Search Results (4,422)

Richter transformation (RT) affects 2–10% of chronic lymphocytic leukemia (CLL) patients, evolving into an aggressive lymphoma—most often diffuse large B-cell lymphoma—with poor prognosis, especially when clonally related to CLL. Key risk factors include unmutated IGHV, TP53 and NOTCH1 mutations, stereotyped B-cell receptors, and complex cytogenetics. This review summarizes RT biology, clinical predictors, and treatment outcomes. Traditional chemoimmunotherapy (e.g., R-CHOP) yields complete response rates around 20–30% and median overall survival of 6–12 months; intensified regimens (R-EPOCH, hyper-CVAD) offer only modest gains. Allogeneic hematopoietic stem cell transplantation is potentially curative but limited to fit patients due to high treatment-related mortality. Emerging therapies now include Bruton’s tyrosine kinase and BCL-2 inhibitors, which achieve partial responses but short progression-free survival. CD19-directed chimeric antigen receptor T-cell therapies produce overall response rates of 60–65%, though relapses remain frequent. Bispecific antibodies (e.g., CD3×CD20 agents epcoritamab and mosunetuzumab) show promising activity and tolerable toxicity in relapsed/refractory RT. Ongoing trials are exploring combinations with checkpoint inhibitors, triplet regimens, and novel targets such as ROR1, CD47, and CDK9. Continued research into optimized induction, consolidation, and innovative immunotherapies is essential to improve outcomes in this biologically distinct, high-risk CLL-related lymphoma. Full article

Purpose: Near-infrared fluorescence-guided surgery (FGS) using cancer-specific tracers is promising for tailored gastric cancer (GC) surgery. Carcinoembryonic antigen (CEA) is a potential target due to its high expression in various digestive cancers, including GC. Materials and Methods: SGM-101, a chimeric anti-CEA monoclonal antibody conjugated with the near-infrared dye BM-104, was evaluated in GC. CEA expression was identified in GC cell lines at the mRNA and protein levels. Xenograft models (MKN-45, SNU-16, SNU-668, 85As2mLuc) were established in mice and injected with SGM-101 or PBS. Biodistribution was monitored using in vivo fluorescence imaging. Tumors were further analyzed by immunofluorescence. In a peritoneal carcinomatosis model, 85As2mLuc cells were injected intraperitoneally, and tumors were evaluated by bioluminescence and fluorescence and histology. Results: MKN-45, SNU-16, and 85As2mLuc were CEA-positive, while SNU-668 was CEA-negative. Flow cytometry confirmed CEA expression: MKN-45 (98%), SNU-16 (85.6%), SNU-668 (6.42%) and 85As2mLuc (78.4%). SGM-101 selectively targeted CEA-expressing tumors, with fluorescence peaking at 48 h, and immunofluorescence verified localization in tumor cells. In the peritoneal models, SGM-101 enabled precise detection of CEA-positive tumors. Conclusions: This study provides the first evidence for the feasibility of SGM-101 in gastric cancer, demonstrating its novelty and translational potential as a cancer-specific imaging agent for fluorescence-guided surgery. Full article

Attenuated Salmonella strains offer an opportunity for delivering DNA vaccines to antigen-presenting cells. DNA vaccines trigger cellular immune responses, making them suitable for targeting intracellular pathogens, such as Mycobacterium avium subspecies paratuberculosis (MAP). Since whole organism MAP vaccines interfere with tuberculosis diagnosis, innovative vaccine technologies have been introduced to elicit an immune response targeting species-specific antigens. Fibronectin attachment protein (FAP), a MAP surface antigen that is species-specific, can induce cellular immune responses. The present study aims to explore the immunogenic potential of a mammalian expression plasmid encoding the fap-P gene of MAP within a mouse model, utilizing a Salmonella vector for oral immunization using a fluorescent assay and Western blot analysis. The results proved the ability of the constructed plasmid to stimulate the humoral immune response in mice. Moreover, fluorescence microscopy of splenocytes confirmed the successful delivery of the plasmid to the immune system at 24, 48, and 72 h following oral administration. It can be concluded that FAP-P could be considered a candidate for further investigation in the context of MAP vaccine development. Additionally, the use of Salmonella as a delivery system not only improves the efficacy of DNA vaccines but also helps in the preliminary evaluation of the antigens’ immunogenic properties. Full article

Cancer-associated fibroblasts (CAFs) are crucial regulators of the tumor microenvironment (TME), promoting cancer progression, immune suppression, and therapy resistance. Single-cell transcriptomics has identified at least five distinct CAF subtypes: myofibroblastic (myCAFs), inflammatory (iCAFs), antigen-presenting (apCAFs), metabolic (meCAFs), and vascular/developmental (vCAFs/dCAFs), each with unique localization, signaling, and functions. While CAFs are well studied in epithelial cancers, their roles in sarcomas are less understood despite the shared mesenchymal origin of tumor and stromal cells. This overlap blurs the line between malignant and non-malignant fibroblasts, raising fundamental questions about the identity of CAFs in mesenchymal tumors. In this narrative review, we explore the heterogeneity and plasticity of CAFs across solid tumors, focusing on their role in immune evasion, epithelial-to-mesenchymal transition (EMT), and resistance to chemotherapy, targeted therapy, and immunotherapy. We highlight emerging evidence on CAF-like cells in sarcomas and their contribution to tumor invasion, immune exclusion, and metastatic niche formation. We also assess new strategies to target or reprogram CAFs and suggest that CAF profiling may serve as a potential biomarker for patient stratification. Understanding CAF biology across various tumor types, including those with dense stroma and immunologically cold sarcomas, is crucial for developing more effective, personalized cancer treatments. Full article

Malignant neoplasms, like non-small cell lung cancer (NSCLC), remain a major global health challenge. Lung cancer is the leading cause of cancer-related deaths worldwide, with over two million new cases and 1.8 million deaths annually. NSCLC accounts for approximately 85% of cases, underscoring its substantial public health impact. Advances in molecular biology have driven the development of new therapies beyond traditional treatments. Among them, mRNA-based immunoadjuvant therapies, like cancer vaccines, have emerged as promising utilities in NSCLC by triggering targeted immune responses. The aim of this paper is to review ongoing and completed studies on mRNA vaccines in NSCLC. The efficacy of mRNA vaccines in NSCLC relies on the identification of immunogenic tumor-specific antigens, frequently derived from genomic profiling databases. Completed clinical trials have assessed the safety and potential benefit of selected mRNA vaccines—such as CV9202—administered alone or in combination with radiotherapy or tyrosine kinase inhibitors. Ongoing studies are exploring the therapeutic potential of mRNA-based approaches targeting defined molecular alterations in NSCLC, particularly in conjunction with Programmed Death-Ligand 1 (PD-L1) immune checkpoint inhibitors to enhance antitumor immune responses. mRNA vaccines have emerged as a promising therapeutic option for NSCLC, with the potential to enhance immune responses and limit tumor progression, as demonstrated in ongoing clinical trials. They offer the possibility of personalized treatment with relatively few side effects. However, larger and long-term studies are required to fully confirm their safety and efficacy. Future research should aim to identify the most effective antigens, enhance stability, and refine delivery strategies to improve efficacy and personalization, while also addressing immune suppression within the tumor microenvironment. Full article

Background/Objectives: Rheumatoid arthritis (RA) is a chronic autoimmune disorder marked by persistent synovial inflammation, progressive joint destruction, and systemic complications. Despite significant progress in targeted therapies, major clinical challenges persist, including heterogeneous treatment responses and therapeutic resistance. This review aims to critically evaluate emerging immunomodulatory strategies—focusing on immune checkpoints, microRNAs (miRNAs), and cell-based therapies—as potential diagnostic and therapeutic tools. Methods: This non-systematic literature review involved a comprehensive analysis of recent studies to investigate emerging immunomodulatory strategies in RA. Special attention was given to immune checkpoint pathways—cytotoxic T-lymphocyte antigen 4 (CTLA-4); programmed death-1 (PD-1) and its ligand, PD-L1; and inducible T-cell costimulator (ICOS)—as well as cell-based therapies. Additionally, miRNA-based interventions were examined for their diagnostic and therapeutic potential. Results: Immune checkpoint modulation has demonstrated preclinical efficacy in attenuating inflammatory responses and restoring immune tolerance. Concurrently, miRNAs have emerged as both biomarkers and therapeutic agents, with exosome-based delivery systems enhancing their function. Cell-based therapies have shown robust immunoregulatory effects with acceptable safety profiles. Notably, integrative strategies that combine checkpoint inhibitors, cell-based interventions, and miRNA delivery exhibit synergistic effects and offer a promising avenue for personalised treatment, when guided by molecular and transcriptomic profiling. The majority of these approaches remain at the preclinical or early translational stage. Conclusions: Targeted immunomodulation is poised to transform RA management. The integration of cell therapies, checkpoint inhibition, and miRNA manipulation with omics technologies holds promise for enhancing therapeutic precision and safety. Advancing towards personalised immunotherapy will necessitate a multidisciplinary and patient-centred effort. Full article

Background/Objectives: Hepatitis B virus (HBV) infection poses a major global health challenge, with current therapies like nucleos(t)ide analogs and pegylated interferon alpha offering limited functional cure rates due to persistent HBsAg-driven immune tolerance. This study aimed to develop a targeted immunoadsorption system using a high-affinity humanized anti-HBsAg monoclonal antibody for efficient HBsAg and viral particle clearance, providing a novel approach to overcome therapeutic bottlenecks in chronic hepatitis B (CHB). Methods: A murine anti-HBsAg monoclonal antibody was humanized via complementarity-determining region grafting, resulting in HmAb-12 (equilibrium dissociation constant, K_D = 0.36 nM). A stable Chinese Hamster Ovary K1 (CHO-K1) cell line was established for high-yield expression (fed-batch yield: 8.31 g/L). The antibody was covalently coupled to agarose microspheres (coupling efficiency > 95%) to prepare the immunoadsorbent. Efficacy was evaluated through in vitro dynamic circulation assays with artificial sera and preclinical trials using an integrated blood purification system in two CHB participants. Clearance rates for HBsAg and HBV DNA were quantified, with safety assessed via blood component monitoring. Results: In vitro, a single treatment cycle achieved HBsAg clearance rates of 70.14% (high antigen load, >10⁵ IU/mL) and 92.10% (low antigen load, ~3000 IU/mL). Preclinically, one treatment session resulted in acute HBsAg reductions of 78.30% and 74.31% in participants with high and moderate antigen loads, respectively, alongside HBV DNA decreases of 65.66% and 73.55%. Minimal fluctuations in total protein and albumin levels (<15%) confirmed favorable safety profiles, with no serious adverse events observed. Conclusions: Preliminary findings from this study indicate that the HBsAg-specific immunoadsorption system can achieve efficient HBV antigen clearance with an initial favorable safety profile in a small cohort. These results support its further investigation as a potential therapeutic strategy for functional cure in CHB. Future work will focus on validating these findings in larger studies and exploring the system’s combinatory potential with existing blood purification platforms. Full article

CD19-targeted therapies, including monoclonal antibodies, antibody–drug conjugates, and chimeric antigen receptor (CAR) T-cell products, have significantly improved outcomes in relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). Despite their clinical efficacy, resistance and antigen modulation pose substantial challenges, especially in patients requiring sequential therapy. This review provides a comprehensive overview of CD19 biology and its relevance as a therapeutic target. We examine mechanisms of resistance such as antigen loss, epitope masking, and T-cell exhaustion, as well as the implications of tumor microenvironmental immunosuppression. Future efforts should prioritize the integration of real-time diagnostics, such as flow cytometry, immunohistochemistry, and transcriptomic profiling, and AI-assisted predictive models to optimize therapeutic sequencing and expand access to personalized immunotherapy. Full article

Background: Tuberculosis (TB) remains a global health priority, with current interventions like the Bacille Calmette–Guérin (BCG) vaccine lacking efficacy against latent infection and drug-resistant strains. Novel vaccines targeting both latent and active TB are urgently needed. Objective: This study aims to design a multi-epitope vaccine (MEV) and evaluate its immunogenicity, structural stability, and interactions with toll-like receptor 2/4 (TLR-2/4) via computational biology approaches. Methods: We designed MEV using bioinformatics tools, prioritizing immunodominant epitopes from Mycobacterium tuberculosis antigens. Structural stability was optimized through disulfide engineering, and molecular docking/dynamics simulations were used to analyze interactions and conformational dynamics with TLR-2/4. Antigenicity, immunogenicity, population coverage, and immune responses were computationally assessed. Results: The MEV candidate, CP91110P, exhibited 86.18% predicted global human leukocyte antigen (HLA)-I/II coverage, high antigenicity (VaxiJen: 0.8789), and immunogenicity (IEDB: 4.40091), with favorable stability (instability index: 33.48) and solubility (0.485). Tertiary structure analysis indicated that 98.34% residues were located in favored regions. Molecular docking suggested strong TLR-2 (−1535.9 kcal/mol) and TLR-4 (−1672.5 kcal/mol) binding. Molecular dynamics simulations indicated stable TLR-2 interactions (RMSD: 6–8 Å; Rg: 38.50–39.50 Å) and flexible TLR-4 binding (RMSD: 2–6 Å; Rg: 33–36 Å). Principal component analysis, free energy landscapes, and dynamic cross-correlation matrix analyses highlighted TLR-2’s structural coherence versus TLR-4’s adaptive flexibility. Immune simulations predicted potential robust natural killer cell activation, T helper 1 polarization (interferon-gamma/interleukin-2 dominance), and elevated IgM/IgG levels. Conclusions: CP91110P is predicted to stably bind to TLR-2 and flexibly interact with TLR-4, with prediction of its high antigenicity and broad coverage across immune populations. However, this conclusion requires confirmation through experimental validation. Therefore, it may provide a promising candidate for experimental validation in the development of tuberculosis vaccines. Full article

Antibody–drug conjugates (ADCs) are a rapidly advancing class of targeted cancer therapeutics that couple the antigen specificity of monoclonal antibodies (mAbs) with the potent cytotoxicity of small-molecule drugs. In their core design, a tumor-targeting antibody is covalently linked to a cytotoxic payload via a chemical linker, enabling the selective delivery of highly potent agents to malignant cells while sparing normal tissues, thereby improving the therapeutic index. Humanized and fully human immunoglobulin G1(IgG1) antibodies are the most common ADC backbones due to their stability in systemic circulation, robust Fcγ receptor engagement for immune effector functions, and reduced immunogenicity. Antibody selection requires balancing tumor specificity, internalization rate, and binding affinity to avoid barriers to tissue penetration, such as the binding-site barrier effect, while emerging designs exploit tumor-specific antigen variants or unique post-translational modifications to further enhance selectivity. Advances in antibody engineering, linker chemistry, and payload innovation have reinforced the clinical success of ADCs, with more than a dozen agents FDA approved for hematologic malignancies and solid tumors and over 200 in active clinical trials. This review critically examines established and emerging conjugation strategies, including lysine- and cysteine-based chemistries, enzymatic tagging, glycan remodeling, non-canonical amino acid incorporation, and affinity peptide-mediated methods, and discusses how conjugation site, drug-to-antibody ratio (DAR) control, and linker stability influence pharmacokinetics, efficacy, and safety. Innovations in site-specific conjugation have improved ADC homogeneity, stability, and clinical predictability, though challenges in large-scale manufacturing and regulatory harmonization remain. Furthermore, novel ADC architectures such as bispecific ADCs, conditionally active (probody) ADCs, immune-stimulating ADCs, protein-degrader ADCs, and dual-payload designs are being developed to address tumor heterogeneity, drug resistance, and off-target toxicity. By integrating mechanistic insights, preclinical and clinical data, and recent technological advances, this work highlights current progress and future directions for next-generation ADCs aimed at achieving superior efficacy, safety, and patient outcomes, especially in treating refractory cancers. Full article

Primary central nervous system lymphoma (PCNSL) is a rare extra-nodal non-Hodgkin lymphoma confined to the central nervous system. The cancer biology of PCNSL remains incomplete and is often associated with genetic aberrations with abnormal signaling pathways, cell differentiation, regulation of epigenetic modification, and the tumor microenvironment. Stereotactic brain biopsy remains the gold standard for the diagnosis of PCNSL. For patients ill-suited for biopsy, MYD88 and IL-10 may be important biomarkers to diagnose PCNSL. High-dose methotrexate-based polychemotherapy is currently the standard induction treatment for PCNSL, followed by consolidation treatments including autologous stem cell transplant and whole-brain radiotherapy. Some studies suggest that low-dose lenalidomide is recommended as a maintenance therapy for PCNSL. Currently, relapse rates of PCNSL range from 25 to 50% with poor prognosis. Insight research is necessary to identify novel targeted treatments to improve outcomes in relapsed/refractory disease, such as immunomodulatory drugs, immune checkpoint inhibitors, signaling pathway inhibitors, and chimeric antigen receptor T-cell therapy. Full article

Antigenicity and immunogenicity define a potent immunogen in vaccinology. Nowadays, there are simplified platforms to produce nanocarriers for small-peptide antigen delivery, derived from various infectious agents for the treatment of a variety of diseases, based on virus-like particles (VLPs). They have good cell-penetrating properties and protective action for target molecules from degradation. Human papillomavirus (HPV) causes anogenital warts and six types of cancer in infected women, men, or children, posing a challenge to global public health. The HPV capsid is composed of viral type-specific L1 and evolutionarily conserved L2 proteins. Produced in heterologous systems, the L1 protein can self-assemble into VLPs, nanoparticles sized around 50–60 nm, used as prophylactic vaccines. Devoid of the viral genome, they are safe for users, offering no risk of infection because VLPs do not replicate. The immune response induced by HPV VLPs is promoted by conformational viral epitopes, generating effective T- and B-cell responses. Produced in different cell systems, HPV16 L1 VLPs can be obtained on a large scale for use in mass immunization programs, which are well established nowadays. The expression of heterologous proteins was evaluated at various transfection times by transfecting cells with vectors encoding codon-optimized HPV16L1 and HPV16L2 genes. Immunological response induced by chimeric HPV16 L1/L2 VLP was evaluated through preclinical assays by antibody production, suggesting the potential of broad-spectrum protection against HPV as a prophylactic nanovaccine. These platforms can also offer promising therapeutic strategies, covering the various possibilities for complementary studies to develop potential preventive and therapeutic vaccines with broad-spectrum protection, using in silico new epitope selection and innovative nanotechnologies to obtain more effective immunobiologicals in combating HPV-associated cancers, influenza, hepatitis B and C, tuberculosis, human immunodeficiency virus (HIV), and many other illnesses. Full article

Background: Chimeric Antigen Receptor (CAR) T-cell therapy has transformed the treatment of hematological malignancies, yet its application in solid tumors remains constrained by unique biological and logistical barriers. Objective: This review critically examines the evolving landscape of CAR T-cell therapy in solid malignancies, with a focus on antigen heterogeneity, the immunosuppressive tumor microenvironment, and risks of on-target, off-tumor toxicity. Methods: We outline recent advances in CAR engineering, including co-stimulatory optimization, dual- and multi-antigen targeting, armored CARs, and gene-edited constructs designed to enhance persistence and anti-tumor activity. Clinical progress is highlighted by recent FDA approvals of genetically modified T-cell therapies in synovial sarcoma and melanoma, underscoring the potential for broader solid tumor application. Additionally, we synthesize early-phase clinical trial findings across multiple solid tumor types (e.g., lung, colorectal, ovarian, glioblastoma), and discuss innovative approaches such as regional delivery, checkpoint blockade combinations, and incorporation of chemokine receptors for improved tumor infiltration. The review also considers future strategies, including artificial intelligence-guided target discovery and rational trial design to overcome translational bottlenecks. Conclusions: With expanding clinical experience and continued technological innovation, CAR T-cell therapy is steadily transitioning from an experimental strategy to a therapeutic reality in solid tumors, poised to reshape the future of cancer immunotherapy. Full article

Background: The COVID-19 pandemic provided a unique opportunity to evaluate how the human immune system responded to a novel pathogen and to determine whether immune responses initiated through natural infection differ from those elicited by vaccination against the same antigen. Here, we provide a comprehensive analysis of SARS-CoV-2 Spike (S-antigen)-reactive memory B cells (B_mem) elicited in previously immunologically naïve subjects following their first infection with the original Wuhan-Hu-1 (WH1)-like strain or their initial COVID-19 mRNA prime-boost regimen encoding the same WH1-S-antigen. In particular, we tested the hypothesis that the primary encounter of SARS-CoV-2 S-antigen in lung mucosal tissues during infection vs. intramuscular COVID-19 mRNA injection would elicit different B_mem responses. Methods: Cryopreserved peripheral blood mononuclear cell (PBMC) samples collected following primary infection with the WH1 strain or completion of the initial prime-boost vaccination regimen were tested in ImmunoSpot^® assays to assess the frequency, Ig class/subclass usage, and cross-reactivity of the S-antigen-reactive B_mem compartment; pre-pandemic blood draws served as naïve controls. Results: The B_mem repertoires generated post-infection vs. post-vaccination were found to be quite similar but with some subtle differences. In both cases, the prevalent induction of IgG1-expressing B_mem in similar frequencies was seen, ~30% of which targeted the receptor binding domain (RBD) of the WH1-S-antigen. Also, the extent of cross-reactivity with the future Omicron (BA.1) RBD was found to be similar for both cohorts. However, IgA⁺ B_mem were preferentially induced after infection, while IgG4⁺ B_mem were detected only after vaccination. Conclusions: B_mem elicited in naïve human subjects following SARS-CoV-2 infection or after WH1-S encoding mRNA vaccination were only subtly different, although the relevance of these differences as it relates to immune protection warrants further investigation. Our findings serve to illustrate the usefulness and feasibility of performing comprehensive monitoring of antigen-specific B cell memory in larger cohorts using the ImmunoSpot^® technique. Full article

Introduction: Dengue virus (DENV) remains a global health threat, with four distinct serotypes (DENV1-4) that complicate vaccine development due to low-affinity, cross-reactive antibodies that increase the risk of antibody-dependent enhancement (ADE). Objective: To address the challenge of inducing strictly serotype-specific immune responses, this study explored the use of targeting individual lymph nodes (LNs) for the creation of simultaneous but independent immune responses as a targeted approach to reduce cross-reactivity and improve vaccine specificity. Methods: In the initial experiments, targeting individual LN successfully induced specific germinal centers (GCs) for different antigens in distinct LNs, highlighting its potential to enhance immune specificity. This approach was further tested using two virus-like particle (VLP)-based vaccines based on AP205 for DENV1 and DENV4, selected due to their genetic divergence and to probe the potential to minimize cross-reactive immune responses. In this setup, AP205-DV1 and AP205-DV4 were administered in targeted separate LNs, and the specificity of the immune response was compared to subcutaneous administration of a mixture of both vaccines. Results: Our data show that targeting distinct LNs elicited antibodies with significantly higher avidity, which is a critical factor in determining the neutralizing capacity of the immune response. Avidity measurements confirmed that this segregation approach results in a more refined selection of high-affinity B cells. Neutralization experiments demonstrated that targeting distinct LNs with individual vaccines induced a more potent and serotype-specific neutralizing response, compared to the injection of a vaccine mixture. Conclusions: These findings suggest that targeting individual LNs could be a promising method for enhancing both the specificity and potency of immune responses, particularly for flaviviruses. Targeting distinct LNs by direct administration of individual vaccines into distinct watersheds rather than individual lymph nodes will offer the opportunity to facilitate the approach in humans. Full article