Search Results (33)

Background: Antibody-drug conjugates (ADCs) are gaining rapidly expanding clinical utility, with a growing number of approved indications across compounds that differ in target antigen, payload mechanism, and linker design. However, treatment response remains heterogeneous, and predictive biomarkers to identify patients most likely to benefit are limited. Given that ADC efficacy depends on sufficient target antigen expression and distribution across tumor lesions, positron emission tomography (PET) imaging offers a unique opportunity to non-invasively assess whole-body target availability. We therefore conducted a systematic literature review to evaluate the relationship between PET-measured tumor antigen expression and the therapeutic response to ADCs targeting the same antigen. Method: A systematic comprehensive search of PubMed, EMBASE and Web of Science databases was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, using terms related to targeted PET, ADC treatment and response assessment. Article screening, eligibility assessment, and data extraction were performed independently using predefined criteria by two reviewers. Disagreements were resolved by consensus. Results: A total of 5628 records were identified. After removing duplicates, 4323 records were screened by title and abstract. Fifty-eight underwent full-text review and seven were included in the final review. Four trials investigated human epidermal growth factor receptor 2 (HER2)-targeted therapy, one Nectin-4, one mesothelin and one STEAP1. In all HER2- and Nectin-4-related trials, patients with a higher uptake on targeted PET had a higher probability of responding to targeted treatment. Included trials were generally small and had a moderate risk of bias. Conclusion: Targeted PET imaging showed potential to predict treatment response in trials evaluating clinically active agents. Additional clinical trials across a broader range of targets, along with standardized acquisition protocols and harmonized study designs, are needed to enable the integration of this technique into clinical practice and ultimately translate its benefits to patients. Full article

Glioblastoma (GB) remains one of the most therapy-resistant solid tumors, characterized by profound metabolic plasticity, intratumoral heterogeneity, and a highly immunosuppressive microenvironment. While immunotherapies such as chimeric antigen receptor T (CAR-T) cells have shown promise in hematological malignancies, their efficacy in GB has been limited. Emerging evidence suggests that tumor-specific metabolic dependencies and post-translational modifications (PTMs) may represent exploitable vulnerabilities. This review discusses disulfidptosis, a recently described form of regulated cell death driven by disulfide stress under conditions of limited reducing capacity, as a context-dependent metabolic–redox vulnerability in GB. We further discuss how altered protein glycosylation and glycocalyx architecture in glioblastoma regulate cell survival, death signaling, and immune recognition. Particular emphasis is placed on the glycosylation of surface antigens targeted by CAR-T cells, including EGFR/EGFRvIII, IL-13Rα2, mesothelin, B7-H3, HER2, and GD2, and on how glycan-dependent epitope accessibility may limit therapeutic efficacy. Finally, we distinguish disulfidptosis, whose direct relevance to CAR-T-cell responses remains to be established, from glycosylation and glycocalyx remodeling as more direct determinants of target–antigen accessibility and immune recognition. Therapeutic strategies addressing these vulnerabilities may provide rational opportunities to improve CAR-T-based and combinatorial therapies for GB. Full article

Mesothelin (MSLN) is a cell surface glycoprotein with limited expression in normal tissues but frequent overexpression in solid tumors, including gynecological malignancies. This review summarizes the state of the art on the biological role, diagnostic value, prognostic significance, and therapeutic potential of MSLN in ovarian, endometrial, and cervical cancers. Evidence from clinical and experimental studies indicates that MSLN contributes to tumor progression through interactions with CA125, promotion of cell adhesion and peritoneal metastasis, activation of oncogenic signaling pathways, modulation of immune responses, and development of chemoresistance. Elevated MSLN expression has been associated with advanced clinical stage of the disease, platinum resistance, and poorer survival outcomes, particularly in ovarian cancer patients, although prognostic findings remain inconsistent. Circulating soluble MSLN may serve as a minimally invasive biomarker and may improve diagnostic accuracy when combined with established markers. Therapeutic MSLN strategies—antibody-drug conjugates, CAR-T and NK cell therapies, monoclonal antibodies, immunotoxins, vaccines, and checkpoint blockade—provide promising pre-clinical and early clinical results, particularly in resistant or recurrent forms of the disease. Overall, MSLN constitutes a promising target for precision oncology in gynecological cancers, although further clinical studies are required to validate its diagnostic utility and optimize targeted therapeutic approaches. Full article

Background: For almost two decades now, chimeric antigen receptor-natural killer cells (CAR-NK) have been investigated in pre-clinical breast cancer models, yet clinical evidence on efficacy remains scarce. This meta-analysis provides pooled evidence of pre-clinical CAR-NK effectiveness and safety in breast cancer and an overview of current clinical trials to support clinical translation. Methods: Following PRISMA guidelines and a registered protocol (PROSPERO, CRD420251131530), PubMed, Web of Science, and Scopus were searched up to 30 June 2025 for pre-clinical CAR-NK studies in breast cancer. Clinical studies were retrieved from clinicaltrials.gov and the International Clinical Trial Registry Platform (ICTRP) up to 1 March 2026. Pre-clinical studies without in vivo data or non-human CAR-NK cells were excluded. Primary outcomes were tumor burden (ratio of means, ROMs) and survival (median survival ratio, MSR). Data were analyzed in JASP™ and risk of bias (RoB) was assessed using SYRCLE’s tool. Results: Fourteen pre-clinical studies (38 CAR-NK treatment groups targeting EGFR, HER2, tissue factor, CD70, mesothelin, or folate receptor, with peripheral blood as the primary NK source, and a 5–10 million cell dose) and 11 early-phase clinical studies (targeting HER2, TROP2, PD-L1, MUC1, or NKG2D ligands under ongoing investigation) were included. In pooled pre-clinical analysis, CAR-NK significantly reduced tumor burden against untreated and unmodified/mock controls (ROM 0.311 [0.22–0.44] and 0.42 [0.33–0.53], p < 0.001, respectively). Survival was also prolonged significantly (MSR 1.47 [1.15–1.87], p = 0.010 vs. untreated; 1.30 [1.09–1.60], p = 0.007 vs. unmodified/mock NK cells). Subgroup analyses indicated improved efficacy with peripheral blood source and 5–10 M dosing. No treatment-related toxicities were reported. CAR-NK persistence was generally higher than unmodified/mock NK cells. Discussion and Conclusions: Significant heterogeneity was observed in ROM analysis which the multi-level meta-analysis configured as intra-study interventional variability. There was moderate RoB in pre-clinical studies. Published results from clinical trials remain limited, highlighting early stages of investigation. Overall, CAR-NK therapy demonstrated consistent pre-clinical efficacy and safety, supporting further translational and clinical evaluation in breast cancer. Full article

Background/Objectives: Malignant mesothelioma has a poor prognosis and limited therapeutic options. C-ERC/mesothelin is highly expressed in mesotheliomas and is a potential target for radioimmunotherapy (RIT). This study evaluated the radiolabeled anti-C-ERC/mesothelin antibody mAb 22A31 as a therapeutic agent. Methods: C-ERC/mesothelin expression in mesothelioma cell lines was assessed by Western blotting, and the specific binding of ¹²⁵I-labeled mAb 22A31 was examined. Biodistribution of ¹¹¹In-labeled mAb 22A31 was evaluated in a mesothelioma cell line, MSTO-211H tumor-bearing mice. The therapeutic efficacy of ⁹⁰Y-labeled mAb 22A31 was evaluated in subcutaneous and pleural dissemination models. Results: mAb 22A31 showed specific binding considering the level of C-ERC/mesothelin expression in each mesothelioma cell line. ¹¹¹In-mAb 22A31 accumulated in tumors with minimal uptake in normal tissues. ⁹⁰Y-mAb 22A31 significantly delayed the growth of subcutaneous tumors and improved survival in a pleural dissemination model. Conclusions: Radiolabeled mAb 22A31 specifically targeted C-ERC/mesothelin and demonstrated therapeutic efficacy in a mesothelioma xerograph model. Therefore, ⁹⁰Y-mAb 22A31 is a promising RIT agent and supports the further development of C-ERC/mesothelin-targeted therapy for mesothelioma. Full article

Breast cancer remains a leading cause of cancer-related morbidity and mortality worldwide, with therapeutic response being shaped by the unique biology of each breast cancer subtype. Immunotherapy has emerged as a transformative approach in selected disease subtypes, with the most successful results being found in relation to triple negative breast cancer (TNBC). Immune checkpoint inhibitors (ICIs) have transformed the management of many solid tumours. In breast cancer, they have demonstrated clinical benefit in TNBC when combined with chemotherapy, establishing a new standard of care in both early-stage and metastatic settings. However, the majority of breast cancers exhibit intrinsic or acquired resistance to checkpoint blockade, driven by low tumour immunogenicity and an immunosuppressive tumour microenvironment. Recent advances in cellular immunotherapy could represent the next frontier in the therapeutic landscape of breast cancer. Chimeric antigen receptor (CAR) T cell targeting antigens such as HER2, ROR1, MUC1, mesothelin, and B7-H3 are entering early-phase clinical evaluation with results eagerly awaited. Parallel approaches, including tumour-infiltrating lymphocyte (TIL) therapy, T cell receptor (TCR)-engineered T cells, and CAR-natural killer (CAR-NK) platforms, offer alternative mechanisms to overcome antigen presentation barriers and immune evasion. This review summarises current clinical evidence for immunotherapies in breast cancer, highlights emerging cellular strategies, and discusses key challenges including antigen specificity, off-tumour toxicity, and tumour microenvironment-mediated resistance. Future progress will likely depend on rational combination approaches and next-generation engineered immune cell platforms to achieve durable and personalised clinical benefit. Full article

Background: Advancing chimeric antigen receptor (CAR) T cell therapy for solid tumors remains a major challenge in cancer immunotherapy. Prostate cancer (PCa), particularly in its aggressive forms, may be a suitable target for CAR-T therapy given the range of associated tumor antigens. However, due to the high plasticity and heterogeneity of aggressive PCa and the complexity of the tumor environment, there is a need to broaden the repertoire of targetable antigens and deepen our understanding of CAR-T behavior in stressed microenvironmental conditions. Growing evidence supports mesothelin as a promising cancer-associated marker and a compelling target for CAR-T cell approaches in solid tumors. Objectives and Methods: Here, we employed gene expression datasets to investigate mesothelin expression in both primary and metastatic PCa tumors. Additionally, we evaluated mesothelin expression across various preclinical PCa models and assessed the therapeutic efficacy of second-generation mesothelin-targeted CAR-T (meso-CAR-T) cells under both normoxic and hypoxic conditions, with hypoxia as a representative tumor-associated stress condition. Results: Our results revealed a significant enrichment of mesothelin in 3–10% of metastatic prostate tumors, contrasting with its minimal expression in primary tumors. In line with these findings, we observed increased mesothelin expression in an aggressive variant of the 22Rv1 cell line, which displayed an epithelial–mesenchymal plasticity (EMP) phenotype. Meso-CAR-T cells demonstrated potent cytotoxicity and remarkable selectivity toward these carcinoma cells under both severe hypoxia (1% O₂) or normoxia (21% O₂), highlighting their ability to withstand metabolic stress within the tumor microenvironment. Conclusions: Our study underscores the potential of meso-CAR-T cells as a promising strategy for targeting specific subtypes of metastatic prostate cancer. Full article

Mesothelioma is characterized by the inactivation of tumor suppressor genes, with frequent mutations in neurofibromin 2 (NF2), BRCA1-associated protein 1 (BAP1), and cyclin-dependent kinase inhibitor 2A (CDKN2A). These mutations lead to disruptions in the Hippo signaling pathway and histone methylation, thereby promoting tumor growth. NF2 mutations result in Merlin deficiency, leading to uncontrolled cell proliferation, whereas BAP1 mutations impair chromatin remodeling and hinder DNA damage repair. Emerging molecular targets in mesothelioma include mesothelin (MSLN), oxytocin receptor (OXTR), protein arginine methyltransferase (PRMT5), and carbohydrate sulfotransferase 4 (CHST4). MSLN-based therapies, such as antibody–drug conjugates and immunotoxins, have shown efficacy in clinical trials. OXTR, upregulated in mesothelioma, is correlated with poor prognosis and represents a novel therapeutic target. PRMT5 inhibition is being explored in tumors with MTAP deletions, commonly co-occurring with CDKN2A loss. CHST4 expression is associated with improved prognosis, potentially influencing tumor immunity. Immune checkpoint inhibitors targeting PD-1/PD-L1 have shown promise in some cases; however, resistance mechanisms remain a challenge. Advances in multi-omics approaches have improved our understanding of mesothelioma pathogenesis. Future research will aim to identify novel therapeutic targets and personalized treatment strategies, particularly in the context of epigenetic therapy and combination immunotherapy. Full article

Mesothelin (MSLN), a glycoprotein-based tumor antigen, is elevated in several malignancies and it is related to a poor prognosis, as it enhances tumor aggression, dissemination and chemotherapy resistance. MSLN plays a crucial role in epigenetic and signal pathway regulation and it can be an important biomarker. MSLN targeting is in particular, associated with CA125/MUC16, which offers the potential to improve lung, pancreatic, colon and ovarian cancer detection as well as therapeutic strategies. MSLNtargeted therapies have shown favorable results, such as CAR NK cells, 227Th conjugate and CAR-T cells, which target mesothelin. Significant advancements can be achieved with novel techniques, such as mesothelin-targeting BiTEs and simultaneous CAR-T cells. Immunotherapies targeting mesothelin have the potential to completely transform the way cancer is therapy in patients with limited options. To fully comprehend the mechanisms of MSLN, more investigation is required to explore its role in cancer for improved patient outcomes. The complex control, cellular functions and clinical significance of MSLN in the advancement of cancer are highlighted in this review.  Full article

Mesothelioma (MM) is an aggressive and lethal disease with few therapeutic opportunities. Platinum-pemetrexed chemotherapy is the backbone of first-line treatment for MM. The introduction of immunotherapy (IO) has been the only novelty of the last decades, allowing an increase in survival compared to standard chemotherapy (CT). However, IO is not approved for epithelioid histology in many countries. Therefore, therapy for relapsed MM remains an unmet clinical need, and the prognosis of MM remains poor, with an average survival of only 18 months. Increasing evidence reveals MM complexity and heterogeneity, of which histological classification fails to explain. Thus, scientific focus on possibly new molecular markers or cellular targets is increasing, together with the search for target therapies directed towards them. The molecular landscape of MM is characterized by inactivating tumor suppressor alterations, the most common of which is found in CDKN2A, BAP1, MTAP, and NF2. In addition, cellular targets such as mesothelin or metabolic enzymes such as ASS1 could be potentially amenable to specific therapies. This review examines the major targets and relative attempts of therapeutic approaches to provide an overview of the potential prospects for treating this rare neoplasm. Full article

The success of chimeric antigen receptor T-cell (CAR-T) therapies in the treatment of hematologic malignancies has led to the investigation of their potential in the treatment of solid tumors, including ovarian cancer. While the immunosuppressive microenvironment of ovarian cancer has been a barrier in their implementation, several early phase clinical trials are currently evaluating CAR-T cell therapies targeting mesothelin, folate receptor a, HER2, MUC16, and B7H3. Ongoing challenges include cytokine-associated and “on-target, off-tumor” toxicities, while most common adverse events include cytokine release syndrome, hemophagocytic lymphohistiocytosis/macrophage activation-like syndrome (HLH/MAS), and neurotoxicity. In the present review, we summarize the current status of CAR-T therapy in ovarian cancer and discuss future directions. Full article

Malignant pleural mesothelioma (MPM) is a heterogeneous cancer composed of distinct molecular and pathologic subtypes. Unfortunately, MPM is aggressive, and current therapies for advanced, unresectable disease remain limited to cytotoxic chemotherapy and immunotherapy. Our understanding of the genomic landscape of MPM is steadily growing, while the discovery of effective targeted therapies in MPM has advanced more slowly than in other solid tumors. Given the prevalence of alterations in tumor suppressor genes in MPM, it has been challenging to identify actionable targets. However, efforts to characterize the genetic signatures in MPM over the last decade have led to a range of novel targeted therapeutics entering early-phase clinical trials. In this review, we discuss the advancements made thus far in targeted systemic therapies in MPM and the future direction of targeted strategies in patients with advanced MPM. Full article

Since its first approval by the FDA in 2017, tremendous progress has been made in chimeric antigen receptor (CAR) T cell therapy, the adoptive transfer of engineered, CAR-expressing T lymphocyte. CAR T cells are all composed of three main elements: an extracellular antigen-binding domain, an intracellular signaling domain responsible for T cell activation, and a hinge that joins these two domains. Continuous improvement has been made in CARs, now in their fifth generation, particularly in the intracellular signaling domain responsible for T cell activation. CAR T cell therapy has revolutionized the treatment of hematologic malignancies. Nonetheless, the use of CAR T cell therapy for solid tumors has not attained comparable levels of success. Here we review the challenges in achieving effective CAR T cell therapy in solid tumors, and emerging CAR T cells that have shown great promise for non-small cell lung cancer (NSCLC). A growing number of clinical trials have been conducted to study the effect of CAR T cell therapy on NSCLC, targeting different types of surface antigens. They include epidermal growth factor receptor (EGFR), mesothelin (MSLN), prostate stem cell antigen (PSCA), and mucin 1 (MUC1). Potential new targets such as erythropoietin-producing hepatocellular carcinoma A2 (EphA2), tissue factor (TF), and protein tyrosine kinase 7 (PTK7) are currently under investigation in clinical trials. The challenges in developing CAR T for NSCLC therapy and other approaches for enhancing CAR T efficacy are discussed. Finally, we provide our perspective on imaging CAR T cell action by reviewing the two main radionuclide-based CAR T cell imaging techniques, the direct labeling of CAR T cells or indirect labeling via a reporter gene. Full article

Pleural mesothelioma (PM) is a type of cancer that is highly related to exposure to asbestos fibers. It shows aggressive behavior, and the current therapeutic approaches are usually insufficient to change the poor prognosis. Moreover, apart from staging and histological classification, there are no validated predictors of its response to treatment or its long-term outcomes. Numerous studies have investigated minimally invasive biomarkers in pleural fluid or blood to aid in earlier diagnosis and prognostic assessment of PM. The most studied marker in pleural effusion is mesothelin, which exhibits good specificity but low sensitivity, especially for non-epithelioid PM. Other biomarkers found in pleural fluid include fibulin-3, hyaluronan, microRNAs, and CYFRA-21.1, which have lower diagnostic capabilities but provide prognostic information and have potential roles as therapeutic targets. Serum is the most investigated matrix for biomarkers of PM. Several serum biomarkers in PM have been studied, with mesothelin, osteopontin, and fibulin-3 being the most often tested. A soluble mesothelin-related peptide (SMRP) is the only FDA-approved biomarker in patients with suspected mesothelioma. With different serum and pleural fluid cut-offs, it provides useful information on the diagnosis, prognosis, follow-up, and response to therapy in epithelioid PM. Panels combining different markers and proteomics technologies show promise in terms of improving clinical performance in the diagnosis and monitoring of mesothelioma patients. However, there is still no evidence that early detection can improve the treatment outcomes of PM patients. Full article

Malignant pleural mesothelioma (MPM) is a malignancy associated with asbestos exposure and is typically categorized as an orphan disease. Recent developments in immunotherapy with anti-PD-1 and anti-CTLA-4 antibodies, specifically with agents nivolumab and ipilimumab, have demonstrated an improvement in overall survival over the previous standard chemotherapy leading to their FDA-approval as first-line therapy for unresectable disease. For quite some time, it has been known that these proteins are not the only ones that function as immune checkpoints in human biology, and the hypothesis that MPM is an immunogenic disease has led to an expanding number of studies investigating alternative checkpoint inhibitors and novel immunotherapy for this malignancy. Early trials are also supporting the notion that therapies that target biological molecules on T cells, cancer cells, or that trigger the antitumor activity of other immune cells may represent the future of MPM treatment. Moreover, mesothelin-targeted therapies are thriving in the field, with forthcoming results from multiple trials signaling an improvement in overall survival when combined with other immunotherapy agents. The following manuscript will review the current state of immune therapy for MPM, explore the knowledge gaps in the field, and discuss ongoing novel immunotherapeutic research in early clinical trials. Full article