BACKGROUND: Patients with gastro-oesophageal adenocarcinoma with tumour-positive lymph nodes (ypN+) or positive surgical margins (R1) following neoadjuvant chemotherapy and resection are at high risk of recurrence. Adjuvant nivolumab is effective in oesophageal/oesophagogastric junction cancer and residual pathological disease following chemoradiation and surgery. Immune checkpoint inhibition has shown efficacy in advanced gastro-oesophageal cancer. We hypothesised that nivolumab/ipilimumab would be more effective than adjuvant chemotherapy in high-risk (ypN+ and/or R1) patients with gastro-oesophageal adenocarcinoma following neoadjuvant chemotherapy and resection. PATIENTS AND METHODS: VESTIGE was an academic international, multicentre, open-label, randomised phase II trial evaluating the efficacy of adjuvant nivolumab/ipilimumab versus chemotherapy in gastro-oesophageal adenocarcinoma at high risk of recurrence. Patients were randomised 1 : 1 to receive standard adjuvant chemotherapy (same regimen as neoadjuvant) or nivolumab 3 mg/kg intravenously (i.v.) every 2 weeks plus ipilimumab 1 mg/kg i.v. every 6 weeks for 1 year. Key inclusion criteria included ypN+ and/or R1 status after neoadjuvant chemotherapy plus surgery. The primary endpoint was disease-free survival in the intent-to-treat population. Secondary endpoints included overall survival, locoregional and distant failure rates, and safety according to National Cancer Institute Common Terminology Criteria for Adverse Events v5.0. RESULTS: The independent Data Monitoring Committee reviewed data from 189 of the planned 240 patients in June 2022 and recommended stopping recruitment due to futility. At the time of final analysis, median follow-up was 25.3 months for 195 patients (98 nivolumab/ipilimumab and 97 chemotherapy). Median disease-free survival for the nivolumab/ipilimumab group was 11.4 months [95% confidence interval (CI) 8.4-16.8 months] versus 20.8 months (95% CI 15.0-29.9 months) for the chemotherapy group, hazard ratio 1.55 (95% CI 1.07-2.25, one-sided P = 0.99). The 12-month disease-free survival rates were 47.1% and 64.0%, respectively. There were no toxicity concerns or excess early discontinuations. CONCLUSION: Nivolumab/ipilimumab did not improve disease-free survival compared with chemotherapy in patients with ypN+ and/or R1 gastro-oesophageal adenocarcinoma following neoadjuvant chemotherapy and surgery.
- MeSH
- Adenocarcinoma * pathology drug therapy therapy MeSH
- Chemotherapy, Adjuvant methods MeSH
- Adult MeSH
- Gastrectomy MeSH
- Esophagogastric Junction * pathology MeSH
- Immunotherapy methods MeSH
- Ipilimumab administration & dosage therapeutic use MeSH
- Middle Aged MeSH
- Humans MeSH
- Neoplasm Recurrence, Local * pathology prevention & control drug therapy epidemiology MeSH
- Esophageal Neoplasms * pathology drug therapy therapy MeSH
- Stomach Neoplasms * pathology drug therapy therapy surgery MeSH
- Neoadjuvant Therapy * methods adverse effects MeSH
- Nivolumab administration & dosage therapeutic use MeSH
- Disease-Free Survival MeSH
- Antineoplastic Combined Chemotherapy Protocols * therapeutic use MeSH
- Aged MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase II MeSH
- Multicenter Study MeSH
- Randomized Controlled Trial MeSH
CONTEXT: Adjuvant immune checkpoint inhibitors (ICIs) have recently emerged as guideline-recommended treatments of high-risk muscle-invasive urothelial carcinoma (MIUC). However, there is limited evidence regarding the optimal candidates and the differential efficacy of adjuvant ICI regimens. OBJECTIVE: To synthesize and compare the efficacy and safety of adjuvant ICIs for high-risk MIUC using updated data from phase III randomized controlled trials. EVIDENCE ACQUISITION: In April 2024, three databases were searched for eligible randomized controlled trials that evaluated oncologic outcomes in patients with MIUC treated with adjuvant ICIs. Pairwise meta-analysis (MA) and network meta-analyses were performed to compare the hazard ratios of oncological outcomes, including disease-free survival (DFS), overall survival (OS), and adverse events. Subgroup analyses were conducted on the basis of predefined clinicopathological features. EVIDENCE SYNTHESIS: Three randomized controlled trials that assessed the efficacy of adjuvant nivolumab, pembrolizumab, and atezolizumab were included in the MAs and network meta-analyses groups. Pairwise MAs showed that treatment with adjuvant ICIs significantly improved DFS [hazards ratio: 0.77, 95% confidence interval (CI): 0.66-0.90] as well as OS (hazards ratio: 0.87, 95% CI 0.76-1.00) in patients with MIUC compared with in the placebo/observation group. The DFS benefit was prominent in patients who underwent neoadjuvant chemotherapy (P = 0.041) and in those with bladder cancer (P = 0.013) but did not differ across programmed death-ligand 1 and lymph node status. Adjuvant ICI therapy was associated with increased risk of any (OR: 2.98, 95% CI 2.06-4.33) and severe adverse events (OR: 1.78, 95% CI 1.49-2.13). The treatment rankings revealed that pembrolizumab for DFS (84%) and nivolumab for OS (93%) had the highest likelihood of improving survival. CONCLUSIONS: Our analyses demonstrated the DFS and OS benefits of adjuvant ICIs for high-risk MIUC. Furthermore, patients with bladder cancer who underwent neoadjuvant chemotherapy appeared to be the optimal candidates for adjuvant ICIs regarding prolonged DFS. Adjuvant ICIs are the standard of care for high-risk MIUC, and differential clinical behaviors and efficacy will enrich clinical decision-making.
- MeSH
- Chemotherapy, Adjuvant methods MeSH
- Immune Checkpoint Inhibitors * therapeutic use pharmacology MeSH
- Neoplasm Invasiveness MeSH
- Carcinoma, Transitional Cell drug therapy pathology MeSH
- Humans MeSH
- Urinary Bladder Neoplasms drug therapy pathology MeSH
- Network Meta-Analysis as Topic MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Meta-Analysis MeSH
- Systematic Review MeSH
BACKGROUND: Prostate cancer (PCa) is a malignancy with significant immunosuppressive properties and limited immune activation. This immunosuppression is linked to reduced cytotoxic T cell activity, impaired antigen presentation, and elevated levels of immunosuppressive cytokines and immune checkpoint molecules. Studies demonstrate that cytotoxic CD8+ T cell infiltration correlates with improved survival, while increased regulatory T cells (Tregs) and tumor-associated macrophages (TAMs) are associated with worse outcomes and therapeutic resistance. Th1 cells are beneficial, whereas Th17 cells, producing interleukin-17 (IL-17), contribute to tumor progression. Tumor-associated neutrophils (TANs) and immune checkpoint molecules, such as PD-1/PD-L1 and T cell immunoglobulin-3 (TIM-3) are also linked to advanced stages of PCa. Chemotherapy holds promise in converting the "cold" tumor microenvironment (TME) to a "hot" one by depleting immunosuppressive cells and enhancing tumor immunogenicity. SUMMARY: This comprehensive review examines the immune microenvironment in PCa, focusing on the intricate interactions between immune and tumor cells in the TME. It highlights how TAMs, Tregs, cytotoxic T cells, and other immune cell types contribute to tumor progression or suppression and how PCa's low immunogenicity complicates immunotherapy. KEY MESSAGES: The infiltration of cytotoxic CD8+ T cells and Th1 cells correlates with better outcomes, while elevated T regs and TAMs promote tumor growth, metastasis, and resistance. TANs and natural killer (NK) cells exhibit dual roles, with higher NK cell levels linked to better prognoses. Immune checkpoint molecules like PD-1, PD-L1, and TIM-3 are associated with advanced disease. Chemotherapy can improve tumor immunogenicity by depleting T regs and myeloid-derived suppressor cells, offering therapeutic promise.
- MeSH
- Immunotherapy methods MeSH
- Humans MeSH
- Tumor-Associated Macrophages immunology MeSH
- Tumor Microenvironment * immunology MeSH
- Prostatic Neoplasms * immunology pathology therapy MeSH
- T-Lymphocytes, Regulatory immunology MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
Spinocelulární karcinom kůže (cutaneous squamous cell carcinoma, cSCC) je jedním z nejčastějších kožních nádorů. Hlavní léčbou cSCC je chirurgický zákrok. Nicméně neoperabilní nebo metastazující cSCC zůstává neléčitelný. S nástupem imunoterapie se dostaly do popředí při léčbě těchto forem onemocnění checkpoint inhibitory, jako je cemiplimab. Cemiplimab je lék modulující imunitu, který se zaměřuje na receptor PD-1. Dosavadní výsledky ukazují nejen dobrou léčebnou odpověď, ale také dlouhodobou účinnost. Následující kazuistika dokazuje účinnost cemiplimabu i u zdánlivě neřešitelných případů.
Cutaneous squamous cell carcinoma (cSCC) is one of the most common skin cancers. The primary treatment for cSCC is surgical intervention. However, inoperable or metastatic cSCC remains difficult to treat. With the advent of immunotherapy, checkpoint inhibitors, such as cemiplimab, have become prominent in the treatment of these forms of the disease. Cemiplimab is an immune-modulating drug that targets the PD-1 receptor. Current results indicate not only a good therapeutic response but also long-term efficacy. The following case study demonstrates the effectiveness of cemiplimab even in seemingly intractable cases.
Immune checkpoints are critical in modulating immune responses and maintaining self-tolerance. Cancer cells can exploit these mechanisms to evade immune detection, making immune checkpoints attractive targets for cancer therapy. The introduction of immune checkpoint inhibitors (ICIs) has transformed cancer treatment, with monoclonal antibodies targeting CTLA-4, PD-1, and PD-L1 demonstrating clinical success. However, challenges such as immune-related adverse events, primary and acquired resistance, and high treatment costs persist. To address these challenges, it is essential to explore alternative strategies, including small-molecule and peptide-based inhibitors, aptamers, RNA-based therapies, gene-editing technologies, bispecific and multispecific agents, and cell-based therapies. Additionally, innovative approaches such as lysosome-targeting chimeras, proteolysis-targeting chimeras, and N-(2-hydroxypropyl) methacrylamide copolymers are emerging as promising options for enhancing treatment effectiveness. This review highlights significant advancements in the field, focusing on their clinical implications and successes.
BACKGROUND: The treatment of non-small cell lung cancer (NSCLC) patients is correlated with the efficacy of immune checkpoint blockade therapy (ICB) targeting programmed cell death ligand 1 (PD-L1) or its cognate receptor (PD-1) on cancer cells or infiltrating immune cells. Analysis of PD-L1/PD-1 expression in tumor tissue represents a crucial step before PD-L1/PD-1 blocker usage. METHODS: We used directed evolution of protein variants derived from a 13 kDa Myomedin loop-type combinatorial library with 12 randomized amino acid residues to select high-affinity binders of human PD-L1 (hPD-L1). After the ribosome display, individual clones were screened by ELISA. Detailed analysis of binding affinity and kinetics was performed using LigandTracer. The specificity of Myomedins was assessed using fluorescent microscopy on HEK293T-transfected cells and cultured cancer cells in vitro, formalin-fixed paraffin-embedded (FFPE) sections of human tonsils, and FFPE tumor samples of NSCLC patients. RESULTS: Seven identified PD-L1 binders, called MLE, showed positive staining for hPD-L1 on transfected HEK293T cells and cultured MCF-7 cells. MLE031, MLE105, MLE249, and MLE309 exhibited high affinity to both human and mouse PD-L1-transfected HEK293T cells measured with LigandTracer. The diagnostic potential of MLE variants was tested on human tonsillitis tissue and compared with diagnostic anti-PD-L1 antibody DAKO 28-8 and PD-L1 IHC 22C3 pharmDx antibody. MLE249 and MLE309 exhibited an excellent overlap with diagnostic DAKO 28-8 (Pearson ́s coefficient (r) = 0.836 and 0.731, respectively) on human tonsils on which MLE309 exhibited also excellent overlap with diagnostic 22C3 antibody (r = 0.876). Using three NSCLC tissues, MLE249 staining overlaps with 28-8 antibody (r = 0.455-0.883), and MLE309 exhibited overlap with 22C3 antibody (r = 0.534-0.619). Three MLE proteins fused with Fc fragments of rabbit IgG, MLE249-rFc, MLE309-rFc and MLE031-rFc, exhibited very good overlap with anti-PD-L1 antibody 28-8 on tonsil tissue (r = 0.691, 0.610, and 0.667, respectively). Finally, MLE249-rFc, MLE309-rFc and MLE031-rFc exhibited higher sensitivity in comparison to IHC 22C3 antibody using routine immunohistochemistry staining system Ventana, which is one of gold standards for PD-L1 diagnosis. CONCLUSIONS: We demonstrated the development of MLE Myomedins specifically recognizing hPD-L1 that may serve as a refinement tool for clinical PD-L1 detection.
- MeSH
- Adenocarcinoma of Lung drug therapy MeSH
- Diagnosis, Differential MeSH
- Adrenal Cortex Hormones pharmacology therapeutic use MeSH
- Immune Checkpoint Inhibitors adverse effects MeSH
- Colitis * chemically induced MeSH
- Middle Aged MeSH
- Humans MeSH
- Drug-Related Side Effects and Adverse Reactions drug therapy MeSH
- Nivolumab adverse effects MeSH
- Diarrhea * etiology MeSH
- Intestine, Large pathology MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Publication type
- Case Reports MeSH
- MeSH
- Brentuximab Vedotin therapeutic use MeSH
- Hodgkin Disease diagnosis therapy MeSH
- Immunotherapy methods MeSH
- Immune Checkpoint Inhibitors therapeutic use MeSH
- Clinical Trials as Topic MeSH
- Drug Therapy, Combination MeSH
- Response Evaluation Criteria in Solid Tumors MeSH
- Humans MeSH
- Recurrence MeSH
- Risk Factors MeSH
- Neoplasm Staging MeSH
- Stem Cell Transplantation MeSH
- Risk Adjustment MeSH
- Check Tag
- Humans MeSH
Východiska: Protinádorová imunoterapie je již standardem léčby nemalobuněčného karcinomu plic (non-small cell lung cancer – NSCLC) a to nejen u metastatického, ale i lokálně pokročilého onemocnění a také časných, operabilních stadií. Cíl: Článek podává přehled aktualizovaných výsledků studií EMPOWER-Lung 1 a EMPOWER-Lung 3. Ve studiích byla hodnocena účinnost cemiplimabu (monoklonální protilátky, která se váže na receptor programované buněčné smrti – PD-1) u pacientů s metastatickým a lokálně pokročilým NSCLC, kteří nejsou kandidáti operace a chemoradiace. Také uvádíme zkušenosti z našeho pracoviště, kde byl cemiplimab podán v monoterapii u pacientů s vysokou expresí ligandu PD-L1. Závěr: Cemiplimab prokázal účinnost v monoterapii u pacientů s NSCLC exprimujícím PD-L1 u ≥ 50 % nádorových buněk a v kombinaci s chemoterapií na bázi platinového dubletu při expresi PD-L1 u ≥ 1 % nádorových buněk v první linii léčby metastatického, ale také neresekovatelného lokálně pokročilého onemocnění, nevhodného pro definitivní chemoradiaci. Pro tyto pacienty je cemiplimab novou léčebnou možností.
Background: Immuno-oncotherapy is already the standard treatment for non-small cell lung cancer (NSCLC), not only for metastatic disease, but also for locally advanced disease as well as early, operable stages. Aim: The article provides an overview of the updated results of the EMPOWER-Lung 1 and EMPOWER-Lung 3 studies. The studies evaluated the efficacy of cemiplimab (a monoclonal antibody that binds to the programmed cell death receptor – PD-1) in patients with metastatic and locally advanced NSCLC who are not surgery and chemoradiation candidates. We also present the experience from our institution, when cemiplimab was administered as monotherapy in patients with high PD-L1 ligand expression. Conclusion: Cemiplimab demonstrated efficacy as monotherapy in patients with NSCLC expressing PD-L1 in ≥ 50% of tumor cells and in combination with platinum-doublet chemotherapy when expressing PD-L1 in ≥ 1% of tumor cells in the first-line treatment of metastatic but also unresectable locally advanced disease unsuitable for definitive chemoradiation, demonstrating a new treatment option for these patients.
- Keywords
- cemiplimab, EMPOWER-Lung 1, EMPOWER-Lung 3,
- MeSH
- Antibodies, Monoclonal, Humanized pharmacology therapeutic use MeSH
- Immunotherapy methods MeSH
- Immune Checkpoint Inhibitors * pharmacology classification therapeutic use MeSH
- Clinical Studies as Topic MeSH
- Humans MeSH
- Carcinoma, Non-Small-Cell Lung * diagnosis drug therapy MeSH
- Treatment Outcome MeSH
- Check Tag
- Humans MeSH
- Publication type
- Review MeSH
Článek obsahuje výsledky studií a přehled literatury týkající se výskytu melanomu u pacientů mladších 21 let. Jsou diskutovány charakteristické znaky melanomu u dětí, rizikové faktory, histologické a imuno-histochemické rysy a možnosti léčby. Ze studií vyplývá, že pečlivá analýza histologických a imuno-histochemických rysů by měla umožnit správnou diagnózu ve většině případů melanomů u dětí. Pacienti s melanomem v dětském věku mají sice vyšší pravděpodobnost přežití než dospělí, u řady dětí se ale vyvinou metastázy, zvláště když je melanom diagnostikován po pubertě. Melanom patří sice mezi vzácná onemocnění dětského věku, přesto je nejčastějším typem kožního zhoubného nádoru u mladých lidí. Se zvyšující incidencí je potřeba brát toto onemocnění do úvahy; na melanom u dětí se často nepomýšlí a diagnóza je opožděná.
Melanoma in children is relatively rare, making it difficult to determine prognostic factors, biological behavior, and efficacy of therapy in the pediatric population. The article presents the results of studies and a review of the literature regarding the incidence of melanoma in patients younger than 21 years. The characteristic features of melanoma in children, risk factors, histological and immunohistochemical features, and treatment options are discussed. Studies suggest that careful analysis of histological and immunohistochemical features should allow for the correct diagnosis in most cases of melanoma in children. Although patients with melanoma in childhood have a higher chance of survival than adults, many children develop metastases, especially when melanoma is diagnosed after puberty. Although melanoma is a rare childhood disease, it is the most common type of skin cancer in young people. With its increasing incidence, it is important to consider this disease; melanoma in children is often overlooked and diagnosis is delayed.
- MeSH
- Diagnosis, Differential MeSH
- Child MeSH
- Nevus, Epithelioid and Spindle Cell diagnosis genetics MeSH
- Skin Diseases, Genetic diagnosis genetics classification MeSH
- Immune Checkpoint Inhibitors pharmacology therapeutic use MeSH
- Humans MeSH
- Melanoma * diagnosis genetics classification MeSH
- Adolescent MeSH
- Skin Neoplasms diagnosis genetics classification MeSH
- Nevus diagnosis genetics classification complications MeSH
- Prognosis MeSH
- Ultraviolet Rays adverse effects MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Adolescent MeSH
- Publication type
- Review MeSH
