Search Results (4,523)

Epidermal growth factor receptor (EGFR) inhibitors remain a cornerstone in the treatment of metastatic colorectal cancer with RAS and BRAF wild-type cancer. Yet, primary and acquired resistance limit their benefit for many patients. A growing body of evidence reveals that resistance is not random but rather driven by a complex network of molecular alterations that sustain tumor growth independent of EGFR signaling. These include amplification of ERBB2 (HER2) and MET, activation of the PI3K and AKT pathways, EGFR extracellular domain mutations, and rare kinase fusions. The concept of negative hyperselection has emerged as a powerful strategy to refine patient selection by excluding tumors with these resistance drivers. Multiple clinical trials have consistently shown that patients who are hyperselected based on comprehensive molecular profiling achieve significantly higher response rates and improved survival compared to those selected by RAS and BRAF status alone. Liquid biopsy through circulating tumor DNA has further transformed this landscape, offering a noninvasive tool to capture tumor heterogeneity, monitor clonal evolution in real time, and guide rechallenge strategies after resistance emerges. Together, negative hyperselection, ctDNA-guided monitoring, and emerging therapeutics define a precision-oncology framework for identifying, tracking, and overcoming resistance to anti-EGFR therapy in mCRC, moving the field toward more effective and individualized care. Looking ahead, the development of innovative therapeutics such as bispecific antibodies, antibody drug conjugates, and RNA-based therapies promises to further expand in this challenging clinical scenario. These advances move precision oncology in colorectal cancer from concept to clinical reality, reshaping the standard of care through molecular insights. Full article

Despite improved diagnostic and treatment protocols, cancer remains a leading cause of morbidity and mortality globally. There are increasing rates of certain cancer types, including the highly drug-resistant colorectal cancer, in younger population cohorts. Therapeutic advances in oncology have led to the application of immunotherapy-based agents, including checkpoint inhibitors, antibodies, and adoptive cell therapies. Such immunotherapy approaches are greatly hindered by the tumour microenvironment and lack of specificity. Therapeutic vaccines are an innovative and rapidly advancing area of oncology, having potential for application as mono- and combined therapy in clinical settings, offering long term efficacy against disease recurrence. Advances in vaccine production using gene editing and bioprocessing techniques allows for novel vaccine types, including protein-based subunit vaccines, virus-like particle vaccines, and viral vector- and nucleic acid-based (RNA and DNA) vaccines. Cancer vaccines are designed to deliver specific tumour antigens, which activate anti-cancer cytotoxic T cells and helper T cells to produce immune memory, providing long term anti-cancer action. When coupled with advances in machine learning and artificial intelligence, anti-cancer vaccines may revolutionise oncology protocols and improve patient prognosis. This review aims to discuss current immunotherapy options in cancer treatment and recent advances in anti-cancer vaccine modalities. Full article

Eph receptor B2 (EphB2) overexpression is associated with poor clinical outcomes in various tumors. EphB2 is involved in malignant tumor progression through the promotion of invasiveness and metastasis. Genetic and transcriptome analyses implicated that EphB2 is a therapeutic target for specific tumor types. A monoclonal antibody (mAb) is one of the essential therapeutic strategies for EphB2-positive tumors. We previously developed an anti-EphB2 mAb, Eb₂Mab-12 (IgG₁, kappa), by immunizing mice with EphB2-overexpressed glioblastoma. Eb₂Mab-12 specifically reacted with the EphB2-overexpressed Chinese hamster ovary-K1 (CHO/EphB2) and some cancer cell lines in flow cytometry. In this study, we engineered Eb₂Mab-12 into a mouse IgG_2a type (Eb₂Mab-12-mG_2a) and a human IgG₁-type (Eb₂Mab-12-hG₁) mAb. Eb₂Mab-12-mG_2a and Eb₂Mab-12-hG₁ retained the reactivity to EphB2-positive cells and exerted antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity in the presence of effector cells and complements, respectively. In CHO/EphB2, triple-negative breast cancer, and lung mesothelioma xenograft models, both Eb₂Mab-12-mG_2a and Eb₂Mab-12-hG₁ exhibited potent antitumor efficacy. These results indicated that Eb₂Mab-12-derived mAbs could be applied to mAb-based therapy against EphB2-positive tumors. Full article

Nasopharyngeal carcinoma (NPC) is a rare malignancy with a distinct epidemiological pattern and is most often associated with Epstein–Barr virus (EBV). EBV plays a critical role in NPC pathogenesis, with viral proteins driving oncogenesis by altering immune regulation, apoptosis, and tumor progression. The unique molecular landscape of NPC presents both challenges and opportunities for therapeutic development, particularly in the recurrent and metastatic (R/M) setting, where treatment resistance remains a major hurdle. While platinum-based chemotherapy has traditionally been the standard of care for R/M NPC, immune checkpoint inhibitors (ICIs) have emerged as a key component of treatment. However, both intrinsic and acquired resistance to PD-1/PD-L1 blockade underscore the need for alternative strategies, including modulation of alternative immune checkpoints and simultaneous engagement of non-redundant pathways to enhance responses and durability. Leveraging EBV-driven biology, emerging immunotherapeutic approaches, such as EBV-specific adoptive cellular therapies and therapeutic vaccines, aim to induce durable immunity to viral proteins. Additionally, targeted therapies including receptor tyrosine kinase inhibitors, epigenetic modulators, and antibody–drug conjugates are redefining precision medicine by selectively delivering cytotoxic agents to tumors. With growing insights into the biology of NPC and evolving therapeutics, the integration of immunotherapy, targeted agents, and biomarker-driven strategies is poised to transform NPC treatment, emphasizing biology-driven, multimodal approaches to optimize patient outcomes. Full article

Background/Objectives: The COVID-19 pandemic and the development of vaccines provided the opportunity to monitor disease prevalence and outcomes, vaccinations, their side effects and serological responses in patients with inflammatory bowel disease (IBD). Methods: IBD patients of the outpatient clinic at the University Hospital Heidelberg who completed at least one questionnaire on COVID-19 and related vaccinations from July 2021 to August 2022 were included. Spike-IgG antibody titres were determined. Friedman tests, Wilcoxon signed-rank tests and Kruskal–Wallis tests were used for comparisons. The influence of IBD therapy was analysed using linear models with mixed effects. Results: The cohort included 520 patients (269 females, mean age = 45.3 years, 60.6% with Crohn’s disease, 35.4% with ulcerative colitis, and 4.0% with unclassified IBD). Four hundred eighty patients (92.3%) received at least one COVID-19 vaccination, and 154 patients (29.6%) were infected by SARS-CoV-2. Among all of them, 94.4% achieved seroconversion. Triple-vaccinated patients with additional SARS-CoV-2 infection developed the highest serological responses (χ² = 16.51, p < 0.001, df = 3). An antibody decay over time was observed after the second (p < 0.001) and third vaccinations (p < 0.001). Regarding individual IBD medications, no differences in mean titres were found after two (χ² = 6.60, p = 0.36, df = 6) versus three vaccinations (χ² = 4.97, p = 0.42, df = 5). Linear models with mixed effects revealed no influence of IBD therapies on serological responses. Conclusions: The highest serological responses were observed in IBD patients after three vaccinations plus SARS-CoV-2 infection without significant differences between IBD therapies. Full article

Background: Sirolimus is an effective treatment for kaposiform hemangioendothelioma (KHE), a rare vascular tumor in children. However, its immunosuppressive properties raise concerns regarding the safety and efficacy of vaccinations during treatment. This study aims to evaluate the safety and immunogenicity of inactivated and live-attenuated vaccines administered to pediatric KHE patients undergoing sirolimus therapy. Methods: We conducted a prospective study involving 56 KHE children receiving sirolimus who were vaccinated during treatment. Data on vaccine-related adverse events were collected to assess safety. Immunogenicity was evaluated by measuring seroconversion or protective antibody titers against vaccines, including Hepatitis B, DTaP, and MMR. Results: Among 56 catch-up vaccinated children, no serious adverse events related to vaccination were observed. Mild local or systemic reactions occurred in a minority of patients. Serological analysis demonstrated that children with kaposiform hemangioendothelioma (KHE) receiving sirolimus therapy were able to generate and sustain robust protective antibody responses following vaccination. High seroconversion rates and antibody titers were observed for both inactivated vaccines (e.g., hepatitis B and DTaP) and live-attenuated vaccines (e.g., MMR). Protective antibody levels were maintained both within 3 months and beyond 6 months post-vaccination, indicating durable immunogenicity under sirolimus treatment. Conclusions: Vaccination during sirolimus therapy appears to be safe and immunogenic in children with KHE. These findings support the administration of both inactivated and live-attenuated vaccines under appropriate clinical monitoring in this rare patient population. Full article

Background/Objectives: Multifocal Motor Neuropathy (MMN) and Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) are immune-mediated polyneuropathies often treated with immunoglobulin therapy. They were prioritized for COVID-19 vaccination during the pandemic. However, their immune response following COVID-19 vaccination remains unclear. We investigated short- and long-term immune responses to COVID-19 vaccination in patients with MMN and CIDP compared to controls. Methods: In a prospective observational study, patients with CIDP or MMN and matched controls were followed over 24 months. Controls were age- and sex-matched 1:9. Participants received COVID-19 vaccines in accordance with the Danish vaccination program. Primary outcomes were levels of SARS-CoV-2 IgG antibodies and virus-neutralizing capacity. A positive vaccine response was defined as IgG > 225 AU/mL and neutralizing capacity ≥ 25%. Results: We included 34 patients and 306 matched controls. While baseline SARS-CoV-2 IgG levels were similar, controls exhibited higher IgG levels at 6- (mean difference, 88%; p = 0.008), 18- (91%; p = 0.023), and 24 months (160%; p < 0.001). Neutralization capacity was also higher in controls at 6 (10%, p = 0.004), 18 (7%, p < 0.001), and 24 months (9%, p = 0.002). Despite this, the proportion of vaccine responders did not differ between the two groups after 24 months (p = 0.196). In patients receiving immunoglobulin therapy, IgG levels were lower than in controls at 24-month follow-up alone (56%, p < 0.001); all demonstrated a positive vaccine response. Conclusions: Patients with CIDP and MMN demonstrated a positive humoral response to COVID-19 vaccination. Although IgG and neutralization levels were lower than in controls, all patients receiving immunoglobulin therapy were vaccine responders. Full article

Background/Objectives: Hypertriglyceridemia (HTG) is a common multifactorial metabolic disorder often with genetic predisposition. Multiple lines of evidence support a causal role of triglyceride-rich lipoproteins (TRLs) in atherosclerotic cardiovascular disease (ASCVD), with severe HTG leading to pancreatitis and hepatic steatosis. This review covers TRL metabolism, causes and consequences of HTG, current management, and emerging TRL-targeted therapies. Methods: A narrative review was conducted. Results: Pharmacologic therapy with fibrates and omega-3 fatty acids remains the standard treatment for HTG but its efficacy in preventing pancreatitis and ASCVD is limited. Genetic studies have identified apolipoprotein C-III (ApoC-III) and angiopoietin-like 3 (ANGPTL3), both inhibitors of lipoprotein lipase, as potential therapeutic targets for reducing TG levels and ASCVD risk. Monoclonal antibodies and RNA-based therapies have enabled the development of inhibitors of ApoC-III and ANGPTL3, with promising results in phase 2 and small phase 3 trials. Angiopoietin-like 4 inhibitors and Fibroblast growth factor 21 analogs are in early-stage clinical development. Conclusions: Current pharmacologic therapies exhibit notable limitations in effectively managing severe HTG and in reducing the risk of ASCVD. Emerging therapies targeting TRLs metabolism showed favourable results in initial clinical trials. Full article

This review aims to point out the main achievements in the cutting-edge field of aptamer nanotechnology and its applications in the most frequent neuro-oncological and neurodegenerative diseases. The article discusses the properties, advantages and drawbacks of aptamers (AP), and their design and selection by various SELEX methods, as well as the synergical advantages as theranostics of the aptamer-functionalized nanoparticles (Ap-NP). The Ap-nanoconjugates properties are compared to those of Ap and unconjugated NP. Moreover, the article comparatively analyzes the aptamer-based approaches vs. antibody-drug conjugates vs. exosome-based delivery systems vs. unconjugated NP, as targeted therapies in neurodegenerative diseases and gliomas. The review presents major challenges in Ap-NP conjugates’ clinical progress (concerning the in vivo enzymatic stability, blood–brain barrier (BBB) permeability, selective intracellular uptake in the brain parenchyma and target tissues, rapid renal clearance, off-target toxicity, immunogenicity, reproductible manufacturing) and the investigated developmental strategies to solve them. Furthermore, relevant examples and comparative insights regarding preclinically tested Ap and Ap-NP conjugates are presented for targeted delivery systems loaded with chemotherapeutical drugs or genes, Ap-siRNA chimeras and immunotherapeutical aptamers, which are evaluated in glioblastomas (GBM), amyloidogenic diseases and multiple sclerosis (MS); radiotherapy enhancers in GBM; aptasensors for diagnostic and bioimaging-guided therapy in GBM, MS and amyloidopathies. The review finally points out future research directions in order to accelerate the clinical translation and the real-world impact as theranostics of the most preclinically advanced Ap-NP conjugates in major neuro-oncological and neurodegenerative disorders. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterised by cognitive decline, synaptic loss, and multifaceted pathology involving amyloid-β (Aβ) aggregation, tau hyperphosphorylation, neuroinflammation, and impaired proteostasis. In recent years, biologic therapies, such as monoclonal antibodies, vaccines, antisense oligonucleotides (ASOs), and gene therapies, have gained prominence as promising disease-modifying strategies. In this review, we provide a comprehensive synthesis of current biologic approaches under clinical evaluation for AD. Drawing on data curated from ClinicalTrials.gov (as of 2025), we systematically summarise the molecular targets, therapeutic modalities, mechanisms of action, trial phases, and sponsors of over 60 biologic agents. These include Aβ-directed antibodies targeting distinct conformers such as protofibrils, pyroglutamate-modified species, and soluble oligomers; tau-targeted immunotherapies and RNA-based interventions; and emerging platforms focused on neuroimmune modulation, peptide hormones, and microbiota-based strategies. Gene and RNA therapeutics, particularly ASOs and small interfering RNAs (siRNAs) delivered intrathecally or via lipid nanoparticles, are also reviewed for their potential to modulate intracellular targets with high specificity. We also analyse the historical landscape of biologic candidates that failed to reach approval, discussing key reasons for trial discontinuation, including lack of clinical efficacy, safety concerns (e.g., amyloid-related imaging abnormalities), or inadequate biomarker responses. These cases offer crucial insights for refining future drug design. Looking ahead, we highlight major challenges and evolving perspectives in AD biologic therapy: expanding therapeutic targets beyond Aβ and tau, overcoming delivery barriers to the brain, designing prevention-oriented and genetically stratified trials, and navigating regulatory and ethical considerations. Together, these efforts signal a paradigm shift in AD drug development, from symptomatic treatment to mechanism-based precision biologics. By integrating real-time clinical trial data with mechanistic insight, this review aims to inform both translational research and therapeutic innovation in AD. Full article

Nephrotic syndrome (NS) is a complex kidney disorder characterized by profound proteinuria, hypoalbuminemia, hyperlipidemia, and edema, significantly impacting patients’ quality of life. While corticosteroids and calcineurin inhibitors (CNIs) have traditionally been the primary treatments, B cell-targeted therapies, especially the anti-CD20 monoclonal antibody rituximab, have transformed the management of steroid-dependent and multidrug-resistant NS (MRNS). Rituximab has demonstrated efficacy in reducing relapse rates and steroid dependence by depleting CD20+ B cells, which play a pivotal role in autoantibody production and immune dysregulation. However, limitations such as incomplete B cell depletion, immunogenicity leading to anti-rituximab antibodies, and variable efficacy in refractory cases have led to the development of next-generation therapies. This review critically examines recent advances in B cell-targeted therapies for NS, with a particular focus on overcoming the limitations of conventional rituximab treatment. This review systematically analyzes next-generation anti-CD20 monoclonal antibodies, CD38-targeted therapies, and emerging CAR-T cell approaches, evaluating their distinct mechanisms of action and clinical trial outcomes. The analysis extends to innovative combination strategies and biomarker-guided treatment algorithms for refractory cases. By synthesizing preclinical data with clinical evidence, this work provides a framework for optimizing therapeutic decision-making in NS, while identifying key knowledge gaps that warrant future investigation. Collaborative research and translational studies are essential for advancing precision medicine in NS, ensuring that new therapies provide lasting clinical benefits for patients. The evolving field of anti-B cell therapies marks a new era in managing refractory NS, offering hope for better long-term prognoses. Full article

Background: Ustekinumab (UST) is a monoclonal antibody (mAb) used in the treatment of inflammatory bowel disease (IBD). Elevated serum concentrations are typically associated with improved therapeutic outcomes, and therapeutic drug monitoring (TDM) is a useful tool for guiding mAbs treatment. This study aimed to develop a dried blood spot (DBS) method for TDM of UST in patients with IBD. Methods: The commercial enzyme-linked immunosorbent assay for plasma samples was optimized for DBS samples and subsequently validated according to international guidelines for classical and DBS-specific validation parameters. It was then applied to analyze serum and DBS samples obtained from venous and capillary blood of IBD patients undergoing UST therapy. Results: The method was linear (3–12 mg/L) with acceptable inter-day accuracy (90.1–106%) and precision (<12%). We confirmed that there was no hematocrit effect and that DBS samples were stable for one month under room conditions. A linear model was developed between venous DBS and serum UST concentrations, which showed no systemic bias, and 71% of the samples were within ±20% of the mean. In addition, a linear correlation between venous DBS and capillary DBS samples was established, showing no significant bias, with 84% of samples within ±20% of the mean. Finally, a novel strategy was developed to overcome the limitations of poor-quality samples (irregular shapes) based on area image analysis. Conclusions: The newly developed DBS method is the first to enable reliable measurement of UST in capillary blood, appropriate clinical interpretation of the measured concentrations, and remote monitoring of patients in the early phase of therapy. Full article

Background/Objectives: Human epidermal growth factor 2 (HER2) scoring is critical for modern breast cancer therapies, especially with emerging indications of antibody–drug conjugates for HER2-low tumors. However, inter-observer agreement remains limited in borderline cases. Automatic artificial intelligence-based scoring has the potential to improve diagnostic consistency and scalability. This study aimed to develop two transformer-based models for HER2 scoring of breast cancer whole-slide images (WSIs) and compare their performance. Methods: We adapted a large-scale foundation model (Virchow) and a lightweight model (TinyViT). Both were trained using patch-level annotations and integrated into a WSI scoring pipeline. Performance was evaluated on a clinical test set (n = 66), including clinical decision tasks and inference efficiency. Results: Both models achieved substantial agreement with pathologist reports (linear weighted kappa: 0.860 for Virchow, 0.825 for TinyViT). Virchow showed slightly higher WSI-level accuracy than TinyViT, whereas TinyViT reduced inference times by 60%. In three binary clinical tasks, both models demonstrated a diagnostic performance comparable to pathologists, particularly in identifying HER2-low tumors for antibody–drug conjugate (ADC) therapy. A continuous scoring framework demonstrated a strong correlation between the two models (Pearson’s r = 0.995) and aligned with human assessments. Conclusions: Both transformer-based artificial intelligence models achieved human-level accuracy for automated HER2 scoring with interpretable outputs. While the foundation model offers marginally higher accuracy, the lightweight model provides practical advantages for clinical deployment. In addition, continuous scoring may provide a more granular HER2 quantification, especially in borderline cases. This could support a new interpretive paradigm for HER2 assessment aligned with the evolving indications of ADC. Full article

Background: Children with inflammatory bowel disease (IBD) are at heightened risk for vaccine-preventable infections because of underlying immune dysregulation and long-term immunosuppressive therapy. Despite published guidelines affirming vaccine safety, real-world coverage remains suboptimal. It is a pilot, single-country survey designed to explore baseline knowledge and practices regarding vaccination in paediatric IBD within a specific local healthcare context. Objective: The objective of this study is to evaluate the knowledge, attitudes, and practices of paediatric gastroenterologists (PGs) regarding the immunisation of children with IBD. Methods: We conducted an exploratory pilot, cross-sectional survey of paediatric gastroenterologists in Russia, focusing on immunisation knowledge and practical barriers in routine care. A cross-sectional, anonymous online survey was distributed to PGs nationwide between January 2022 and April 2022. The online questionnaire explored demographic characteristics, awareness of international recommendations, perceptions of vaccine safety at various disease and treatment stages, and routine vaccination practices. Responses were analysed with non-parametric statistics (α = 0.05). In a parallel prospective cohort, the vaccination certificates of 98 paediatric IBD patients (January 2022–April 2023) were audited to quantify real-world coverage. Results: Fifty-one PGs completed the survey. Forty-one per cent agreed that vaccines do not provoke IBD flares, while 17.6% considered live vaccines acceptable during immunosuppressive remission. Nearly one-third (32%) did not personally oversee immunisation, and 18% occasionally discouraged vaccination during therapy. Only 35.3% deemed baseline serology essential before starting immunosuppression; 46.5% supported antibody checks immediately prior to vaccination. The certificate audit revealed a full schedule completion rate of 66.3% for measles–mumps–rubella and 74.2% for hepatitis B, contrasting with parental reports of 82.3% complete coverage. Conclusions: Knowledge gaps, limited guideline awareness, and parental concerns contribute to suboptimal vaccination of paediatric IBD patients. Targeted educational initiatives, clearer shared-care pathways, and routine certificate audits are needed to close the coverage gap and reduce infection-related morbidity. Findings are hypothesis-generating and reflect local practice; as a pilot study, results should be interpreted with caution and may not generalise beyond similar settings. Full article

The therapeutic landscape of adults with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is undergoing a paradigm shift, driven by the development of immunotherapy-based “chemo-free” and “chemo-light’ regimens. These strategies aim to achieve high efficacy with reduced toxicity, particularly in older adults who may not tolerate intensive chemotherapy. In Philadelphia chromosome-positive (Ph+) BCP-ALL, the incorporation of ABL tyrosine kinase inhibitors (TKIs) with blinatumomab (CD3/CD19 bispecific T-cell engager) has shown remarkable efficacy, with some studies reporting molecular response rates in the range of 90–100% and long-term survival exceeding 80% without the need for intensive chemotherapy or allogeneic hematopoietic cell transplantation (allo-HCT). In Philadelphia-negative (Ph−) BCP- ALL, an immunotherapy-based combination of blinatumomab and inotuzumab ozogamicin (anti-CD22 antibody-drug conjugate) has demonstrated high rates of complete remission and measurable residual disease (MRD) negativity, with manageable toxicity. While chimeric antigen receptor (CAR) T-cell therapy remains a transformative option for relapsed/refractory B-ALL, its integration into frontline treatment is still under investigation. Ongoing trials are evaluating the optimal sequencing and combinations of these agents and their potential to obviate the need for chemotherapy and/or allo-HCT in selected patients. As evidence continues to accumulate, chemo-free and chemo-light regimens, incorporating minimal chemotherapy with targeted agents to balance efficacy and reduced toxicity, are poised to redefine the standard of care for adults BCP-ALL, offering the possibility of durable remissions with reduced treatment-related morbidity. Full article