Search Results (1,076)

T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domains (TIGIT) emerged as one of the most promising next-generation immune checkpoint targets following the success of programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) blockade. TIGIT suppresses antitumor immunity through interaction with cluster of differentiation 155 (CD155), inhibition of CD226-mediated co-stimulation, and promotion of immunosuppressive regulatory T-cell (Treg) activity within the tumor microenvironment (TME). Strong preclinical evidence demonstrated that TIGIT blockade, particularly in combination with PD-1/PD-L1 inhibition, restored T-cell and natural killer (NK) cell function and produced durable antitumor responses in multiple tumor models, leading to rapid clinical development. Despite this compelling biological rationale, most late-stage clinical programs failed to reproduce early success. Although the phase II CITYSCAPE trial showed encouraging activity in PD-L1-high non-small cell lung cancer (NSCLC), subsequent phase III trials, including SKYSCRAPER-01, SKYSCRAPER-02, SKYSCRAPER-03, SKYSCRAPER-14, AdvanTIG-302, KEYVIBE, and STAR-221, failed to improve survival outcomes or meet primary endpoints. The notable exception was SKYSCRAPER-08 in esophageal squamous cell carcinoma, suggesting that TIGIT blockade may be effective only in selected biological contexts. This review critically examines the molecular biology of the TIGIT–CD155–CD226 axis, its role in immune regulation and tumor immune evasion, and the preclinical and clinical evidence supporting TIGIT-targeted therapy. Particular emphasis is placed on understanding the causes of clinical failure, including CD226 loss during T-cell exhaustion, checkpoint network redundancy, Fc-engineering uncertainty, immunosuppressive TMEs, inadequate biomarker-guided patient selection, and tumor-type-specific dependence on the TIGIT pathway. We also present original bioinformatics analyses demonstrating that broader checkpoint network signatures outperform TIGIT expression alone for patient stratification. Finally, we evaluate emerging solutions including biomarker-guided precision immunotherapy, Fc-optimized antibodies, bispecific checkpoint inhibitors, TIGIT-engineered chimeric antigen receptor T-cell (CAR-T) cells, radiotherapy combinations, and multi-checkpoint blockade. Collectively, current evidence suggests that the future of TIGIT-directed therapy lies not in universal checkpoint inhibition but in biologically informed, precision-guided immunotherapy strategies. Full article

Background: Tisagenlecleucel (tis-cel) is the sole chimeric antigen receptor T-cell (CAR-T) therapy approved for pediatric/adolescent relapsed/refractory B-cell acute lymphoblastic leukemia (r/r B-ALL). Infection-related adverse events (IRAEs) represent a leading cause of non-relapse mortality, yet dedicated analysis in patients <18 years remains limited. Objective: This study aimed to analyze the characteristics of IRAEs in pediatric and adolescent patients with r/r B-ALL treated with tis-cel, based on the FDA Adverse Event Reporting System (FAERS) database. The analysis included the reporting proportion, temporal distribution, pathogen spectrum, and overlapping features with other adverse events, generate hypotheses for infection prevention and control in patients aged <18 years. Research Design and Methods: We analyzed FAERS data (August 2017–March 2025) and included 492 cases of <18-year-old r/r B-ALL patients treated with tis-cel. Disproportionality analyses (reporting odds ratio, ROR; information component, IC), time-to-onset analysis, and co-occurrence assessments were performed on 149 infection-related reports. Results: Infection-related AEs occurred in 30.28% of cases, with significantly higher mortality in infected versus non-infected patients (40.27% vs. 12.83%, p < 0.001). Most infections (93.86%) occurred within one month (median time-to-onset = 4 days), peaking within 15 days (77.50%); 2.65% occurred after one year. Significant disproportionate reporting signals were observed for Clostridioides difficile (ROR₀₂₅ = 5.45), influenza virus (ROR₀₂₅ = 7.16), and adenovirus (ROR₀₂₅ = 3.51). Hypogammaglobulinemia (52.94%) and hypoxia (54.90%) exhibited higher co-occurrence with infections than CAR-T-specific toxicities (23.08–35.41%). Conclusions: Infection-related AEs following tis-cel treatment are frequent and associated with significantly increased mortality in pediatric and adolescent r/r B-ALL patients. While most occur early, late infections warrant long-term vigilance. Disproportionality analyses identified signals suggestive of potential high-risk pathogens such as Clostridioides difficile,, influenza, and adenovirus, and hypogammaglobulinemia/hypoxia may serve as early warning indicators. These hypothesis-generating findings require validation in prospective studies. Full article

Background: The treatment paradigm for relapsed/refractory (R/R) large B-cell lymphoma (LBCL) has undergone significant change with the advent of CD19-directed chimeric antigen receptor T-cell (CAR-T) therapies and CD20 × CD3 bispecific antibodies (BsAbs). Although both approaches have shown high response rates in single-arm studies, the absence of prospective randomized head-to-head comparisons has resulted in true clinical equipoise. Methods: A narrative synthesis was conducted, incorporating pivotal and updated phase 2 and 3 trial data, real-world evidence, and published meta-analyses. Results: In the second-line setting, CAR-T therapy demonstrates superior event-free survival, progression-free survival, and overall survival compared to standard-of-care chemo-transplant regimens. In the third-line setting, a pooled meta-analysis indicates significantly higher complete response rates for CAR-T compared with BsAbs, as well as superior 12-month progression-free survival. BsAbs provide immediate availability, greater accessibility, more favorable neurotoxicity profiles, and are feasible for frail or elderly patients. Real-world data show that BsAb complete response rates are consistently lower than those observed in clinical trials, whereas CAR-T real-world effectiveness closely aligns with pivotal trial outcomes. Emerging phase 3 data on fixed-duration and monotherapy bispecific regimens suggest that a genuine, if less mature, curative fraction may also be achievable among BsAb-treated complete responders. Conclusions: CAR-T therapy remains the standard of care for fit, eligible patients with R/R LBCL in second- and third-line settings with curative intent, providing superior depth and durability of response and a growing potential for long-term cure. BsAbs constitute a critical therapeutic alternative for patients ineligible for CAR-T, those with rapidly progressive disease, frail or elderly individuals, and as bridging strategies. A patient-centered, scenario-specific clinical decision framework is recommended. Full article

A single-chain variable fragment (scFv) is an engineered antibody derivative that retains antigen-binding specificity while having a much smaller size than an antibody, improved tissue penetration, and enhanced versatility for genetic manipulation. When an scFv is fused with diverse protein payloads, multifunctional biologics can be created for targeted delivery and therapy. Over the past decade, scFv fusion proteins have gained significant traction in oncology, where they have been incorporated into immunotoxins, immunocytokines, bispecific antibodies, Chimeric Antigen Receptor (CAR)-T cells constructs, and immune cell engagers. In addition, advances in blood–brain barrier (BBB)-targeting strategies have enabled the exploration of scFv-based therapeutics for neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. Despite promising preclinical and clinical outcomes, challenges such as structural instability, short half-life, immunogenicity, and manufacturing complexity remain. This review provides an in-depth and up-to-date overview of scFv fusion protein engineering and its therapeutic applications in cancer and neurodegenerative disorders. We also highlight the clinical translations and design principles of scFv fusion proteins. Full article

Chimeric antigen receptor T-cell (CAR-T) therapy has substantially improved outcomes for patients with B-cell-associated hematological malignancies. While acute and early toxicities are well characterized, late complications (LCs) remain poorly understood. This scoping review aimed to identify and map the existing evidence on LCs in adult patients with hematological malignancies treated with CAR-T products approved by the European Medicines Agency (EMA). PubMed, Web of Science, and the Cochrane Library were searched for primary studies published from 2018 onwards. We included studies of adult patients receiving EMA-approved CAR-T therapies targeting CD19 or CD269. LCs were defined as diagnosis-based adverse events occurring ≥12 months after CAR-T infusion. Of 7715 records identified, 261 studies underwent full-text screening and 18 met the inclusion criteria. LCs clustered mainly as infections and secondary malignancies (SMs). Non-relapse mortality was reported in seven studies, with infections and SMs frequently reported as causes when cause-of-death data were available. Future studies should place emphasis on long-term clinical events after CAR-T therapy to improve the management of LCs and ultimately support better long-term outcomes for patients. Full article

Systemic sclerosis (SSc) is a rare, clinically heterogeneous connective tissue disease defined by the triad of autoimmunity, microvasculopathy, and fibrosis of the skin and internal organs. Among the immune effectors implicated in SSc, B cells have moved from being regarded mainly as the source of disease-defining autoantibodies to being recognized as multifunctional drivers of disease through antibody-independent mechanisms. This review summarizes current understanding of B-cell biology in SSc across three domains. First, we consider the classical role of B cells as antibody-producing cells, including the diagnostic and prognostic value of SSc-specific autoantibodies, the evidence for polyclonal B-cell activation and altered B-cell homeostasis, and the contested question of autoantibody pathogenicity. Second, we examine antibody-independent functions, focusing on cytokine production by effector and regulatory B-cell subsets, the B-cell-activating factor (BAFF) axis, antigen presentation, and T-cell co-stimulation, together with the imbalance between pro-inflammatory effector B cells and interleukin (IL)-10-producing regulatory B cells that characterizes active disease. Third, we review B cells as therapeutic targets, from the rituximab experience—including the randomized DESIRES trial and its open-label extension—through anti-BAFF strategies to the emerging use of CD19-directed chimeric antigen receptor (CAR) T-cell and CAR-natural killer (NK) cell therapies that achieve deep, durable B-cell depletion. We conclude by highlighting unresolved questions, including patient selection, the balance between depleting pathogenic and protective B-cell subsets, biomarker development, and the long-term safety of deep B-cell depletion. A B-cell-centered view of SSc pathogenesis provides a coherent framework that links autoimmunity to fibrosis and is increasingly translatable into the clinic. Full article

Hydrogel-enabled adoptive cell therapy (ACT) offers a localized and controllable strategy for improving cellular immunotherapy in solid tumors. Hydrogels can enhance cell retention and persistence, support immune cell function within the tumor microenvironment, and reduce systemic toxicity associated with broadly delivered immune stimulants. However, delivery of living immune cells imposes practical constraints on hydrogel selection, including cytocompatible encapsulation, minimal handling and injection stress, adequate transport of oxygen and soluble cues, and an appropriate balance between local retention and timely cell egress. This review summarizes natural, synthetic, and hybrid hydrogel platforms and compares physical/supramolecular assembly, covalent and enzymatic crosslinking, and photo-crosslinking. Injectable in situ-forming depots and shear-thinning/self-healing gels are highlighted for locoregional administration. Key design and reporting dimensions of hydrogels are linked to immune cell outcomes relevant to ACT. These properties include mechanics and viscoelasticity, porosity and mass transport, degradability and remodeling, bioadhesion and extracellular matrix (ECM) mimicry, and immunogenicity versus immune shielding. Finally, a cell-type-tailored framework is presented for chimeric antigen receptor T (CAR-T), T cell receptor-engineered T (TCR-T), and tumor-infiltrating lymphocyte (TIL) products, natural killer (NK) cells, and dendritic cells (DCs) or macrophage/monocyte-derived effectors. Distinct biological requirements are used to motivate corresponding material architectures and cue presentation strategies. The review also provides quantitative reporting guidance, identifies evidence gaps for γδ T cells, and discusses in vivo validation, combination ACT strategies, and translational handling constraints. Full article

HER-positive cancers comprise a heterogeneous group of malignancies driven by dysregulated activation of the human epidermal growth factor receptor (HER/ERBB) family. While chimeric antigen receptor (CAR) T-cell therapies targeting HER2 have demonstrated potent anti-tumor capabilities, their clinical translation remains hampered by safety hurdles and antigen escape. We developed a modular “Targeted Chimeric Artificial Reporter” (TcAR) system using the natural epidermal growth factor (EGF)-like binding domains of neuregulin-1 (NRG1) isoforms to decode complex HER dimerization profiles. Leveraging the superior targeting plasticity of the β-isoform, we engineered NRG1β-based CAR-T and CAR-natural killer (NK) cells. Our study demonstrates that NRG1β-directed therapy overcomes therapeutic antigen escape in HER2-depleted models and exerts potent anti-tumor activity within complex three-dimensional (3D) tissue microenvironments ex vivo, exhibiting a significantly safer, muted inflammatory profile compared to clinical standards. Full article

Relapsed and/or refractory follicular lymphoma (R/R FL) remains a therapeutic challenge due to its chronic relapsing course and increasingly complex treatment landscape. Novel therapies, including immunomodulatory combinations, bispecific antibodies (BsAbs), Bruton tyrosine kinase inhibitors, and chimeric antigen receptor (CAR) T-cell therapies, have expanded treatment options and increased the complexity of treatment selection and sequencing. The Canadian Hematology Consensus Group (CHCG) convened a national panel of lymphoma experts to develop evidence-informed consensus recommendations for the management of adults with R/R FL in the Canadian context. Clinical questions informed a structured literature review of studies published through February 2026, including randomized trials, phase II studies, observational data, conference proceedings, and relevant guidelines. Recommendations were developed using a modified Delphi consensus process and graded using a framework adapted from the British Committee for Standards in Haematology. Key recommendations include repeat biopsy to exclude histologic transformation at relapse, individualized treatment selection based on timing of relapse and patient-specific factors, preferential use of lenalidomide-rituximab (LenR)-based triplet combinations in most second-line settings, and incorporation of BsAb and CAR T-cell therapy in third-line and later disease. These recommendations aim to provide practical guidance for Canadian clinicians managing patients with R/R FL. Full article

Chimeric antigen receptor (CAR)-T therapy has achieved partial therapeutic efficacy in solid tumors, but its overall effectiveness remains limited. IL-21-armored CD276.CAR-T (IL21.CD276.CAR-T) represents a promising strategy to enhance anti-tumor activity against esophageal squamous cell carcinoma (ESCC). However, resistance mechanisms remain unclear. We generated IL21.CD276.CAR-T cells and evaluated their cytotoxicity in vitro and in B-NDG xenograft models. Poliovirus receptor (PVR) expression on ESCC cells was analyzed, and shRNA-mediated PVR knockdown was performed to validate its role in resistance. IL-21R expression on ESCC cells was examined to exclude direct IL-21 signaling. IL-21 enhances the cytotoxicity of CD276.CAR-T cells against ESCC. Although IL21.CD276.CAR-T exhibited potent cytotoxicity in vitro, it failed to achieve complete tumor regression, and resistant cells still emerged. Mechanistically, resistance was not caused by CD276 antigen loss or IL-21R expression, but by upregulation of PVR on cancer cell membrane after IL21.CAR-T exposure. PVR knockdown restored CAR-T sensitivity in vitro, enhanced the anti-tumor capacity of IL21.CD276.CAR-T cells, and partially improved anti-tumor efficacy in vivo without systemic toxicity. PVR may act as a mediator of resistance to IL21.CD276.CAR-T in ESCC. Targeting PVR represents a novel strategy to overcome IL21.CAR-T resistance and improve therapeutic outcomes in ESCC. Full article

Extramedullary disease (EMD)—the proliferation of clonal plasma cells in soft tissues without direct bone connection—represents one of the most challenging manifestations of multiple myeloma, associated with aggressive biology, treatment resistance, and poor outcomes. EMD is driven by distinct pathophysiologic mechanisms including downregulation of adhesion molecules, acquisition of high-risk cytogenetic abnormalities (del(17p), gain(1q)), activation of the RAS–MAPK pathway, epigenetic dysregulation such as EZH2 upregulation, and remodeling of the immune microenvironment toward an immunosuppressive, T-cell-depleted phenotype. Conventional therapies, including anti-CD38-based regimens, yield limited efficacy in EMD, with pooled overall response rates of approximately 20% in triple-class-exposed relapsed/refractory disease. T-cell-redirecting therapies have emerged as the most promising treatment strategy. Both chimeric antigen receptor (CAR) T-cell therapy and bispecific antibodies have demonstrated clinically meaningful activity in soft tissue EMD, with CAR T-cell therapy providing the deepest and most durable responses, and dual-targeting bispecific combinations showing particularly encouraging efficacy. Central nervous system (CNS) myeloma, the most devastating form of EMD, has historically carried a dismal prognosis. Emerging retrospective data suggest that both CAR T-cell therapy and bispecific antibodies can achieve meaningful CNS responses with acceptable safety profiles, as part of multimodal approaches incorporating CNS-directed therapies. Despite these advances, EMD remains associated with inferior outcomes even in the immunotherapy era, underscoring the need for strategies targeting the immunosuppressive microenvironment, novel therapeutic approaches, and prospective EMD-focused clinical trials. This review provides a comprehensive overview of the biology, classification, and evolving treatment landscape of both non-CNS and CNS EMD in the era of T-cell-redirecting immunotherapy. Full article

Chimeric antigen receptor (CAR) T-cell therapies have demonstrated remarkable clinical efficacy in hematological malignancies, yet their broader application is constrained by manufacturing complexity and variability, particularly in autologous settings. The development of allogeneic CAR T-cell therapies offers a promising alternative by enabling scalable, “off-the-shelf” production; however, these approaches introduce additional challenges related to donor variability, genome editing, and product consistency. Robust analytical strategies are therefore required to ensure safety, efficacy, and batch-to-batch reproducibility. Conventional analytical methods, such as flow cytometry and enzyme-linked immunosorbent assays, provide targeted, high-confidence measurements of predefined cellular and soluble markers but are inherently limited in their ability to capture the full molecular and functional complexity of CAR T-cell products. In current manufacturing paradigms, these assays are typically deployed as isolated quality control readouts rather than as components of an integrated control strategy that links donor variability, gene-editing material quality, in-process metabolic state, final product critical quality attributes, and clinical biomarker responses. In this context, mass spectrometry (MS) has emerged as a powerful platform for high-dimensional molecular characterization, enabling analysis of gene-editing reagents, proteins, metabolites, lipids, and both culture and spent-media composition across the CAR T-cell manufacturing workflow. In this review, we examine the various applications and tools of MS across key stages of the allogeneic CAR T-cell workflow, including donor characterization, analysis of gene-editing materials, in-process culture monitoring, drug product quality assessment, and post-infusion biomarker evaluation. Collectively, these approaches demonstrate the potential of MS-driven analytics to address current limitations in CAR T-cell manufacturing by improving process understanding, enabling comprehensive quality assessment, and supporting regulatory decision-making. The integration of MS into CAR T-cell workflows may ultimately facilitate the development of more consistent, scalable, and effective cell therapies. Full article

Dysgeusia is a clinically consequential, but still under-standardized, toxicity of cancer treatment. In the immunotherapy era, taste disturbances are increasingly relevant for patients receiving immune checkpoint inhibitors, chimeric antigen receptor (CAR) T-cell therapies and T-cell-redirecting bispecific antibodies, with G protein-coupled receptor family C group 5 member D (GPRC5D)-directed treatment in multiple myeloma representing a particularly instructive high-burden model. We performed a structured critical narrative review with evidence mapping. PubMed/MEDLINE was searched from database inception to June 2026, complemented by citation tracking in Google Scholar, ClinicalTrials.gov searches and guideline documents relevant to oncology nutrition, oral supportive care and cancer-related taste dysfunction. Search concepts covered cancer-related dysgeusia, immunotherapy-associated oral toxicity, GPRC5D/talquetamab-associated dysgeusia, oncology nutrition, oral–gut microbiome biology, natural taste modulators and miraculin-based interventions. Dysgeusia can reduce appetite, food enjoyment, dietary diversity and protein energy intake, thereby contributing to weight loss, malnutrition risk, distress, social withdrawal and, in severe cases, treatment modification or discontinuation. Available evidence is heterogeneous: general cancer-treatment-associated dysgeusia is supported by broader observational and interventional literature; immunotherapy-associated dysgeusia is less systematically characterized; and GPRC5D/talquetamab-associated dysgeusia represents the most clinically visible and target-specific immunotherapy-associated phenotype. Emerging pilot data suggest that dried miracle berry or miraculin-containing products may improve selected taste perception and nutritional parameters in cancer-related dysgeusia, but direct evidence in immunotherapy-associated dysgeusia is not yet established. We, therefore, propose a claim-disciplined precision supportive-care framework integrating systematic taste phenotyping, early nutritional risk assessment, oral health evaluation, microbiome-aware but hypothesis-generating endpoints, individualized flavor and texture adaptation, cautious use of natural taste modulators in selected patients and iterative monitoring of patient-centered outcomes. Future trials should test whether dysgeusia-focused nutritional and taste-modulating supportive care interventions can improve intake, quality of life and treatment persistence without compromising immunotherapy safety or efficacy. Full article

Chimeric antigen receptor (CAR) therapies are emerging as promising strategies, particularly for metastatic castration-resistant prostate cancer (PCa), as they can act independently of the androgen receptor axis. Adapter CAR-T cell platforms, such as the RevCAR system, offer precise therapeutic control and tumor targeting via small, rapidly eliminated tumor-specific adapters. To enable more convenient late-stage RevCAR-T therapy in PCa patients, allowing for discontinuous reverse target module (RevTM) infusion, we developed novel, larger IgG4-based RevTMs targeting prostate stem cell antigen (PSCA) and benchmarked them against previously described smaller adapter formats. Within the RevCAR system, PSCA-IgG4 RevTMs effectively mediated PCa killing at low effector-to-target ratios and low RevTM concentrations in a strictly antigen-dependent manner. Oncolytic activity was accompanied by a rapid and pronounced release of proinflammatory cytokines across a broad RevTM concentration range, which is particularly advantageous for immunologically cold PCa. Finally, anti-tumor activity was confirmed in a short-term mouse model. Preliminary PET studies further indicate slow blood elimination and tumor-specific accumulation of novel IgG4-RevTMs. Together, these data position PSCA-IgG4 RevTMs as promising candidates for stepwise RevCAR-T treatment in PCa, in which short-lived scFv-RevTMs are initially used to ensure a rapid safety switch, followed by larger IgG4-RevTMs once the risk profile is known. Full article

Chimeric antigen receptor (CAR)-T cell therapy has demonstrated remarkable efficacy in hematologic malignancies; however, durable responses remain limited by tumor microenvironment (TME)-mediated immunosuppression. Galectin-3 (Gal-3), a β-galactoside-binding lectin enriched in the TME, contributes to CAR-T cell dysfunction by impairing cytotoxicity, promoting apoptosis, and altering cellular signaling. While we previously demonstrated that enforced expression of the α2,6 sialyltransferase ST6GAL1 reduces galectin binding and improves CAR-T cell function, the mechanistic basis underlying this protection remains unclear. Here, we report that Gal-3 induced a hypometabolic state in CAR-T cells characterized by reduced mitochondrial function, ATP production, and glucose utilization. In contrast, ST6GAL1-overexpressing CAR-T cells preserved metabolic fitness and functional resilience under Gal-3 stress. Additionally, Gal-3 rewired cytokine signaling by increasing IL-5 expression and dysregulating downstream pathways, whereas enforced ST6GAL1 expressing CAR-T cells exhibited increased SOCS1 and SOCS3 expression and attenuated STAT5 activation. Transcriptomic analysis of CAR-T cells from diffuse large B-cell lymphoma patients further revealed enrichment of STAT5-associated signaling and SOCS1 expression in complete responders compared to partial responders. Collectively, these findings identify glycoengineering as a promising strategy to enhance CAR-T cell persistence and function under Gal-3-mediated immunosuppressive stress. Full article