Search Results (4,546)

Therapeutic cancer vaccines represent a rational immunotherapeutic strategy aimed at inducing tumor-specific adaptive immune responses in patients with established malignancies. In contrast to prophylactic vaccines, these approaches must function within immunosuppressive tumor microenvironments characterized by antigenic heterogeneity, immune dysfunction, and dynamic tumor evolution. Effective vaccine design requires the integration of three essential components: the selection of appropriate tumor-associated or tumor-specific antigens, efficient delivery platforms that enable antigen presentation, and adjuvant systems that promote robust T-cell priming and expansion. Initial clinical investigations in B-cell malignancies and multiple myeloma demonstrated that idiotype-based vaccines can elicit tumor-specific immune responses. However, durable clinical benefit has been inconsistent, reflecting limitations in antigen selection, suboptimal immunogenicity, and tumor-mediated immune evasion. Over the past decade, advances in tumor genomics, next-generation sequencing, and immune monitoring have enabled the development of next-generation vaccine platforms, including dendritic cell-based approaches, personalized neoantigen vaccines, and mRNA-based technologies. Emerging evidence suggests that vaccine efficacy is highly dependent on disease context. Biologically favorable settings such as minimal residual disease (MRD) and post-transplant immune reconstitution provide reduced tumor burden and improved immune competence, thereby enhancing the likelihood of effective immune priming. In parallel, combination strategies incorporating immune checkpoint inhibitors, immunomodulatory agents, and cellular therapies are increasingly being explored to overcome tumor-induced immunosuppression. This review synthesizes current knowledge of therapeutic cancer vaccines in B-cell malignancies and multiple myeloma, with emphasis on immunologic mechanisms, antigen selection, vaccine platforms, and clinical evidence. We further propose a conceptual framework integrating tumor biology, immune context, and combination strategies to guide the rational development of next-generation vaccine therapies. Full article

Background/Objectives: Immune checkpoint inhibitors (ICIs) improve cancer outcomes but may induce immune-related adverse events. Myasthenia gravis (MG), myositis, and myocarditis may co-occur as an overlap syndrome (“Triple-M”), but population-level data remain limited. This study aimed to characterize the pharmacovigilance profile, overlap patterns, and reported fatality of Triple-M associated with ICIs. Methods: A FAERS pharmacovigilance analysis was conducted using OpenVigil FDA and the openFDA API. Disproportionality metrics (ROR, PRR, χ²) were used to evaluate signals for MG, myositis, and myocarditis across nine ICIs. Triple-M was defined as the co-reporting of all three events and was evaluated over the study period from August 2016 to September 2025. Results: Among 272,753 ICI reports, 1395 (0.51%) MG, 3173 (1.16%) myocarditis, and 2018 (0.74%) myositis cases were identified; all nine ICIs met signal-detection criteria for all three toxicities (χ² > 4). Pembrolizumab and nivolumab accounted for the highest absolute report counts, whereas nivolumab-relatlimab demonstrated the strongest disproportionality (ROR = 109.5 for MG, 106.4 for myocarditis, and 29.0 for myositis). Triple-M occurred in 114 unique reports (0.04% of all ICI-related adverse events), representing 8.2% of MG, 5.6% of myositis, and 3.6% of myocarditis cases. Co-reporting was common: among 5308 unique reports involving these toxicities, 1164 reports (21.9%) included at least two components of the triad. Triple-M cases were more common in men (56%), with a median age of 74 years (IQR 68–79), a median time-to-onset of 21 days (IQR 18–28), and 50% mortality among cases with available outcomes. Conclusions: Triple-M appears to be a severe overlap phenotype reported in association with immune checkpoint inhibitors, characterized by early onset, frequent co-reporting, and substantial reported fatality. Early recognition and coordinated multidisciplinary assessment may warrant further clinical evaluation and investigation of this overlap phenotype. Full article

Background and Objectives: Early progression (PFS < 90 days) in NSCLC patients undergoing ICI treatment constitutes a significant clinical challenge. Although predictive biomarkers have been extensively investigated, specific transcriptomic and immune microenvironment characteristics contributing to early progression remain inadequately characterized. Materials and Methods: We analyzed RNA-seq data from 27 NSCLC patients receiving anti-PD-1/PD-L1 therapy (GSE135222). Patients were categorized as Early Progression (PFS < 90 days; n = 17) or Clinical Benefit (PFS ≥ 90 days; n = 10). GSEA was performed with Hallmark and C7 ImmuneSigDB gene sets. Immune cell deconvolution was performed using EPIC. An 87-gene immunosuppressive risk score was derived from TGF-β, WNT/β-catenin, and EMT pathway leading-edge genes. Results: GSEA identified 17 significantly enriched Hallmark pathways in early progressors, predominantly immunosuppressive (TGF-β, WNT/β-catenin) and oncogenic (MYC targets, E2F targets, G2M checkpoint) programs. C7 ImmuneSigDB analysis revealed 131 enriched immune signatures including CD8 T cell dysfunction, Treg activation, and M2 macrophage polarization. An 87-gene immunosuppressive risk score demonstrated a significant negative correlation with PFS (Spearman ρ = −0.516, p = 0.006) and a trend toward poorer survival outcomes (HR = 2.12, p = 0.093). Conclusions: In NSCLC patients receiving ICI, early disease progression is marked by simultaneous activation of TGF-β/WNT-mediated immunosuppressive pathways, oncogenic signaling, and CD8 T cell dysfunction. The 87-gene immunosuppressive risk score demonstrates a statistically significant negative correlation with PFS (Spearman ρ = −0.516, p = 0.006); however, given the small sample size (n = 27) and absence of external validation, these findings should be interpreted as exploratory and hypothesis-generating, warranting prospective validation in independent cohorts. Full article

Background/Objectives: This study evaluates the prognostic value of baseline inflammatory biomarkers, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), lymphocyte-to-monocyte ratio (LMR), systemic immune-inflammation index (SII), and pan-immune-inflammation value (PIV) in advanced cutaneous melanoma treated with first-line immunotherapy. Methods: This multicenter retrospective study included 162 patients with unresectable stage III/IV cutaneous melanoma treated with first-line pembrolizumab, nivolumab, or nivolumab plus ipilimumab. Biomarkers were calculated from complete blood counts obtained within 30 days before treatment start. Cut-offs were defined by ROC analysis. Progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan–Meier and Cox regression. Response was assessed by RECIST v1.1. Results: Higher baseline NLR, PLR, MLR, SII, and PIV were more common in patients with adverse baseline features, including liver metastases, elevated LDH, and poorer ECOG performance status. Patients with biomarker values below the cut-offs had significantly longer PFS and OS. In biomarker-specific multivariable models adjusted for selected clinical covariates, PIV retained the most consistent association with PFS and OS, while MLR was associated with PFS, and PLR with OS. Conclusions: Baseline inflammatory biomarkers from routine blood counts provide useful prognostic information in advanced melanoma treated with first-line ICIs. PIV showed the most consistent association with survival outcomes and may support initial risk stratification alongside LDH, ECOG, and metastasis pattern. However, prospective validation in independent cohorts is needed before routine clinical implementation. Full article

Breast cancer is one of the leading causes of cancer deaths in women worldwide. Neoadjuvant chemotherapy (NACT) has increased rates of breast-conserving procedures and enabled the identification of patients with a particularly poor prognosis. Achieving a pathological complete response (pCR), an indicator of NACT efficacy, contrasts with residual disease (RD), which identifies patients at higher risk of recurrence. This review provides an overview of current evidence on the clinical and prognostic significance of pCR and RD in patients receiving NACT for breast cancer. The analysis is based on data from randomized clinical trials, meta-analyses, and current clinical guidelines for contemporary systemic treatment. Pathological complete response varies according to tumor subtype, with the highest rates observed in triple-negative and non-luminal HER2-positive breast cancer. In HER2-positive disease, the combination of chemotherapy with HER2-targeted therapies increases pCR rates, while the presence of RD supports escalation of postoperative treatment with antibody–drug conjugates. In triple-negative breast cancer (TNBC), the inclusion of platinum agents and immune checkpoint inhibitors improves treatment efficacy. In HER2-negative breast cancer and germline BRCA1/2 mutations, adjuvant PARP inhibitors improve survival independently of pCR, highlighting the complex relationship between pathological response and prognosis. Immunotherapy and targeted therapies are used alongside standard chemotherapy and hormone therapy in perioperative treatment. Further research is required to refine response assessment, integrate new biomarkers such as circulating tumor DNA (ctDNA), and optimize treatment selection, while clarifying the significance of reassessing hormone receptor and HER2 status in residual disease and its impact on subsequent treatment decisions. Full article

Background/Objectives: Endometrial cancer (EC) is the most common gynecologic malignancy in developed countries, with increasing incidence and limited options in advanced disease. Molecular classification has redefined risk stratification and therapeutic decision-making, particularly with the incorporation of immunotherapy. This review provides a clinically oriented overview of immunotherapy in EC across molecular subgroups and treatment settings. Methods: A narrative review was conducted using PubMed/MEDLINE, Embase, and Web of Science, focusing on clinical trials and studies with direct clinical relevance. Results: Immune checkpoint inhibitors targeting the PD-1/PD-L1 axis have demonstrated significant benefit in EC, particularly in mismatch repair-deficient (dMMR)/microsatellite instability–high (MSI-H) tumors, where durable responses are observed. In contrast, mismatch repair-proficient (pMMR) tumors show limited sensitivity to monotherapy and require combination approaches. Recent phase III trials have established chemoimmunotherapy as a first-line standard, with greater benefit in dMMR tumors and clinically meaningful improvements in pMMR disease. In the second-line setting, PD-1 inhibitor monotherapy is standard for dMMR tumors, while lenvatinib plus pembrolizumab is a key option for pMMR disease. However, responses remain heterogeneous and are not fully explained by MMR status alone. Conclusions: Immunotherapy is a cornerstone in advanced EC management, guided by molecular classification. Key challenges include limited efficacy in pMMR tumors, lack of robust predictive biomarkers, and uncertainty in treatment sequencing. Future strategies should focus on biomarker-driven approaches and rational combinations. Full article

Cancer is a leading cause of death in dogs, and incidence rates in dogs exceed those in humans. Current therapeutic options for canine cancer patients remain limited, with most treatments focused on palliative care. Immune checkpoint inhibitors such as anti-PD-1, anti-PD-L1, and anti-CTLA-4 antibodies that have transformed cancer therapy and expanded the therapeutic options in humans could offer the same clinical benefit in canine cancer patients. This study details the engineering and functional characterization of mouse and chimeric mouse–canine anti-canine PD-1 (cPD-1) monoclonal antibodies. We demonstrate that anti-cPD-1 antibodies block the interaction between cPD-1 and its ligand cPD-L1, thereby inhibiting this immune signaling pathway. In a proof-of-concept study in seven companion canine cancer patients, intratumoral therapy with the lead anti-cPD-1 antibody (HugPetmab) was safe, well-tolerated, had no observed adverse events, and showed evidence of tumor control in a subset of injected tumors. These findings support the potential of HugPetmab antibody as an immunotherapeutic option for treating canine cancer patients. Full article

mRNA vaccines are a relevant approach in cancer immunotherapy, using messenger RNA to induce immune responses against tumor-associated antigens. In this review, BNT111 and BNT122 are compared as representative off-the-shelf and personalized models. BNT111 is a fixed mRNA vaccine that has demonstrated significant antitumor efficacy against shared melanoma antigens, particularly when combined with immune checkpoint inhibitors. It allows a standardized production via in vitro transcription (IVT) in a cell-free system. Conversely, BNT122 is a personalized vaccine designed to match an individual’s tumor mutations by targeting patient-specific neoantigens to elicit more robust immune responses. It has significant suitability in the adjuvant setting to target minimal residual disease. Despite favorable safety and immunogenicity, the effectiveness of these vaccines is influenced by various factors, including tumor heterogeneity, differences in antigen expression, off-target effects on mRNA-LNP distribution, molecular instability, and complex manufacturing constraints. Neither approach can be directly considered as the definitive optimal vaccine. A comprehensive analysis of their strengths and limitations is vital for a balanced and objective future research direction. Collectively, this emphasizes the need for further improvements in vaccine design and strategies, prioritizing high-quality, safe, and accessible treatments for every cancer-based patient and ensuring their successful integration into healthcare. Full article

Renal cell carcinoma (RCC) is a predominant malignancy of the urinary system, with clear cell renal cell carcinoma (ccRCC) representing 75–85% of clinical cases. Since the early stages are often asymptomatic, nearly 30% of patients present with metastases at diagnosis, which significantly complicates the prognosis. The diverse mechanisms and clinical indications of current strategies, despite recent breakthroughs in immunotherapy, pose a major challenge for systematic application. This review employs the cancer-immunity cycle as a framework to evaluate four critical steps: antigen presentation, T-cell activation, reversal of exhaustion, and immune evasion in the tumor microenvironment. We introduce the major immunotherapy strategies in RCC in this cycle and summarize their clinical position. Combining immune checkpoint inhibitors (ICIs) with tyrosine kinase inhibitors (TKI) has redefined the first-line standard for advanced RCC by addressing both T-cell infiltration barriers and functional suppression. Standalone approaches such as tumor vaccines and cytokines in contrast have shown limited efficacy in advanced settings. In this context, we further propose emerging research directions, such as individualized immunotherapy and multi-target blockade, and point out the relevant biomarkers, offering an integrated perspective of the RCC immune landscape and providing insights for both clinical practice and future research. Full article

Background and Objectives: Metastatic renal cell carcinoma (mRCC) remains a lethal disease despite advances with immune checkpoint inhibitors such as nivolumab. However, a substantial proportion of patients exhibit primary resistance or early progression, highlighting the need for reliable and easily accessible prognostic biomarkers. The C-reactive protein–albumin–lymphocyte (CALLY) index is a novel immunonutritional biomarker integrating systemic inflammation, nutritional status, and immune competence. Materials and Methods: In this retrospective single-center study, 91 patients with mRCC treated with nivolumab were analyzed. Patients were stratified into low and high CALLY index groups based on a receiver operating characteristic-derived cut-off (0.322). Survival outcomes were assessed using Kaplan–Meier analysis and Cox regression models. Results: Patients with a low CALLY index demonstrated significantly shorter progression-free survival (4.5 vs. 13.5 months, p < 0.001) and overall survival (9.1 vs. 25.5 months, p = 0.003). Multivariate analysis confirmed the CALLY index as an independent prognostic factor for both progression-free survival (HR: 2.63, p = 0.002) and overall survival (HR: 1.88, p = 0.035). Conclusions: The CALLY index is a simple, cost-effective, and reproducible biomarker that independently predicts survival in nivolumab-treated mRCC. It may serve as a practical tool for risk stratification and personalized treatment planning in the immunotherapy era. Full article

Background: Although immune checkpoint inhibitors (ICIs) have improved survival in advanced melanoma, predicting individual responses remains challenging; thus, practical and inexpensive biomarkers are needed. In this study, we investigated the prognostic value of the neutrophil percentage–albumin ratio (NPAR) in patients with advanced melanoma receiving ICI therapy. Methods: Fifty patients treated in our clinic were included, with a mean age of 53.3 years and 66% being male. Visceral metastases were present in 76% of the cohort. Through conducting Receiver Operating Characteristic (ROC) analysis, we determined an NPAR cut-off value of 1.81, with patients categorized into low (<1.81, n = 27)- and high (≥1.81, n = 23)-NPAR groups. The progression-free survival (PFS) and overall survival (OS) were evaluated using Kaplan–Meier and Cox regression analyses. Results: High NPAR (≥1.81) significantly shortened both PFS and OS. In the univariate analysis, high NPAR emerged as a strong risk factor for PFS (HR: 2.68, p = 0.002) and OS (HR: 3.70, p < 0.001), while multivariate analysis confirmed NPAR as an independent negative prognostic factor for PFS (HR: 2.45, p = 0.006) and OS (HR: 2.82, p = 0.003), regardless of clinical variables. Additionally, visceral metastasis was an independent negative predictor of survival. Conclusions: Pre-treatment NPAR levels may be an independent and potential predictor of survival in advanced melanoma patients receiving ICIs. This easily calculable ratio could provide a practical guide for risk stratification. Full article

Esophageal squamous cell carcinoma (ESCC) is a highly aggressive malignancy in which radiotherapy plays a uniquely central role compared with other gastrointestinal cancers. Definitive chemoradiotherapy (dCRT) is widely used as a curative treatment; however, a substantial proportion of patients develop residual or recurrent disease, creating a complex clinical scenario that requires tailored salvage strategies. Salvage esophagectomy offers the potential for long-term survival but remains technically demanding and is associated with significant morbidity because of radiation-induced tissue damage. Less invasive local therapies, such as endoscopic submucosal dissection and photodynamic therapy, may provide effective treatment in selected patients, although their indications are limited by tumor characteristics and post-radiation fibrosis. In addition, immune checkpoint inhibitors have demonstrated promising efficacy in advanced ESCC and may represent a potential therapeutic option in the salvage setting. For patients who are not candidates for curative treatment, palliative esophageal stenting remains an important option for symptom relief, although prior radiotherapy may increase the risk of treatment-related complications. Given the diversity of available treatment modalities and their associated risks, a multidisciplinary and individualized treatment approach is essential. Further prospective studies are warranted to optimize treatment algorithms and improve outcomes in patients with ESCC after dCRT. Full article

Introduction: The role of immune checkpoint inhibitors (ICIs) in locally advanced head and neck squamous cell carcinoma (LA HNSCC) remains uncertain, with randomized trials showing inconsistent results in heterogeneous populations. We conducted a systematic review of randomized trials evaluating ICI-based strategies in LA HNSCC, with outcomes stratified by PD-L1 expression, HPV/p16 status, and cisplatin eligibility to identify patient subgroups most likely to benefit from ICIs. Methods: MEDLINE, Cochrane, and EMBASE databases were systematically searched up to 10 January 2026. Randomized controlled trials (RCTs) evaluating ICIs in patients with LA HNSCC were included. The primary outcome was pooled time-to-event efficacy, including event-free survival (EFS), progression-free survival (PFS), and disease-free survival (DFS) as reported across trials. A generic inverse variance method was used to calculate the estimated pooled hazard ratio (HR) for PFS with 95% confidence interval (CI). Heterogeneity was assessed with Cochran’s Q test. Random effects model was applied. Results: A total of 3605 patients from seven phase II/III RCTs were included. In the overall population, no significant difference in EFS/PFS/DFS was observed between ICI and standard therapy (HR 0.90; 95% CI: 0.77–1.06; p = 0.20). However, in subgroup analyses stratified by PD-L1 expression, patients with PD-L1-positive tumors demonstrated improved PFS with ICIs compared with control (HR 0.78; 95% CI: 0.67–0.91; p < 0.0001). In contrast, PD-L1-negative tumors demonstrated inferior PFS in the ICIs arm (HR 1.31; 95% CI: 1.02–1.68; p = 0.03). No significant differences in PFS were observed based on HPV or p16 status. A subset analysis of cisplatin-eligible LA HNSCC trials evaluating the addition of ICIs to standard therapy showed a similar pattern. ICI use in PD-L1-positive patients demonstrated significantly improved PFS (HR 0.76; 95% CI: 0.63–0.92; p < 0.0001), while ICI use in PD-L1-negative patients demonstrated decreased PFS (HR 1.28; 95% CI: 0.99–1.66; p = 0.06). In cisplatin-ineligible populations, ICI regimens did not improve PFS compared with cetuximab plus RT. Conclusions: This study showed that although in the overall population there was no significant difference in EFS/PFS/DFS, in the PD-L1-positive subgroup, patients experienced significantly improved PFS with ICIs compared with control, while in the PD-L1-negative subgroup, patients demonstrated inferior PFS in the ICIs arm; these results were mirrored in the cisplatin-eligible subgroup. Full article

Sex differences influence cancer incidence, treatment response, and susceptibility to cardiovascular toxicity. Males exhibit higher rates and poorer outcomes in most non-sex-specific cancers, while females more frequently experience treatment-related adverse events, including cancer therapy-related cardiac dysfunction. Biological factors such as hormonal status, genetic polymorphisms, immune responses, and pharmacokinetics contribute to these disparities. In cardio-oncology, women—particularly premenopausal or with specific genotypes—may be at increased risk for cardiotoxicity after treatment with anthracyclines, immune checkpoint inhibitors or radiotherapy. Clonal hematopoiesis and certain germline genetic variants such as single nucleotide polymorphisms (e.g., RARG rs2229774, HAS3 rs2232228) are emerging as potential sex-informed biomarkers for predicting cardiotoxicity risk. Despite growing evidence, sex remains insufficiently integrated into clinical trials and guideline development in cardio-oncology. This review highlights the importance of sex-specific surveillance, prevention, and multi-omic risk stratification to advance precision cardio-oncology and support better outcomes for patients across the cancer care continuum. Full article

Colorectal cancer (CRC) is the third most frequently diagnosed malignancy and the second leading cause of cancer-related mortality worldwide, underscoring the need for the development of more effective and durable therapeutic strategies. A key mechanism of tumor immune evasion involves activation of immune checkpoint pathways through the upregulation of inhibitory ligand expression within the tumor microenvironment, leading to lymphocyte exhaustion and impaired antitumor immunity. Consequently, immune checkpoints have emerged as important targets for immunotherapeutic intervention, with significant advances over the past decade. Nevertheless, despite demonstrated clinical benefits in selected patient subpopulations, the overall therapeutic efficacy of immune checkpoint inhibitors remains limited, particularly in the context of CRC. In this review, we provide a comprehensive overview of currently approved immune checkpoint-based immunotherapies for cancer treatment, with a specific focus on CRC, as well as ongoing clinical trials and evolving trends in this area. Furthermore, we discuss emerging targets and novel therapeutic strategies, with particular emphasis on innovative small-molecule inhibitors as potential alternatives to monoclonal antibody-based approaches. Finally, we outline future perspectives and potential directions for advancing immune checkpoint-targeted therapies in CRC. Full article