; allogeneic cell therapy; cancer immunotherapy; immunogenetics; population-informed matching

DOI:  https://doi.org/10.3389/fimmu.2026.1803331
Arthritis Rheumatol. 2026 May 07.

B-cell Maturation Antigen Targeted Chimeric Antigen Receptor T-cell Therapy for Refractory Systemic Lupus Erythematosus and Systemic Sclerosis.

Shlomit Kfir-Erenfeld, Shlomo Elias, Nathalie Asherie, Hadass Pri Chen, Elena Karger, Miri Assayag, Emilie Bohbot, Rim Elmikawy, Shaheen Alaa, Ahmad Bazbaz, Tal Friedman-Korn, Vered Molho-Pessach, Ada Vaknin, Sigal Grisariu, Batia Avni, Eran Zimran, Nomi Zalcman, Alaa Shehadeh, Aseel Ishtay, Tatyana Dubnikob, Shelly Regev, Rivka Alexander-Shani, Miriam Schlossberg, Shlomit Herr, Stephanie Ben-Shahan, Elina Zorde-Khevalevsky, Marina Krizhevskaya, Daphna Paran, Lior Ravkaie, Cyrille J Cohen, Hagit Peleg, Dror Mevorach, Polina Stepensky, Chamutal Gur.

OBJECTIVE: To evaluate the safety and preliminary efficacy of HBI0101, B-cell maturation antigen-targeted chimeric antigen receptor T-cell therapy, in patients with severe refractory systemic lupus erythematosus or systemic sclerosis.
METHODS: We conducted an ongoing phase 1 trial of HBI0101 in six patients with severe systemic lupus erythematosus (n=3) or systemic sclerosis (n=3). The median age was 41 years (range, 21-65), the median disease duration was 2.7 years (range, 1.1-20.5), and patients had received a median of 3.5 prior lines of immunomodulatory therapy (range, 1- 9). The median follow-up was 6 months (range, 6-9).
RESULTS: Grade 3-4 neutropenia occurred in two patients and was managed with supportive care. Cytokine-release syndrome occurred in five patients (grade 2 in three and grade 1 in two) and was absent in one patient. No immune effector cell associated neurotoxicity syndrome was observed. In systemic lupus erythematosus, SLEDAI-2K decreased to 0 in two patients and to 4 in one patient. In systemic sclerosis, skin involvement improved in all three patients with reductions in modified Rodnan skin score and EUSTAR activity indices.
CONCLUSION: HBI0101 demonstrated an acceptable safety profile and early clinical activity in patients with severe refractory systemic lupus erythematosus or systemic sclerosis, supporting further prospective evaluation.

DOI: https://doi.org/10.1002/art.70211