Search Results (2,870)

Keyhole limpet hemocyanin (KLH) is a large copper-containing glycoprotein derived from the marine gastropod Megathura crenulata. Originally functioning as an oxygen transport molecule, KLH has gained considerable attention in biomedical research due to its exceptional immunogenic and immunostimulatory properties. Its complex quaternary structure, extensive glycosylation, and xenogeneic origin contribute to its ability to induce robust humoral and cellular immune responses in mammals without significant toxicity. These characteristics have established KLH as one of the most widely used carrier proteins in vaccine development and as a valuable model antigen for the investigation of adaptive immune responses. This review summarizes current knowledge on the biological origin, molecular structure, biosynthesis, and post-translational processing of KLH, with particular emphasis on its unique glycan architecture and its contribution to immunogenicity. Advances in glycomic and structural analyses have revealed an extraordinary diversity of N-linked glycans that distinguish KLH from mammalian glycoproteins and play a central role in immune recognition. The review further discusses methods for KLH isolation, purification, and characterization, as well as its application in experimental and clinical immunology as a standardized tool for assessing antigen-specific immune responses. In addition, the therapeutic and translational potential of KLH is examined across multiple biomedical fields. Particular attention is given to its use as a carrier protein in conjugate vaccines, its role in cancer immunotherapy, and its emerging applications in the development of vaccines and immunotherapeutic strategies targeting neurodegenerative diseases, atherosclerosis, and substance use disorders. Collectively, the available evidence highlights KLH as a unique marine-derived biomolecule that bridges glycobiology, immunology, and translational medicine, and continues to serve as an important platform for the development of next-generation immunotherapeutics and vaccine technologies. Full article

Human Papillomavirus (HPV) is a highly prevalent sexually transmitted infection associated with malignancies of the cervix, vulva, and vagina. While prophylactic vaccination with Gardasil^®9 is FDA-approved through age 45, no clinical trials have evaluated its use in older adults who remain sexually active and at risk for HPV-related cancers. We describe the case of a woman who presented with recurrent high-risk HPV and received the three-dose Gardasil^®9 series off-label at the age of 67. Following vaccination, her cervical cytology was negative for HPV and subsequent colposcopy did not demonstrate any evidence of intraepithelial lesion or malignancy. As this is a single case report, this temporal association cannot establish that vaccination caused viral clearance. Nonetheless, this case raises important questions regarding age-based HPV vaccination limits. Immunosenescence in older populations may impair viral clearance and could increase cumulative risk of progression from dysplasia to malignancy. Vaccination may therefore serve both prophylactic and potentially therapeutic roles; however, this must be evaluated in further controlled studies. This case highlights the need for further research into HPV vaccination in patients over the age of 45 years with or without history of HPV infection. Full article

The XII Forum on Translational Immunology and Cancer Immunotherapy (FIT Cancer 12), organized by the Spanish Group for Cancer Immuno-Biotherapies (GÉTICA), took place on 5–6 March 2026 in Málaga, Spain. This edition gathered clinicians, basic scientists, and translational researchers from Spain and international institutions to discuss the latest advances in cancer immunotherapy. Scientific contributions spanned a wide range of topics, including engineered T-cell therapies targeting solid tumors and hematological malignancies, neoantigen-based cancer vaccines in preventive and therapeutic settings, oncolytic virotherapy combined with immune cell recruitment strategies, metabolic reprogramming of the tumor microenvironment, epigenetic liquid biopsy biomarkers, and the management of immune-related adverse events in clinical practice. The abstracts presented here reflect the breadth and translational depth of immuno-oncology research currently underway within the GÉTICA network and its international collaborators. Full article

This review describes the cellular and molecular mechanisms underlying multi-dose bacille Calmette-Guérin (BCG) as an investigational immunotherapy for glycemic improvement in autoimmune diabetes. The BCG data is most often human clinical trial data over the last 15 years paired with mechanistic insights. BCG as a vaccine has an excellent safety record with a century-long safety record in tuberculosis prevention worldwide and, for 36 years, has been FDA-approved at higher doses for the treatment of bladder cancer. Our group and others have conducted multiple clinical trials evaluating multi-dose BCG immunotherapy in adults with the two forms of longstanding autoimmune diabetes. In type 1 diabetes (T1D), clinical trials of multi-dose BCG have shown stable repeated reductions in the FDA-recommended biomarker glycated hemoglobin (HbA1c) to near-normal levels (vs placebo) for at least 8 years. This improvement paradoxically occurs without any recovery of pancreatic function from its negligible baseline level. Evidence from long-term trials, together with companion global mechanistic studies, indicates that glycemic improvement is associated with BCG-induced correction of aerobic glycolysis defects in lymphoid and myeloid cells, an outcome also observed in the granuloma of BCG’s close relative, tuberculosis. Restoration of energy metabolism to aerobic glycolysis in diabetic lymphoid cells increases glucose utilization, thereby enhancing systemic glucose uptake from the bloodstream, as demonstrated by longitudinal PET/CT imaging. In contrast, latent autoimmune diabetes in adults (LADA), a form of slow autoimmune diabetes that occurs late into adulthood, has minimal or lacks the clinically significant aerobic glycolysis defect. In LADA with multi-dose BCG immunotherapy glycemic improvement in BCG-treated patients does not occur commonly, based on 8 years of data. LADA nevertheless displays other favorable immune and clinical responses suggestive of BCG-induced regulatory T cell (Treg) induction. In LADA, multi-dose BCG decreases inflammation, thus halting pancreatic autoimmunity with insulin rescue and also halts inflammatory driven insulin resistance. BCG’s consistent clinical benefits in autoimmune diabetes coincide with the gradual pace of upstream epigenetic reprogramming of genes involved in metabolic and T cell pathways without changing genotype. Understanding the mechanistic chain linking BCG-induced epigenetic changes to clinical efficacy may offer insights into the treatment and potential prevention of autoimmune diabetes. Full article

Despite longstanding vaccine availability, human papillomavirus (HPV) remains the most common sexually transmitted infection in the United States and a leading cause of preventable cancers. Additionally, HPV vaccination rates remain below other routinely recommended adolescent immunizations, particularly in rural populations. This study aimed to identify barriers related to healthcare access, socioeconomic conditions, cultural beliefs, and provider–patient communication in rural communities. A bibliographical review of articles published in English from 2020 to 2025 and an analysis of national datasets were conducted to establish trends in HPV vaccination rates. State-level HPV vaccination data for adolescents aged 13–17 years were obtained from America’s Health Rankings and the Centers for Disease Control and Prevention National Immunization Survey-Teen. States were classified as predominantly rural or urban using Rural–Urban Continuum Codes, and mean vaccination completion rates were compared. The mean HPV vaccination completion rate was lower in rural states (60.55%) compared to urban states (67.31%); however, this difference did not meet the selected threshold for statistical significance (p = 0.025). Barriers identified in the literature included reduced access to healthcare, differences in provider communication, socioeconomic constraints, and limited health literacy in rural communities. Of the identified barriers, healthcare provider recommendations emerged as one of the strongest predictors of vaccine acceptance. These findings highlight multilevel determinants contributing to differences in HPV vaccine uptake and underscore the need for targeted, evidence-based strategies to improve vaccine access and coverage in underserved adolescent populations. Full article

Background/Objectives: Human papillomavirus (HPV) causes several cancers in both females and males. In France, HPV vaccination coverage among adolescents remains suboptimal, particularly among boys, and knowledge about HPV infection and vaccination is limited. This study assessed HPV-related knowledge, attitudes, and vaccination uptake among adolescents attending Rural Family Homes (RFHs). Methods: A sequential mixed-methods study was conducted between September 2023 and June 2024 among 895 adolescents aged 15–19 years attending 19 RFHs in France. Participants completed an anonymous self-administered questionnaire assessing sociodemographic characteristics, general vaccination knowledge, HPV-related knowledge, vaccination status, and determinants of vaccine uptake. Focus groups involving 59 adolescents explored perceptions of, barriers to, and information needs regarding HPV vaccination. Quantitative data were analyzed using chi-square tests and multivariable logistic regression; qualitative data were analyzed thematically. Results: Overall, 44% of participants had received at least one HPV vaccine dose and 31% received at least two doses. Coverage was significantly higher among girls than boys (55% vs. 28%, p < 0.001). Only 35% demonstrated adequate HPV-related knowledge. Parents and general practitioners were the main information sources. Vaccination uptake was associated with favorable subjective norms, female sex, and the belief that vaccination reduces cancer risk. Qualitative findings revealed persistent misconceptions about HPV-related risks, particularly among boys, and a substantial need for reliable information. Conclusions: Adolescents attending RFHs showed limited HPV-related knowledge and suboptimal vaccination coverage, particularly boys. Parental support and healthcare professional recommendations were associated with vaccine uptake. Targeted educational interventions and catch-up vaccination strategies among this population are needed to improve coverage and reduce the burden of HPV-related diseases. Full article

Cancer vaccination addresses four distinct problems: preventing oncogenic infection, intercepting premalignant clones, clearing molecular residual disease, and treating established cancer. This hypothesis framework proposes seven sequential gates for antigen-defined, HLA-restricted T-cell vaccines: tumor specificity, natural peptide–HLA presentation, population coverage, persistence under immune selection, selective T-cell recognition, manufacturability, and randomized clinical benefit. The proposed architecture combines a pre-manufactured core of validated shared antigens with a personalized shell when shared targets do not cover the tumor or the patient’s HLA type. Current evidence supports restraint. Individualized mRNA neoantigen therapy with pembrolizumab produced a recurrence-free-survival signal in a randomized phase 2b melanoma trial, whereas a 20-antigen shared cassette produced immunodominant responses toward encoded TP53 epitopes rather than the KRAS neoantigens carried by the tumors. No quantitative coverage or persistence score is presented because the required population frequencies and persistence measurements cannot be supplied reliably from the published record. Four falsifiable predictions define the experiments needed to test presentation-first selection, antigen persistence, escape-route independence, and biomarker-directed treatment. The framework is therefore a research agenda, not a validated decision tool. Full article

Although cryoablation of tumor tissue is known to induce systemic antitumor immune responses, the underlying mechanisms remain poorly understood, and therapeutic efficacy is often unpredictable. During cryoablation, the cryoprobe creates a temperature gradient, resulting in a central zone of lethal tissue destruction and a periphery characterized by sub-lethal injury. In this peripheral zone, cells undergo programmed cell death triggered by thermal shock and ischemia. A widely cited, yet debated, hypothesis suggests that these apoptotic events in the tumor periphery may suppress the antitumor immune response. The purpose of this study was to experimentally test this hypothesis. We utilized the murine breast cancer cell line (4T1-Luc) and a panel of human cell lines (MCF-7, BT-20, BT-474, MDA-MB-231, MDA-MB-453, HBL-100). Following validation via flow cytometry using Annexin V-AF488, Rhodamine 123, TMRE, PI, and 7-AAD, we established −7 °C and −80 °C as temperature conditions that predominantly induce apoptosis and necrosis, respectively. These conditions were used to prepare cryo-treated 4T1-Luc cells for the vaccination of syngeneic mice. Ten days post-immunization, the efficacy of the treatment was evaluated in subcutaneous solid tumor and lung metastasis models by monitoring tumor growth, quantifying tumor-specific antibodies, performing histological analysis of tumor and lung tissues, and quantifying lung metastases via PCR and luciferase assays. Contrary to the initial hypothesis, our findings demonstrate that tumor cells undergoing sub-lethal cryoablation do not acquire immunosuppressive characteristics. Instead, they promote systemic antitumor immunity. Although antitumor immunity induced by apoptotic and necrotic tumor cells was comparable in a subcutaneous tumor model, vaccination with necrotic tumor cells proved more effective than vaccination with apoptotic cells in controlling lung metastasis formation. Full article

Background/Objectives: Regional HPV genotype data for the Yangtze River Delta remain scarce, limiting evidence-based vaccine and screening policies. This study characterised the HPV genotype distribution, the vaccine protection gaps, and the co-infection network structure among clinical women in Wuxi, a prefecture-level city in the Yangtze River Delta region of Jiangsu Province, China. Methods: We retrospectively analysed all 8515 cervical HPV genotyping records from Xishan People’s Hospital of Wuxi City (January 2024–June 2025) using a 23-type fluorescent PCR panel classified by the International Agency for Research on Cancer (IARC) criteria. Results: The overall HPV prevalence was 22.83% (1944/8515; 95% CI 21.9–23.8%). The five leading types were HPV52 (4.82%), HPV58 (3.14%), HPV16 (2.96%), HPV53 (2.50%), and HPV42 (2.08%); HPV18 (0.74%) ranked below two unvaccinated carcinogens, HPV51 (1.76%, IARC Group 1) and HPV68 (1.68%, Group 2A). The age-stratified prevalence was U-shaped (χ² = 123.27, p < 0.001), peaking at ≤20 years (52.94%; exploratory, n = 51) and ≥61 years (34.66%). Among the 1944 women with positive results, 43.0% were completely unprotected by the nonavalent vaccine, and 60.4% harboured at least one non-9vHPV type; HPV51 and HPV68 together accounted for 15.08% of the positive cases. In the co-infection network (n = 585 multiple-type infections), HPV52 achieved the highest degree centrality (281 co-infection events; normalised degree = 0.0218) and appeared in 8 of the 15 most frequent dual-type pairs, with observed/expected ratios of 6.5–14.8-fold. Conclusions: These findings reveal a clinically substantial vaccine protection gap and support the prioritisation of HPV51 and HPV68 in next-generation vaccine design. Full article

Immune checkpoint blockade has changed the management of several digestive system cancers, but its impact is highly context dependent. This review evaluates evidence for esophageal, gastric and gastroesophageal junction, colorectal, hepatocellular, biliary tract and gallbladder, and pancreatic cancers. Randomized phase III trials have established chemoimmunotherapy or dual-checkpoint strategies in advanced esophageal cancer, biomarker- and regimen-dependent first-line therapy in gastric cancer, PD-1-based therapy for MSI-H/dMMR colorectal cancer, atezolizumab–bevacizumab and STRIDE for unresectable hepatocellular carcinoma, and chemoimmunotherapy for advanced biliary tract cancer. Recent results also expand perioperative treatment: neoadjuvant checkpoint blockade produces high pathological response rates in dMMR colon cancer, adjuvant atezolizumab plus mFOLFOX6 improves disease-free survival in stage III dMMR colon cancer, and perioperative serplulimab improves event-free survival in PD-L1-positive resectable gastric cancer. These advances coexist with important negative findings. Pembrolizumab-containing therapy did not meet superiority end points in KEYNOTE-062, the initial adjuvant signal in IMbrave050 was not sustained, and unselected pancreatic ductal adenocarcinoma remains largely resistant to checkpoint blockade. Early vaccine, cellular, TIGIT, radiomics, spatial, and multi-omics studies remain hypothesis-generating and require external or randomized validation. Clinical interpretation should integrate evidence maturity, biomarker validity, immune-related toxicity, patient-reported outcomes, cost, access, and manufacturing demands rather than response rate alone. Full article

Over the past decade, advances in sequencing technologies and computational pipelines enabled the development of personalized cancer vaccines (PCVs). Current PCV strategies primarily target cancer neoantigens generated by non-synonymous DNA mutations, which can result in altered amino acid sequences capable of eliciting tumor-specific immune responses. More recently, a distinct class of tumor-specific antigens (TSA), termed noncanonical or cryptic antigens, has emerged as an additional source of immunogenic targets. Unlike canonical neoantigens, noncanonical antigens typically cannot be identified by tumor/normal whole-exome sequencing, as they do not arise from classical DNA mutations. Instead, they are often associated with less well recognized and/or aberrant processes in the pathways from DNA to human leukocyte antigen (HLA)-presented peptides. Examples include transposable elements, circular RNA, translation of alternative open reading frames and/or long non-coding RNA, among others. Emerging evidence suggests that noncanonical antigens represent a substantial portion of the tumor-specific immunopeptidome and, similar to canonical neoantigens, are absent during thymic selection and can evade central tolerance and elicit T cell responses. Technological advances have increasingly facilitated the identification of noncanonical antigens. Long-read RNA sequencing reveals noncanonical transcripts by improving transcriptome assembly, while ribosome profiling provides genome-wide maps of actively translated regions, facilitating the discovery of peptides from aberrant translation events. Specialized molecular approaches enable enrichment and sequencing of circular RNAs, and immunopeptidomics using mass spectrometry allows for direct characterization of HLA-presented peptides. Together, these technological advances have led to an increasing interest in prioritizing and targeting noncanonical antigens in the next generation of PCVs. This review provides an overview of the diverse origins of TSAs beyond classical neoantigens and discusses emerging approaches that may enable the integration of these antigens in future clinical trials. Full article

Clinical guidelines remain the foundation of evidence-based oncology, translating population-derived evidence into treatment recommendations for defined patient groups. However, patients with rare cancers, complex tumor biology, or treatment-refractory disease may reach a point at which applicable evidence is limited, or guideline-recommended treatment options have been exhausted. We propose Personalized Oncology as a complementary framework for treatment selection in these situations. Rather than asking only which treatments benefited similar patients, Personalized Oncology asks which available treatment is expected to provide the most favorable benefit–risk profile for the individual patient. It does so by integrating population-derived medical evidence with patient-specific biological evidence generated from the individual cancer. Importantly, exhaustion of guideline-recommended treatments does not necessarily mean exhaustion of biologically supported treatment opportunities. The supporting evidence, rationale, alternatives, limitations, and uncertainty are documented to enable transparent clinical decision-making. Neither population-derived evidence nor patient-specific biological evidence determines in advance whether an individual patient will benefit. Treatment response must therefore be systematically monitored and incorporated into subsequent decisions. Personalized Oncology standardizes this process while preserving individualized clinical judgment. Systematic capture of each patient’s biology, treatment, and outcome can create a continuous learning framework in which experience from individual patients informs future cancer care. Full article

Background: Persistent human papillomavirus (HPV) can cause low- or high-grade cervical lesions, which may progress to cervical cancer. This prospective, multicenter, real-world study assessed the effectiveness, tolerability and safety of a Coriolus versicolor-based vaginal gel for the regression of HPV-related low-grade cervical lesions in routine Greek practice. Methods: PAPILOBS-GR is a multicenter, open-label, non-interventional, prospective observational, non-comparative study conducted across 45 sites in Greece. Women aged ≥18 years with ASCUS/LSIL cytology and concordant colposcopy were enrolled. Participants received Coriolus versicolor-based vaginal gel for six months. A second 6-month cycle was offered if needed. The primary endpoint was lesion regression. Secondary endpoints included HPV clearance, patient satisfaction, biopsy evolution, tolerability, and safety. Results: Of 524 enrolled patients (mean age: 34.4 ± 10.0 years; 40.5% HR-HPV), 494 (94.3%) completed the study. Overall, 75.9% achieved lesion regression (72.1% at 6 months and 34.0% at 12 months). HPV clearance occurred in 72.0% overall (68.1% at 6 months and 50.0% at 12 months). Exploratory comparisons showed generally consistent effectiveness across subgroups, including women with HR-HPV, those aged >40 years, and vaccinated participants. No significant differences in clinical endpoints were observed in association with age or vaccination status. Among 22 patients with baseline and 12-month biopsies, 59.1% showed histological improvement. Satisfaction scores exceeded 8/10 at 6- and 12-month follow-ups. Only two non-serious possibly product-related adverse events were reported. Conclusions: Coriolus versicolor-based vaginal gel was associated with high rates of lesion regression and excellent tolerability, reinforcing previous clinical findings and supporting its potential role as an adjunctive approach during watchful waiting for HPV-positive low-grade cervical lesions. Full article

Background/Objectives: Concern that COVID-19 vaccination causes pulmonary nodules persists because vaccination coincided with expanded computed tomography (CT), low-dose CT (LDCT) screening, post-COVID imaging and artificial intelligence (AI)-assisted detection. This review asks whether the current literature supports causality and how vaccination history should inform thoracic imaging. Methods: A focused search of PubMed, PubMed Central and the Cochrane Library was performed through 15 July 2026. Evidence was classified as direct or contextual; no PRISMA screening, risk-of-bias scoring or quantitative synthesis was performed. Results: Direct evidence remains sparse. One case report was too confounded for inference. A two-sample Mendelian randomization study found no broad lung disease risk signal, but nodules were not modeled and the heterogeneous endpoints were exploratory. An ecological study of 1,616,750 samples linked rising detection to SARS-CoV-2 infection waves and AI-assisted reading; lacking individual vaccination data, it cannot establish whether vaccination affected detection. Screening interruption produced the opposite pattern: Lung-RADS 4 nodules rose from 8% to 29%. The most reproducible post-vaccination thoracic finding is regional lymph-node activation on [18F]fluorodeoxyglucose positron emission tomography/computed tomography ([18F]FDG-PET/CT), an expected immune response rather than a parenchymal nodule. Conclusions: Current evidence is insufficient to establish vaccination as an independent, population-level cause of pulmonary nodules. Vaccination history should guide [18F]FDG-PET/CT interpretation; CT-detected parenchymal nodules warrant standard risk stratification. Full article

Background: Cervical cancer remains a major public health problem, causing approximately 660,000 new cases and 348,000 deaths annually, with more than 90% occurring in low- and middle-income countries. The WHO African Region accounts for approximately 20% of global cases and 30% of deaths. In November 2020, the World Health Assembly adopted the Global Strategy for Cervical Cancer Elimination with 90–70–90 targets for 2030. Multi-age cohort (MAC) campaigns have emerged as a high-impact strategy for achieving population-level HPV vaccination coverage. This study documents the implementation and outcomes of HPV MAC campaigns across Côte d’Ivoire, Ghana, Liberia, and Sierra Leone in 2025. Methods: This multi-country mixed-methods analysis integrated quantitative administrative campaign data with qualitative programmatic assessments across eight operational readiness domains from the WHO Immunization Readiness Assessment Tool. Data were collected between January and December 2025 from national reports, WHO supervision missions, and partner reports. Coverage analysis used administrative data triangulated with independent monitoring. Equity analysis used school enrolment data and geographic accessibility indices. Results: The campaigns targeted 7,376,096 girls aged 9–18 years and reached approximately 6,306,294, achieving 85.5% overall coverage. Côte d’Ivoire, Ghana, Liberia and Sierra Leone reported administrative coverage of 88.0%, 84.5%, 60.0% and 100%, respectively. All four countries achieved the minimum operational readiness threshold of 80% across all assessed domains. A total of 35,860 health workers were trained, with post-training competency scores increasing from 58.8% to 89.5%. Cold chain functionality exceeded 98% across all campaigns. A total of 314 cases of Adverse Events Following Immunization (AEFIs) were reported, all classified as mild, giving an approximate rate of 5.0 per 100,000 doses. Coverage gaps between in-school and out-of-school girls ranged from 18 to 35 percentage points. Conclusions: The findings suggest that large-scale adolescent HPV immunization can be successfully implemented in resource-limited settings when supported by political commitment, multisectoral coordination and adequate operational resources. The single-dose schedule transition under Gavi 6.0 offers opportunities to simplify delivery. Priority actions include integrating HPV into routine immunization, scaling equity strategies for out-of-school girls and ensuring sustainable financing. Full article