Search Results (4,716)

The development of cancer immunotherapies has transformed cancer treatment paradigms, yet durable and tumour-specific responses remain elusive for many patients. Neoantigens, immunogenic peptides arising from tumour-specific genomic alterations, have emerged as promising cancer vaccine targets. Early-phase clinical trials using different vaccine platforms, including mRNA, peptide, DNA, and viral vector-based personalised cancer vaccines, have demonstrated the feasibility of targeting neoantigens, with early signals of prolonged survival in some patients. Most current vaccine strategies focus on canonical neoantigens, typically derived from exonic single-nucleotide variants (SNVs) and small insertions/deletions (INDELs), yet this represents only a fraction of the potential neoantigen repertoire. Evidence now shows that non-canonical neoantigens, arising mostly from alternative splicing, intron retention, translation of non-coding RNAs, gene fusions, and retroelement activation, broaden the antigenic landscape, with the potential for increasing tumour specificity and immunogenicity. In this review, we explore the biology of non-canonical neoantigens, the technological advances that now enable their systematic detection, and their potential to inform next-generation personalised cancer vaccines. Full article

Recurrent brain tumors—including high-grade gliomas, brain metastases, and aggressive meningiomas—continue to carry a poor prognosis, with high mortality despite therapeutic advances. The aim of this narrative review is to summarize and critically discuss the current evidence on the role of intra-arterial radioligand therapy (RLT) in the treatment of recurrent brain tumors. RLT, a targeted form of radionuclide therapy, has gained increasing attention for its potential theranostic applications in neuro-oncology. A literature search was conducted using PubMed and Scopus, including clinical studies evaluating intra-arterial radioligand delivery in central nervous system tumors. Recent research has explored intra-arterial administration of radioligands targeting somatostatin receptors and prostate-specific membrane antigen (PSMA). Somatostatin receptors are overexpressed in meningiomas, while PSMA is highly expressed in the neovasculature of glioblastomas and brain metastases; both targets can be addressed using lutetium-177 (¹⁷⁷Lu)- or actinium-225 (²²⁵Ac)-labeled radiopharmaceuticals, traditionally delivered intravenously. Available evidence indicates that the intra-arterial route achieves markedly higher radionuclide uptake on ⁶⁸Ga-PSMA-11 and ⁶⁸Ga-DOTATOC PET, as well as increased absorbed doses in dosimetric models. Dosimetric analyses consistently show greater tracer accumulation compared with intravenous administration, without evidence of significant peri-procedural toxicity. Uptake in healthy brain tissue is minimal, and no relevant differences have been reported in liver or salivary gland accumulation between intra-arterial and intravenous RLT. Although based on heterogeneous and limited data, intra-arterial RLT appears to be a promising therapeutic strategy for recurrent brain tumors. Future research should focus on improving radioligand delivery beyond the blood–brain barrier and enhancing effective tumor targeting. Full article

The rapid evolution of SARS-CoV-2, particularly the emergence of Omicron subvariants, has significantly reduced the efficacy of existing vaccines and monoclonal antibodies. This study investigates the phenomenon of immune imprinting by comparing two phage display antibody libraries derived from early 2020 wild-type SARS-CoV-2 convalescents (WT-AbLib) and early 2023 Omicron convalescents (Omi-AbLib). The capacity and diversity of both antibody libraries were systematically evaluated. The libraries were screened using BF.7 and XBB.1.5 antigens. WT-AbLib showed markedly reduced diversity after Omicron antigen selection, with dominant clones shifting from IGHV3-66-class broadly neutralizing antibodies (bnAbs) targeting the receptor-binding motif to IGHV1-46-class broadly non-neutralizing antibodies targeting conserved lateral receptor-binding domain (RBD) sites. Omi-AbLib maintained higher diversity, but dominant antibodies were also non-neutralizing and targeted the same conserved lateral region. These findings suggest that immune imprinting drives the dominance of broadly non-neutralizing antibodies following Omicron breakthrough or reinfection. This phenomenon provides a mechanistic explanation for persistent viral evasion and recurrent infection, and highlights major challenges for the development of next-generation broadly neutralizing therapeutics. Full article

Tetanus is a zoonotic disease posing significant threats to both humans and animals, particularly horses, sheep, and ruminants. Current antitoxin therapies rely on animal-derived immunoglobulins, presenting challenges including animal welfare concerns, pathogen contamination risks, and manufacturing complexity. Alpaca-derived nanobodies (VHH) are promising alternatives owing to their high antigen-binding affinity, thermostability, and potential for microbial production. We developed highly active trivalent VHH antibodies (tVHH) that target multiple epitopes of tetanus neurotoxin (TeNT). Following alpaca immunization with tetanus toxoid, 41 VHH clones were isolated using phage display. Six VHH clones were selected through in vivo neutralization assays, from which three clones of VHH (8, 11, 36) were selected to construct tVHH-8/11/36 and tVHH-8/36/11. Using an improved 21-day mouse neutralization assay, tVHH-8/11/36 demonstrated exceptional neutralizing activity of approximately 1580 IU/mg against 4000 LD₅₀ of toxin, substantially exceeding current human and veterinary anti-tetanus immunoglobulin preparations. Surface plasmon resonance and ELISA confirmed that each VHH recognizes different TeNT domains, producing synergistic neutralizing effects through multimerization. Since antitoxin therapy challenges are common to both animals and humans, this tVHH technology supports One Health by providing a unified therapeutic platform applicable across species through sustainable microbial production. Full article

Burkholderia pseudomallei complex and B. cepacia complex are two evolutionary distinct clades of pathogens causing human disease. Most vaccine efforts have focused on the former group largely due to their biothreat status and global disease burden. It has been proposed that a vaccine could be developed that simultaneously protects against both groups of Burkholderia by specifically targeting conserved antigens. Only a few studies have set out to identify which antigens may be optimal targets for such a vaccine. We have previously assessed the ability of three highly conserved B. pseudomallei antigens, namely OmpA1, OmpA2, and Pal, coupled to gold nanoparticle vaccines, to protect mice against a homotypic B. pseudomallei challenge. Here, we have expanded our study by demonstrating that antibodies to each of these proteins show varying levels of reactivity to homologues in B. cepacia complex, with OmpA2 antibodies exhibiting the highest cross-reactivity. Remarkably, some nanovaccine immunized mice, particularly those that received OmpA2, produced antibodies that bind Pseudomonas aeruginosa, which harbors distantly related homologous proteins. T cells elicited to Pal and OmpA2 responded to stimulation with B. cepacia complex-derived homologues. Our study supports incorporation of these antigens, particularly OmpA2, for the development of a pan-Burkholderia vaccine. Full article

Glioblastoma (GBM) remains one of the most treatment-resistant human malignancies, largely due to the interplay between disrupted fluid dynamics, immune evasion, and the structural complexity of the tumor microenvironment; in addition to these, treatment resistance is also driven by intratumoral heterogeneity, glioma stem cell persistence, hypoxia-induced metabolic and epigenetic plasticity, adaptive oncogenic signaling, and profound immunosuppression within the tumor microenvironment. Emerging evidence shows that dysfunction of the glymphatic system, mislocalization of aquaporin-4, and increased intracranial pressure compromise cerebrospinal fluid–interstitial fluid exchange and impair antigen drainage to meningeal lymphatics, thereby weakening immunosurveillance. GBM simultaneously remodels the blood–brain barrier into a heterogeneous and permeable blood–tumor barrier that restricts uniform drug penetration yet enables tumor progression. These alterations intersect with profound immunosuppression mediated by pericytes, tumor-associated macrophages, and hypoxic niches. Advances in imaging, including DCE-MRI, DTI-ALPS, CSF-tracing PET, and elastography, now allow in vivo characterization of glymphatic function and interstitial flow. Therapeutic strategies targeting the fluid-immune interface are rapidly expanding, including convection-enhanced delivery, intrathecal and intranasal approaches, focused ultrasound, nanoparticle systems, and lymphatic-modulating immunotherapies such as VEGF-C and STING agonists. Integrating barrier modulation with immunotherapy and nanomedicine holds promise for overcoming treatment resistance. Our review synthesizes the mechanistic, microenvironmental, and translational advances that position the glymphatic–immune axis as a new frontier in glioblastoma research. Full article

Early life is a critical window for immune system development, during which the gut microbiome shapes innate immunity, antigen presentation, and adaptive immune maturation. Disruptions in microbial colonization—driven by factors such as cesarean delivery, antibiotic exposure, and formula feeding—deplete beneficial early-life taxa (e.g., Bifidobacterium, Bacteroides, and Enterococcus) and impair key microbial functions, including short-chain fatty acid (SCFA) production by these keystone species, alongside regulatory T cell induction. These dysbiosis patterns are associated with an increased risk of pediatric autoimmune diseases, notably type 1 diabetes, inflammatory bowel disease, celiac disease, and juvenile idiopathic arthritis. This review synthesizes current evidence on how the early-life microbiota influences immune maturation, with potential effects on the development of autoimmune diseases later in life. We specifically focus on human observational and intervention studies, where treatments with probiotics, synbiotics, vaginal microbial transfer, or maternal fecal microbiota transplantations have been shown to partially restore a disrupted microbiome. While restoration of the gut microbiome composition and function is the main reported outcome of these studies, to date, no reports have disclosed direct prevention of autoimmune disease development by targeting the early-life gut microbiome. In this regard, a better understanding of the early-life microbiome–immune axis is essential for developing targeted preventive strategies. Future research must prioritize longitudinal evaluation of autoimmune outcomes after microbiome modulation to reduce the burden of chronic immune-mediated diseases. Full article

Background: Organ transplant offers patients a second chance at life, yet chronic rejection remains a formidable barrier to long-term success. Unlike the instantaneous storm of acute rejection, chronic rejection is a slow, unremitting process that silently remodels vessels, scars tissues, and diminishes graft function. At the center of this process are macrophages, immune “shapeshifters” that can heal or harm depending on their cues. Methods: This manuscript systematically reviews and synthesizes the current evidence from experimental studies and clinical observations, as well as molecular insights, to unravel how macrophages orchestrate chronic rejection. It travels over macrophage origins alongside their dynamic polarization into pro-inflammatory (M1) or pro-repair yet fibrotic (M2) states. The discussion integrates mechanisms of recruitment, antigen presentation, vascular injury, and fibrosis, while highlighting the molecular pathways (NF-κB, inflammasomes, STAT signaling, metabolic rewiring) that shape macrophage fate. Results: Macrophages play a central role in chronic rejection. Resident macrophages, once tissue peacekeepers, amplify inflammation, while recruited monocyte-derived macrophages fuel acute injury or dysfunctional repair. Together, they initiate transplant vasculopathy through cytokines, growth factors, and matrix metalloproteinases, slowly narrowing vessels and starving grafts. Donor-derived macrophages, often overlooked, act as early sentinels and long-term architects of fibrosis, blurring the line between donor and host immunity. At the molecular level, macrophages lock into destructive programs, perpetuating a cycle of inflammation, vascular remodeling, and scarring. Conclusions: Macrophages are not passive bystanders but pivotal decision makers in chronic rejection. Their plasticity, while a source of pathology, also opens therapeutic opportunities. Emerging strategies like macrophage-targeted drugs, immune tolerance approaches, gene and exosome therapies currently offer ways to reprogram these cells and preserve graft function. By shifting the macrophage narrative from saboteurs to guardians, transplantation medicine may transform chronic rejection from an inevitability into a preventable complication, extending graft survival from fleeting years into enduring decades. Full article

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

Prostate cancer is one of the most common malignancies in men, and advanced or metastatic disease remains associated with substantial morbidity and mortality. Therapeutic progress in recent years has been driven by the introduction of targeted treatment strategies, notably poly (ADP-ribose) polymerase (PARP) inhibitors, prostate-specific membrane antigen (PSMA)–directed radioligand therapy (RLT), and androgen receptor pathway inhibitors (ARPIs). This review summarizes evidence from phase II and III clinical trials, meta-analyses, and real-world studies evaluating the efficacy, safety, and clinical integration of olaparib, lutetium (¹⁷⁷Lu) vipivotide tetraxetan, and abiraterone in advanced prostate cancer. Emphasis is placed on the practical clinical application of these agents, including patient selection, treatment sequencing, and combination strategies. PARP inhibition with olaparib has demonstrated clear benefits in metastatic castration-resistant prostate cancer (mCRPC) with homologous recombination repair (HRR) mutations, particularly BRCA1/2 alterations. PSMA-directed RLT offers a survival advantage in PSMA-positive mCRPC following AR pathway inhibition, with distinct toxicity considerations that influence patient selection. Abiraterone remains a cornerstone therapy across disease stages and plays an important role both as monotherapy and as a combination partner. Emerging data suggest a potential synergy between PARP inhibitors and AR-targeted agents, while also highlighting the limitations of biomarker-unselected approaches. We conclude that the optimal use of PARP inhibitors, PSMA-targeted RLT, and ARPIs requires a personalized strategy guided by molecular profiling, functional imaging, prior treatment exposure, and safety considerations. This clinically focused overview aims to support evidence-based decision-making in an increasingly complex treatment landscape. Full article

Paraneoplastic neurological syndromes (PNSs) are immune-mediated disorders caused by an antitumor response that cross-reacts with the nervous system, leading to severe and often irreversible neurological disability. Once considered exceedingly rare, PNSs are now increasingly recognized owing to the identification of novel neural autoantibodies, wider use of commercial testing, and the emergence of immune checkpoint inhibitor (ICI)-related neurotoxicity that phenotypically overlaps with classic PNS. In this narrative review, we performed a structured search of PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar, without date restrictions, to summarize contemporary advances in the epidemiology, pathogenesis, diagnosis, and management of PNS. Population-based data show rising incidence, largely reflecting improved ascertainment and expanding indications for ICIs. Pathogenetically, we distinguish T-cell-mediated syndromes associated with intracellular antigens from antibody-mediated disorders targeting neuronal surface proteins, integrating emerging concepts of molecular mimicry, tumor genetics, and HLA-linked susceptibility. The 2021 PNS-Care criteria are also reviewed, which replace earlier “classical/non-classical” definitions with risk-stratified phenotypes and antibodies, and demonstrate superior diagnostic performance while underscoring that “probable” and “definite” PNS should be managed with equal urgency. Newly described antibodies and methodological innovations such as PhIP-Seq, neurofilament light chain, and liquid biopsy are highlighted, which refine tumor search strategies and longitudinal monitoring. Management principles emphasize early tumor control, prompt immunotherapy, and a growing repertoire of targeted agents, alongside specific considerations for ICI-associated neurological syndromes. Remaining challenges include diagnostic delays, limited high-level evidence, and the paucity of validated biomarkers of disease activity. Future work should prioritize prospective, biomarker-driven trials and multidisciplinary pathways to shorten time to diagnosis and improve long-term outcomes in patients with PNS. Full article

Chimeric antigen receptor (CAR)-T-cell therapy is a revolutionary approach in immunotherapy that has shown remarkable success in the treatment of blood cancers. Many preclinical studies are currently underway worldwide to extend the CAR-T-cell therapy benefits to a broad spectrum of cancers, using rodent models. Alternative in vivo platforms are essential for overcoming the drawbacks associated with rodent models, including immunodeficiency in humanized models, ethical concerns, extended time requirements, and cost. In this work, we used the chicken chorioallantoic membrane (CAM) assay to evaluate the in vivo efficacy of cluster-of-differentiation 19 (CD19)-targeting CAR-T cells expressing a second-generation CAR construct against human lymphoma derived from the Raji cell line. Our results confirm the efficacy of selected CAR-T cells on tumor growth, metastasis, and angiogenesis. Further, the chicken embryo has an intrinsic active immune system. Therefore, the dialog between CAR-T cells and endogenous immune cells, as well as their participation in the tumor challenge, has also been studied. In conclusion, our study demonstrates that the chicken CAM assay provides a relevant in vivo, 3Rs (Replacement, Reduction and Refinement)-compliant new approach methodology (NAM), which is well-suited for the current needs of preclinical research on CAR-T-cell therapy. Full article

Background: The apicomplexan parasite Toxoplasma gondii causes serious diseases in animals and humans. The in vitro efficacy of the antimicrobial peptide mixture tyrothricin, composed of tyrocidines and gramicidins, against T. gondii tachyzoites was investigated. Methods: Effects against T. gondii were determined by monitoring inhibition of tachyzoite proliferation and electron microscopy, host cell and splenocyte toxicity was measured by Alamar blue assay, and early embryo toxicity was assessed using zebrafish embryos. Differential affinity chromatography coupled to mass spectrometry and proteomics (DAC-MS-proteomics) was employed to identify potential molecular targets in T. gondii cell-free extracts. Results: Tyrothricin inhibited T. gondii proliferation at IC₅₀s < 100 nM, with tyrocidine A being the active and gramicidin A the inactive component. Tyrothricin also impaired fibroblast, T cell and zebrafish embryo viability at 1 µM. Electron microscopy carried out after 6 h of treatment revealed cytoplasmic vacuolization and structural alterations in the parasite mitochondrion, but these changes appeared only transiently, and tachyzoites recovered after 96 h. Tyrothricin also induced a reduction in the mitochondrial membrane potential. DAC-MS-proteomics identified 521 proteins binding only to tyrocidine A. No specific binding to gramicidin A was noted, and four proteins were common to both peptides. Among the proteins binding specifically to tyrocidine A were several SRS surface antigens and secretory proteins, mitochondrial inner and outer membrane proteins associated with the electron transfer chain and porin, and several calcium-binding proteins putatively involved in signaling. Discussion: These results suggest that tyrocidine A potentially affected multiple pathways important for parasite survival and development. Full article

Immunotoxins are chimeric molecules with high potential as therapeutic candidates that combine antibody specificity to recognize and bind tumor-associated antigens and the cytotoxic potency of the enzymatic activity of a toxin, leading to the selective death of target cells. The use of immunotoxins as therapeutic tools remains limited by various issues, such as selecting the appropriate tumor-associated antigen (TAA), penetration difficulties in solid tumors, low renal clearance, and low toxic payload. For this purpose, in this work we have designed a novel trimeric immunotoxin (IMTXTriA33αS) against colorectal cancer, combining the scFv against GPA33 as a targeting domain and the fungal ribotoxin α-sarcin (αS) as the toxic fragment, linked by a trimerization domain (TIE^XVIII). Our results demonstrate that IMTXTriA33αS has greater avidity and toxic load, showing a very significant increase in its in vitro and in vivo antitumor efficacy, due to its trimeric structure. Full article

Prostate cancer remains one of the most common malignancies in men worldwide, with incidence and mortality steadily increasing across diverse populations. While early detection and radical prostatectomy can achieve durable control in a subset of patients, approximately 40% of men will ultimately experience biochemical recurrence often in the absence of clinically detectable disease. Conventional imaging approaches—CT, MRI, and bone scintigraphy—have limited sensitivity for early relapses, frequently leading to delayed diagnosis and suboptimal treatment planning. The discovery of prostate-specific membrane antigen (PSMA) in 1987 and its subsequent clinical translation into positron emission tomography (PET) imaging with [⁶⁸Ga]Ga-PSMA-11 in 2012, followed by U.S. FDA approval in 2020, has transformed the landscape of prostate cancer imaging. PSMA PET has demonstrated superior accuracy over conventional imaging, as highlighted in the landmark proPSMA trial and now serves as the foundation for theranostic approaches that integrate diagnostic imaging with targeted radioligand therapy. The clinical approval of [¹⁷⁷Lu]Lu-PSMA-617 (Pluvicto^®: (lutetium Lu 177 vipivotide tetraxetan, Advanced Accelerator Applications USA, Inc., a Novartis company) has established targeted radioligand therapy as a viable option for men with metastatic castration-resistant prostate cancer, extending survival in patients with limited alternatives. Emerging strategies, including next-generation ligands with improved tumor uptake and altered clearance pathways, as well as the integration of artificial intelligence for imaging quantification, are poised to further refine patient selection, dosimetry, and treatment outcomes. This review highlights the evolution of PSMA-based imaging and therapy, discusses current clinical applications and limitations, and outlines future directions for optimizing theranostic strategies in prostate cancer care. Full article