Search Results (1,338)

Background: Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of select hematologic malignancies and is increasingly being explored for non-oncological indications, including autoimmune diseases and persistent infectious diseases. This systematic review synthesized current evidence on CAR T cell and CAR-Treg approaches beyond oncology, with emphasis on therapeutic targets, translational and clinical outcomes, safety, and implementation barriers. Methods: The review followed PRISMA 2020 guidelines. PubMed/MEDLINE, Scopus, Web of Science, Cochrane Library, ClinicalTrials.gov, and major trial registries were searched for studies published from 1 January 2010 to 31 March 2026. Eligible studies included clinical, preclinical, and translational investigations of CAR T cell or CAR-Treg strategies in autoimmune or infectious diseases. Results: Because of heterogeneity in disease indications, CAR constructs, endpoints, and study designs, findings were synthesized descriptively. The strongest early clinical signals were observed with B cell-directed CAR T cell therapy for severe, refractory autoimmune diseases, particularly systemic lupus erythematosus, systemic sclerosis, and inflammatory myopathies. Infectious disease applications, mainly HIV and hepatitis B, showed preliminary safety, persistence, and partial antiviral activity, but durable pathogen eradication remains unproven. Conclusion: Overall, CAR T cell therapy beyond oncology is promising but remains preliminary, requiring standardized reporting, long-term safety monitoring, scalable manufacturing, and carefully defined risk–benefit thresholds. Human clinical evidence was interpreted separately from preclinical and mechanistic evidence, and clinical conclusions were based primarily on human studies. Full article

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment landscape of relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL), non-Hodgkin lymphoma (NHL), and multiple myeloma (MM); however, a substantial proportion of patients eventually experience disease relapse despite an initial response. This review provides a brief overview of CAR-T cell therapy, including its manufacturing process and associated toxicities, before examining the biological mechanisms underlying post-CAR-T relapse in B-ALL, NHL—particularly large B-cell lymphoma (LBCL)—and MM. We critically review current and emerging strategies to prevent and manage relapse. Strategies for relapse prevention primarily include consolidation approaches, such as allogeneic hematopoietic stem cell transplantation (allo-HSCT), maintenance with targeted agents (e.g., tyrosine kinase inhibitors in Philadelphia chromosome-positive B-ALL), and CAR-T cell reinfusion, whereas relapse management is disease-specific and increasingly incorporates novel therapeutic agents, including bispecific antibodies (BsAbs) and other targeted therapies. However, current evidence remains largely preliminary and is limited by the paucity of randomized prospective trials. Full article

The intestinal microbiome has emerged as a clinically significant modulator of outcomes across multiple domains of cancer care. In hematopoietic stem cell transplantation (HSCT), loss of microbial diversity and depletion of short-chain fatty acid-producing commensals are independently associated with graft-versus-host disease (GvHD), bloodstream infections, transplant-related mortality, and overall survival. Mechanistic studies have identified interconnected pathways—including butyrate-mediated epithelial protection, tryptophan-derived aryl hydrocarbon receptor signaling, bile acid metabolism, and Paneth cell–intestinal stem cell interactions—through which microbial communities regulate intestinal barrier integrity and immune homeostasis. These insights have provided the biological rationale for therapeutic strategies aimed at restoring microbial ecology. Fecal microbiota transplantation (FMT) has demonstrated promising clinical activity in steroid-refractory acute GvHD, with one meta-analysis reporting a pooled clinical remission rate of 64% (95% CI, 51–77%) across prospective single-arm studies, and proprietary live biotherapeutic products (LBPs) such as MaaT013 met the primary endpoint of the single-arm phase III ARES trial, achieving a day-28 gastrointestinal overall response rate of 62%; however, the CHMP adopted a negative opinion on its conditional marketing authorization application in June 2026, citing limitations of the single-arm design, and a re-examination is pending. In parallel, gut microbiome composition has been associated with immune checkpoint inhibitor (ICI) response, and early-phase FMT studies suggest that microbiome modulation may restore sensitivity to anti-PD-1 therapy in some patients with refractory melanoma and may enhance treatment responses in first-line ICI settings; however, these findings derive primarily from small, uncontrolled or early-phase studies. Defined single-strain approaches, notably Clostridium butyricum MIYAIRI 588 (CBM588), have shown encouraging secondary clinical efficacy signals in two small, randomized phase I trials in metastatic renal cell carcinoma, including significantly prolonged progression-free survival in one trial and a higher objective response rate in another; however, neither trial met its prespecified primary microbiome endpoint of increased Bifidobacterium spp. abundance. Emerging evidence further links antibiotic-induced dysbiosis to impaired chimeric antigen receptor T-cell (CAR-T) therapy outcomes, while short-chain fatty acids have been identified as direct enhancers of CAR-T cell effector function. This review synthesizes the current evidence for microbiome-based therapeutics across HSCT, GvHD, ICI therapy, CAR-T cell therapy, and infection prevention, and addresses cross-cutting translational challenges including antibiotic stewardship, donor selection, safety in immunocompromised populations, and pharmacomicrobiomics. While randomized controlled trial data remain limited and many approaches are investigational, the convergence of mechanistic, observational, and early interventional evidence positions microbiome restoration as a promising frontier in precision oncology. Full article

Autoimmune diseases encompass nearly 100 distinct conditions characterized by dysregulated immune responses against self-antigens, resulting in tissue damage, chronic inflammation, and substantial morbidity. Over recent decades, the global burden of autoimmune diseases has increased, while their therapeutic management has undergone a paradigm shift from broad, nonspecific immunosuppression toward targeted biologic therapies. Among these, antibody-based therapeutics, including monoclonal antibodies targeting cytokines, cell-surface molecules, and co-stimulatory pathways, have transformed the treatment of numerous systemic and organ-specific autoimmune disorders. Nevertheless, important challenges remain, including primary non-response, secondary loss of efficacy related to immunogenicity or disease adaptation, increased susceptibility to infections, and mechanistic redundancy among therapeutic targets. This review provides a comprehensive overview of the cellular and molecular mechanisms underlying antibody-based therapies, summarizes major therapeutic target classes across autoimmune diseases, and examines their clinical and mechanistic limitations. Emerging therapeutic platforms, including bispecific antibodies, antibody–drug conjugates (ADCs), novel Fc-engineering, and cellular approaches such as CD19-targeted chimeric antigen receptor (CAR)-T therapy, are also discussed. Finally, antigen-specific immunotherapies designed to restore antigen-specific immune tolerance while preserving systemic host defense are explored. These approaches may represent an important next frontier in the treatment of autoimmune diseases, moving beyond broad systemic immune modulation toward more selective and durable immune control. Full article

Background. Immunosuppressive conditioning regimens for chimeric antigen receptor-modified T cell immunotherapy (CARTx) and subsequent T cell dysfunction increase risk for infection. However, it is difficult to discern infection from CRS in the early (up to Day 30) and late (Days 31–180) periods after CARTx due to overlapping signs and symptoms. Methods. We analyzed infectious complications and predictors of infection during the early and late periods after CARTx in 213 adult patients with malignancies over a 5-year period. Results. Overall, 75 patients (35%) had at least one infection, mostly within the first 30 days after CARTx. Infections occurring early after CARTx were mostly bacterial, whereas viral infections predominated after Day 30. In multivariate analyses, a high baseline CRP (≥5 mg/dL) was significantly associated with increased risk of infection in the early period after CARTx, and a Day-5-to-baseline-CRP ratio of <1.5 was significantly associated with a higher risk of infection through all 180 days after CARTx and during the late period after CARTx. Conclusions. Infections in adult patients are common up to 180 days after receiving CARTx. High baseline CRP without significant temporal changes may predict risk of infection. Tracking CRP trends may be a useful clinical tool for discerning causes of fever and guiding antibiotic stewardship in this population at high risk for infections. Full article

The emergence of seekRNA- and bridgeRNA-guided recombination has introduced a distinct paradigm in genome engineering by coupling programmable RNA-directed DNA recognition with recombinase-mediated insertion, excision, inversion, and genomic rearrangement without canonical double-strand breaks. Since their discovery in 2024, these systems have progressed rapidly from bacterial mobile genetic elements and mechanistic characterization to structural elucidation and programmable genome engineering in human cells. However, these advances remain distributed across foundational and rapidly emerging studies, creating a need for an integrated molecular perspective on their mechanisms, technological development, and position within contemporary genome engineering. This review synthesizes the molecular architecture, RNA-guided recognition, strand-exchange mechanisms, programmability, and engineering of seekRNA and bridgeRNA systems, with particular emphasis on complementary human-cell advances involving ISCro4 and engineered IS621. Whereas ISCro4 systems have enabled multikilobase DNA insertion, genomic excision, and near-megabase inversion, the enIS621–tebRNA platform has enabled scarless kilobase-scale integration across multiple human cell types, including proof-of-concept functional CD19 chimeric antigen receptor and factor IX gene insertion. The review further integrates recent genome-scale bacterial rewriting and Targetable Recombinase Assisted DNA Exchange (TRADE)-mediated DNA replacement, while benchmarking RNA-guided recombination against conventional site-specific recombination, clustered regularly interspaced short palindromic repeats (CRISPR)-based editing, Programmable Addition via Site-specific Targeting Elements (PASTE), CRISPR-associated transposases, and emerging large-payload genome-writing strategies, including kilobase-scale nickase-targeting (KNIT) editing, Prime Assembly, engineered R2 retrotransposons, and TransCRISTI. This comparative framework highlights a broader transition from programmable sequence modification toward direct engineering of genomic architecture, while identifying recognition-site constraints, mismatch-tolerant recombination, unintended recombination products, delivery, and genome-wide specificity as key translational barriers. By integrating foundational mechanisms with recent mammalian engineering, genome-scale bacterial rewriting, large-payload technologies, and emerging computational design strategies, this review provides a contemporary framework for defining the distinctive capabilities, current limitations, and future development of programmable RNA-guided DNA recombination. Full article

Immune–organoid co-culture has been proposed as a bridge between reductionist assays and clinical immuno-oncology, but the urologic evidence remains substantially thinner than this description suggests. This critical narrative review evaluates peer-reviewed work in prostate cancer, urothelial carcinoma and renal cell carcinoma from January 2014 through to 31 July 2026, separating patient-derived immune-preserving models from reconstituted cytotoxicity assays and adjacent engineering studies. Native air–liquid interface cultures have retained endogenous lymphoid, myeloid and stromal compartments in renal cell carcinoma for short-term checkpoint-inhibitor experiments. Reconstituted bladder and kidney organoids have supported mechanistic testing of chimeric antigen receptor T cells, and a bladder study has examined treatment-induced Jurkat-cell migration. These studies establish technical feasibility, but most use small cohorts, short endpoints and incomplete immune composition, and none has prospectively shown that a multi-lineage urologic organoid assay improves treatment selection. Published prostate systems remain largely epithelial or stromal, leaving a conspicuous immune-modelling gap. We therefore argue against equating greater cellular complexity with greater validity. The appropriate model is the least complex system that preserves the mechanism, spatial constraint and temporal window required by the question. A tiered framework is proposed that progresses from analytical quality control, through defined effector and suppressor modules, to perfused or spatially organised cultures only when these features are necessary. Minimum reporting standards, disease-specific immune modules, clinically meaningful endpoints and a four-stage validation ladder are specified. Multi-lineage systems can clarify resistance mechanisms and screen combinations, but predictive or clinical claims require blinded patient concordance and prospective utility studies rather than architectural sophistication alone. Full article

CD97 is an adhesion G-protein-coupled receptor encoded by ADGRE5 that integrates extracellular signals (including cell adhesion, ligand binding, and mechanical stimulation) with intracellular signal transduction. Recent structural studies have further elucidated tethered/intramolecular agonist (TIA)/Stachel recognition and engagement of the seven-transmembrane domain (7TMD), activation-associated 7TMD conformational changes, and G-protein coupling, including the structural basis for the preferential coupling of CD97 to G13. Currently, antibody–drug conjugates (ADCs) targeting CD97 are supported by in vitro proof-of-concept evidence, whereas chimeric antigen receptor (CAR) strategies have shown antitumor activity in animal models of glioblastoma (GBM) and acute myeloid leukemia (AML). Existing research indicates that CD97 is involved in maintaining stem-like states, invasion and metastasis, metabolic adaptation, and stress survival in certain tumors, and its function varies depending on tumor type and cellular environment. Because CD97 is also expressed in normal immune cells and various nonhematopoietic tissues, systemic targeted therapy may be limited by on-target/off-tumor toxicity. This article reviews the latest advances in CD97 structure and signal transduction, and explores its tumor-related functions, biomarker value, evidence for ADC and CAR-related therapies, as well as early exploratory directions involving RNA-mediated downregulation and structure-guided interventions. Full article

Clear cell renal cell carcinoma (ccRCC) is a highly immune-evasive malignancy that exhibits limited and often transient responses to immune checkpoint inhibitors (ICIs) and remains a major challenge for emerging cellular immunotherapies, including chimeric antigen receptor (CAR)-T cells. A defining feature of ccRCC, largely driven by von Hippel–Lindau (VHL) deficiency, is persistent activation of the transforming growth factor-β1 (TGF-β1) and hypoxia-inducible factor (HIF) signaling network. Acting as a central immunometabolic regulatory axis, TGF-β1/HIF promotes angiogenesis, metabolic reprogramming, epigenetic dysregulation, and immune escape through coordinated induction of immunosuppressive mediators, including PD-L1, VEGF, and CTLA-4, resulting in impaired T-cell infiltration, functional exhaustion, and resistance to immunotherapy. Preclinical studies have demonstrated that pharmacologic-dose Seleno-L-methionine (SLM) and its active metabolite, methylseleninic acid (MSA), suppress TGF-β1 and both HIF-1α and HIF-2α, leading to downregulation of multiple downstream immunosuppressive pathways at pharmacologically achievable, non-toxic concentrations. In addition to enhancing the antitumor activity of chemotherapy and VEGF-targeted agents, accumulating evidence suggests that SLM exerts broad immunologic, metabolic, and epigenetic effects that may overcome key mechanisms of therapeutic resistance. This review synthesizes current mechanistic and translational evidence supporting the repurposing of SLM as a first-in-class pleiotropic immunomodulatory agent. Using ccRCC as a model of TGF-β1/HIF-driven immune resistance, we discuss how simultaneous targeting of this central regulatory axis may restore immune surveillance, improve T-cell fitness and trafficking, enhance responses to ICIs and CAR-T cell therapy, and provide a mechanistically rational strategy for the treatment of advanced solid tumors. Full article

Background/Objectives: Chimeric antigen receptor T-cell (CAR-T) therapy has been approved for the management of relapsed and refractory hematologic malignancies, transforming the oncologic landscape and producing durable remissions in patient populations with limited alternatives. The systemic adverse events of CAR-T are well characterized; however, the orofacial adverse events have not been well described. The objective of this study is to leverage a large, de-identified, real-world dataset to (1) estimate the prevalence of orofacial adverse events following CAR-T, (2) compare event rates with the general population, and (3) directly contrast the orofacial toxicity burden of CAR-T with that observed after hemopoietic stem cell transplant (HSCT). Methods: We performed a retrospective cohort study using de-identified electronic health record data from TriNetX. CAR-T and HSCT cohorts were identified via RxNorm and procedure codes; a non-exposed control cohort was included. Patients with prior orofacial conditions or confounding therapies were excluded. New adverse orofacial events within one year were identified by International Classification of Diseases, 10th Revision (ICD-10) codes. Cohorts were 1:1 propensity-matched by age and sex; associations were estimated as odds ratios with two-sided 95% CIs. Results: In 1142 CAR-T recipients (mean age of 62), gastroesophageal reflux disease (GERD) was most frequent (5.18%). Oral mucosal events included stomatitis in 1.52%, mucositis in 1.31%, and lichenoid reactions in 1.03%. Dysphagia occurred in 1.8% and oral candidiasis in 1.6%. Several severe oral conditions were absent. Compared with the general population (CART vs. general population): mucositis—[12/995 vs. 0/1112] (OR 28.3)—and stomatitis—[16/987 vs. 0/1119] (OR 38)—risks were significantly increased, while CAR-T patients had significant lower risks of mucosal complications than HSCT recipients in this analysis (CART vs. HSCT): mucositis—[1.21% vs. 3.72%] (OR 0.316) and stomatitis—[1.42% vs. 3.91%] (OR 0.354). Conclusions: CAR-T therapy carries a distinct and generally lower orofacial toxicity burden than HSCT, but targeted dental assessment and prospective surveillance remain important to optimize supportive care for cellular therapy recipients. Full article

Background/Objectives: Hepatocellular carcinoma (HCC) remains a leading cause of cancer mortality worldwide, due to poor prognosis and limited curative options in advanced stages. Though immune checkpoint inhibitor (ICI)-based combinations have been the first-line therapies, with higher survival compared to tyrosine kinase inhibitors (TKIs), most patients progress within six months and evidence-based guidance for subsequent therapy remains limited. This review summarizes second- and third-line treatment strategies after ICI failure, while highlighting critical research gaps and future advancements needed. Methods: We performed a comprehensive literature review of PubMed, Embase, Cochrane, and major conference proceedings (ASCO, ESMO, AASLD) up to August 2025, including retrospective cohorts, post hoc trial analyses, simulation models, and ongoing prospective trials on second-line therapy in patients with metastatic HCC who progressed on first-line therapy. Discussion and Conclusions: TKIs remain the most widely used second-line option after ICI failure. Lenvatinib, a multi-targeted TKI with strong VEGF inhibition, has shown higher progression-free survival (PFS) compared with sorafenib through tumor vasculature normalization and enhanced T cell infiltration. Other multi-targeted TKIs, like cabozantinib and regorafenib, have shown survival benefits in later line settings. In TKI-refractory or ineligible patients, treatment options are limited, and enrollment in clinical trials is recommended. Retrial of ICIs may be considered in highly selected patients, but evidence remains limited, and this approach is not standard. Concomitant locoregional therapies (LRTs) are useful in oligoprogression where systemic therapy is inadequate, but their integration with systemic therapy is underexplored, and no phase III trials yet define optimal sequencing post-ICI failure. Additionally, we describe novel therapeutic strategies such as chimeric antigen receptor T cell therapy (CAR-T) in HCC. Full article

Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of haematological malignancies, but conventional viral transduction results in semi-random genomic integration, contributing to heterogeneous CAR expression and potential insertional effects. Site-specific genome engineering offers an alternative by directing CAR insertion to defined genomic loci, allowing greater control over transgene expression and cellular function. This narrative review evaluates advances in site-specific CAR T-cell engineering, focusing on integration mechanisms, donor platforms, genomic loci, safety, and translational readiness. Homology-directed repair (HDR) and homology-independent targeted integration (HITI) are critically compared alongside viral and non-viral donor systems. Candidate loci are evaluated according to their functional consequences and level of evidence, with TRAC representing the most extensively characterised target, while PDCD1, CD7, CD247, and other loci offer distinct functional opportunities but remain supported by varying levels of preclinical and translational evidence. The review also examines genomic risks associated with targeted editing, including structural rearrangements and chromosome-scale abnormalities, and considers emerging applications in allogeneic, solid-tumour, and in vivo CAR T-cell engineering. Overall, site-specific integration provides a framework for linking CAR placement to therapeutic function, but no single locus or integration strategy is universally optimal. Clinical evidence remains limited relative to the expanding preclinical landscape, and genomic safety, scalable manufacturing, and clinical validation remain major priorities for translation. Full article

Introduction: Chimeric Antigen Receptor T (CAR-T) cell therapy and autologous stem cell transplantation (ASCT) are both associated with significant physical and psychological challenges during post-transfusion recovery. To date, most assessments of physical recovery rely on subjective measures, which are prone to individual perception and bias. Direct comparative data on objective physical function between these therapies remain lacking. Objective: The study aims to compare physical recovery trajectories following CAR-T cell therapy and ASCT using objective and standardized rehabilitation assessments to identify promising endpoints for future trials. Methods: a total of 331 intraindividual rehabilitation assessments conducted at hospital admission and discharge were retrospectively screened for the Berg Balance Scale (BBS), muscle strength (MS), Timed Up and Go (TUG), 5-Times Sit-to-Stand (5×STS), and 6-minute Walk Test (6MWT). Subjective assessments including self-reported health status and fatigue measured by a Visual Analog Scale were also recorded. Results: Twelve patients met the inclusion criteria and completed all rehabilitation assessments (five CAR-T, seven ASCT). In the ASCT group, 6MWT performance declined significantly from admission to discharge (median change −84 m; range −415 to −31 m; p = 0.016), while CAR-T recipients showed a non-significant numerical improvement (median change +79 m; range −40 to +148 m; p = 0.19). Between-group comparison of 6MWT change favored CAR-T therapy (p = 0.005). For BBS, TUG, 5×STS and MS, no statistically significant within-group changes were observed, although trends suggested better preservation of balance and mobility in the CAR-T group. Conclusions: This pilot study provides preliminary comparative evidence suggesting that patients receiving CAR-T therapy may better preserve functional endurance than those undergoing ASCT, measured by the 6MWT. These findings are consistent with the existing literature highlighting the sensitivity and clinical relevance of the 6MWT in detecting functional changes, supporting its inclusion in standard rehabilitation assessments. Full article

The past decade has witnessed significant expansion in both preclinical and approved receptor-targeted therapeutic cell modalities. These include immune cells engineered to express chimeric antigen receptors (CARs), and bispecific immune cell engagers developed for the treatment of cancer, autoimmune disorders, infectious diseases, and metabolic disorders. Although these approaches have produced remarkable clinical outcomes, cell therapy-associated off-target toxicities continue to present significant safety challenges. This review provides a framework for the rational design of optimized cell therapies aimed at enhancing therapeutic efficacy while minimizing adverse side effects. With the state-of-the-art advances in genomic profiling, artificial intelligence-driven design tools, and scalable manufacturing technologies, the outlook for next-generation receptor-targeted cell therapies is highly promising. Full article

Background/Objectives: Chimeric antigen receptor (CAR)-T cell therapy has achieved substantial clinical success in haematological malignancies but has shown limited efficacy against solid tumours. Key barriers include inadequate tumour trafficking, immunosuppressive tumour microenvironments, poor selectivity and heterogeneity of antigen expression, and challenges related to safety and manufacturing. Biomaterial-based technologies have emerged as a potential strategy to address many of these limitations. This review aims to critically evaluate biomaterial approaches designed to enhance CAR-T cell therapy of solid tumours and assess their translational potential. Methods: A narrative review of recent pre-clinical translational studies was conducted, focussing on biomaterial platforms developed to improve CAR-T cell delivery, persistence, functionality, safety control, and manufacturing efficiency in solid-tumour settings. Approaches were analysed according to their mechanisms of action, therapeutic benefits, and stage of translational readiness. Results: Biomaterial strategies, including nanoparticles, injectable and implantable hydrogels, scaffolds, and hybrid delivery systems, have improved CAR-T infiltration, survival, and therapeutic efficacy in several solid-tumour models. Localised delivery of cytokines and other immunomodulatory cues enabled improved spatio-temporal control of CAR-T activation, reducing systemic toxicity, and increasing persistence. Additional applications include amplified ex vivo CAR-T expansion and support for non-viral or in vivo CAR-T generation. However, increased material complexity was frequently associated with challenges in scalability, regulatory approval, and long-term safety. Conclusions: Biomaterial-enabled approaches offer a versatile toolkit to address key biological and translational barriers limiting CAR-T cell therapy of solid tumours. Strategies based on clinically familiar materials and simplified designs appear most suitable for near-term clinical translation, emphasising the need to balance engineering innovation with safety, scalability, and integration into existing clinical workflows. Full article