Recent advances in avian melanogenesis have pinpointed multiple genetic loci associated with color polymorphisms, predominantly in the plumage of chickens, quails, and pigeons. However, the genetic basis of melaninization in parrot plumage remains elusive. Previously, we showed that mutations in the melanosomal ion-transporter SLC45A2 lead to a complete loss of blue structural color in green parrot feathers, leaving only yellow psittacofulvin. Yet, several color morphs involving partial or complete melanin reduction are common in captive-bred parrots that have not been studied. To bridge this gap, we investigated two new color morphs of parrot plumage: non-sex-linked recessive lutino (NSL), which entirely inhibits blue structural coloration, and the sex-linked recessive cinnamon, which reduces the intensity of blue structural coloration. Our genotypic analysis revealed that tyrosinase (TYR) variants are responsible for the NSL phenotype in Fischer's lovebird and green-cheeked parakeet, while tyrosinase related protein 1 (TYRP1) variants are associated with the cinnamon phenotype in the rose-ringed parakeet. When transfected into HEK293T cells, the candidate substitutions significantly affected tyrosinase enzymatic activity. This study underscores tyrosinase and related enzymes' role in parrot feather coloration, enhancing our understanding of avian melanogenesis as well as the conserved functions of melanogenic components across different species.

• MeSH
• Phenotype MeSH
• Humans MeSH
• Melanins metabolism   MeSH
• Oxidoreductases * metabolism   genetics   MeSH
• Parrots * genetics   metabolism   MeSH
• Feathers * enzymology   metabolism   MeSH
• Pigmentation * genetics   MeSH
• Avian Proteins * metabolism   genetics   MeSH
• Monophenol Monooxygenase * metabolism   genetics   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

T-cell engagers represent a transformative approach to cancer immunotherapy leveraging bispecific and multispecific antibody constructs to redirect T-cell cytotoxicity toward malignant cells. These molecules bridge T cells and tumor cells by simultaneously binding CD3 on T cells and tumor-associated antigens on cancer cells, thereby enabling precise immune targeting even in immunologically "cold" tumors. Recent advancements include conditional T-cell engagers activated by tumor microenvironment proteases to minimize off-tumor toxicity as well as T-cell receptor-based engagers targeting intracellular antigens via MHC presentation. Clinical successes, such as Kimmtrak in metastatic uveal melanoma, underscore good potential of these modalities, while challenges persist in the management of cytokine release syndrome, neurotoxicity, and tumor resistance. Emerging multispecific engagers are aimed at enhancing efficacy via incorporation of costimulatory signals, thus offering a promising trajectory for next-generation immunotherapies. T-cell engagers are also gaining attention in the treatment of autoimmune disorders, where they can be designed to selectively modulate pathogenic immune responses. By targeting autoreactive T or B cells, T-cell engagers hold promise for restoring immune tolerance in such conditions as HLA-B*27-associated autoimmunity subtypes, multiple sclerosis, rheumatoid arthritis, and type 1 diabetes mellitus. Engineering strategies that incorporate inhibitory receptors or tissue-specific antigens may further refine T-cell engagers' therapeutic potential in autoimmunity, by minimizing systemic immunosuppression while preserving immune homeostasis.

• MeSH
• Immunotherapy * methods   MeSH
• Humans MeSH
• Tumor Microenvironment immunology   MeSH
• Neoplasms * immunology   therapy   MeSH
• Antibodies, Bispecific therapeutic use   immunology   MeSH
• Receptors, Antigen, T-Cell immunology   metabolism   MeSH
• T-Lymphocytes * immunology   metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Tinostamustine is a first-in-class alkylating deacetylase inhibitor that facilitates access to cancer cell DNA, resulting in its damage and counteracting DNA repair systems. We hypothesize that the addition of tinostamustine to immune checkpoint inhibitors (ICIs) improves melanoma treatment. This open-label, nonrandomized phase IB study characterized dose-limiting toxicity (DLT) and the recommended dose (RD) of 2-weekly intravenous tinostamustine at escalating doses of 15 and 30 mg/m 2 when administered with 2-weekly nivolumab 3 mg/kg added in cycle 2 in patients with melanoma. We included 17 patients (four at 15 mg/m 2 and 13 at 30 mg/m 2 tinostamustine). A total of 13/17 (77%) patients were ICI-resistant, 7/17 (41%) had unfavorable melanoma subtypes. No DLT was identified. Tinostamustine RD was 30 mg/m 2 every 2 weeks. One patient experienced grade 2 nivolumab-associated immune-related pneumonitis. Tinostamustine-associated grade 3 leukocytopenia was documented in one patient, grade 2 leukocytopenia in five patients, and grade 1 thrombocytopenia in three patients. Treatment discontinuation occurred in one patient for nivolumab-associated immune-related pneumonitis and in another patient for tumor-related hemorrhage. A total of 7/13 (54%) evaluable patients had at least stable disease as best treatment response, including 3/13 (23%) patients with a confirmed partial response. Median progression-free survival was 8.3 weeks [95% confidence interval (CI): 2.4-15.4 weeks), median overall survival was 19.1 weeks (95% CI: 2.4-41 weeks). Two-weekly intravenous tinostamustine at an immune-modulatory dose of 30 mg/m 2 is safe when coadministered with nivolumab 3 mg/kg and resulted in 54% disease stabilization and 23% confirmed partial responses in patients with predominantly ICI-resistant, advanced melanoma.

• MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Melanoma * drug therapy   pathology   MeSH
• Skin Neoplasms * drug therapy   pathology   MeSH
• Nivolumab * pharmacology   therapeutic use   administration & dosage   MeSH
• Antineoplastic Combined Chemotherapy Protocols * therapeutic use   pharmacology   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase I MeSH

• Publication type
• News MeSH

PURPOSE: There are limited treatment options for advanced melanoma that have progressed during or after immune checkpoint inhibitor therapy. Intratumoral (IT) immunotherapy may improve tumor-specific immune activation by promoting local tumor antigen presentation while avoiding systemic toxicities. The phase 3 ILLUMINATE-301 study (ClinicalTrials.gov identifier: NCT03445533) evaluated tilsotolimod, a Toll-like receptor-9 agonist, with or without ipilimumab in patients with anti-PD-1 advanced refractory melanoma. METHODS: Patients with unresectable stage III-IV melanoma that progressed during or after anti-PD-1 therapy were randomly assigned 1:1 to receive 24 weeks of tilsotolimod plus ipilimumab or 10 weeks of ipilimumab alone. Nine IT injections of tilsotolimod were administered to a single designated lesion over 24 weeks. Intravenous ipilimumab 3 mg/kg was administered once every 3 weeks from week 2 in the tilsotolimod arm and week 1 in the ipilimumab arm. The primary end point was efficacy measured using objective response rate (ORR; independent review) and overall survival (OS). RESULTS: A total of 481 patients received tilsotolimod plus ipilimumab (n = 238) or ipilimumab alone (n = 243). ORRs were 8.8% in the tilsotolimod arm and 8.6% in the ipilimumab arm, with disease control rates of 34.5% and 27.2%, respectively. Median OS was 11.6 months in the tilsotolimod arm and 10 months in the ipilimumab arm (hazard ratio, 0.96 [95% CI, 0.77 to 1.19]; P = .7). Grade ≥3 treatment-emergent adverse events occurred in 61.1% and 55.5% of patients in the tilsotolimod and ipilimumab arms, respectively. CONCLUSION: Combining IT tilsotolimod with ipilimumab did not significantly improve the ORR or OS compared with ipilimumab alone in patients with anti-PD-1 advanced refractory melanoma.

• MeSH
• Adult MeSH
• Ipilimumab * administration & dosage   adverse effects   MeSH
• Middle Aged MeSH
• Humans MeSH
• Melanoma * drug therapy   pathology   immunology   mortality   MeSH
• Skin Neoplasms * drug therapy   pathology   immunology   MeSH
• Oligonucleotides MeSH
• Antineoplastic Combined Chemotherapy Protocols * therapeutic use   adverse effects   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Multicenter Study MeSH
• Randomized Controlled Trial MeSH

BACKGROUND: Immune checkpoint inhibitors (ICIs), including those targeting PD-1, are currently used in a wide range of tumors, but only 20-40% of patients achieve clinical benefit. The objective of our study was to find predictive peripheral blood-based biomarkers for ICI treatment. METHODS: In 41 patients with advanced malignant melanoma (MM) and NSCLC treated with PD-1 inhibitors, we analyzed peripheral blood-based immune subsets by flow cytometry before treatment initialization and the second therapy dose. Specifically, we assessed basic blood differential count, overall T cells and their subgroups, B cells, and myeloid-derived suppressor cells (MDSC). In detail, CD4 + and CD8 + T cells were assessed according to their subtypes, such as central memory T cells (TCM), effector memory T cells (TEM), and naïve T cells (TN). Furthermore, we also evaluated the predictive value of CD28 and ICOS/CD278 co-expression on T cells. RESULTS: Patients who achieved disease control on ICIs had a significantly lower baseline proportion of CD4 + TEM (p = 0.013) and tended to have a higher baseline proportion of CD4 + TCM (p = 0.059). ICI therapy-induced increase in Treg count (p = 0.012) and the proportion of CD4 + TN (p = 0.008) and CD28 + ICOS- T cells (p = 0.012) was associated with disease control. Patients with a high baseline proportion of CD4 + TCM and a low baseline proportion of CD4 + TEM showed significantly longer PFS (p = 0.011, HR 2.6 and p ˂ 0.001, HR 0.23, respectively) and longer OS (p = 0.002, HR 3.75 and p ˂ 0.001, HR 0.15, respectively). Before the second dose, the high proportion of CD28 + ICOS- T cells after ICI therapy initiation was significantly associated with prolonged PFS (p = 0.017, HR 2.51) and OS (p = 0.030, HR 2.69). Also, a high Treg count after 2 weeks of ICI treatment was associated with significantly prolonged PFS (p = 0.016, HR 2.33). CONCLUSION: In summary, our findings suggest that CD4 + TEM and TCM baselines and an early increase in the Treg count induced by PD-1 inhibitors and the proportion of CD28 + ICOS- T cells may be useful in predicting the response in NSCLC and MM patients.

• MeSH
• Inducible T-Cell Co-Stimulator Protein metabolism   MeSH
• Programmed Cell Death 1 Receptor antagonists & inhibitors   MeSH
• CD28 Antigens MeSH
• CD8-Positive T-Lymphocytes immunology   drug effects   metabolism   MeSH
• Adult MeSH
• Immune Checkpoint Inhibitors * therapeutic use   pharmacology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Melanoma * drug therapy   immunology   blood   pathology   MeSH
• Lung Neoplasms * drug therapy   immunology   blood   pathology   MeSH
• Carcinoma, Non-Small-Cell Lung * drug therapy   immunology   blood   pathology   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Terapie maligního melanomu zaznamenala v poslední dekádě výrazné změny. Důvodem bylo pochopení molekulárních pochodů v patogenezi maligního melanomu a identifikace klíčových struktur kontrolujících průběh imunitní reakce. Standardem léčby pokročilého maligního melanomu u nemocných nesoucích mutaci genu BRAF je v současné době cílená léčba. Kazuistika popisuje účinnost enkorafenibu s binimetinibem po selhání adjuvantní imunoterapie.

The therapy for malignant melanoma has undergone significant changes in the past decade. This progress is attributed to the understanding of molecular processes in the pathogenesis of malignant melanoma and the identification of key structures controlling the immune response. Currently, the standard treatment for advanced malignant melanoma in patients with a BRAF gene mutation is targeted therapy. This case study describes the effectiveness of encorafenib with binimetinib following the failure of adjuvant immunotherapy.

• Keywords
• enkorafenib, biminetinib,
• MeSH
• Molecular Targeted Therapy * classification   methods   MeSH
• Adult MeSH
• Immunotherapy classification   methods   MeSH
• Humans MeSH
• Melanoma * diagnostic imaging   diagnosis   drug therapy   MeSH
• Proto-Oncogene Proteins B-raf analysis   genetics   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Male MeSH
• Publication type
• Case Reports MeSH

Advances in cancer treatments have significantly improved their effectiveness, yet access to first-line therapies remains limited. A 2017 survey revealed that over 25 % of metastatic melanoma patients in Europe lacked access to recommended therapies. To address this, the European Association of Dermato-Oncology and the European Melanoma Registry conducted a follow-up study on the registration and reimbursement of first-line treatments.A web-based survey using LimeSurvey was distributed to melanoma experts across 27 European countries from February to April 2022 and updated from February to April 2024. The questionnaire covered the percentage of patients receiving recommended treatments, as well as treatment authorization and reimbursement dates for systemic and adjuvant therapies.There has been significant improvement in the registration and reimbursement of BRAFi/MEKi, anti-PD1, and anti-PD1/anti-CTLA4 therapies, increasing from 48 %, 63 %, and 37 % in 2017 to 96 %, 96 %, and 78 % in 2024, respectively. Despite these gains, restrictions persist. Anti-PD1/anti-CTLA4 combination immunotherapy is still not available without restrictions in 48 % of the surveyed countries. The nivolumab/relatlimab combination is licensed only for PDL-1-negative melanoma and reimbursed in seven countries of Europe. Tebentafusp is reimbursed in 15 countries and talimogene laherpervec in 5. In 2024, adjuvant treatments for stage III melanoma are reimbursed in 22 countries for dabrafenib/trametinib and 24 of 27 for anti-PD1 antibodies. Pembrolizumab and nivolumab are reimbursed in 15 and 8 countries, respectively, for stage IIB/IIC disease.While there have been improvements in the reimbursement of metastatic melanoma treatments in Europe, challenges and discrepancies remain. Further efforts at European and global levels are needed to harmonize and enhance access to cancer medicines.

• MeSH
• Health Services Accessibility MeSH
• Immunotherapy methods   MeSH
• Immune Checkpoint Inhibitors therapeutic use   MeSH
• Humans MeSH
• Melanoma * drug therapy   MeSH
• Skin Neoplasms * drug therapy   MeSH
• Surveys and Questionnaires MeSH
• Registries * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Europe MeSH

V posledním desetiletí bylo dosaženo značných pokroků v léčbě metastatického maligního melanomu, a to především díky imunoterapii, která významně zvýšila počet pacientů s dlouhodobou kontrolou onemocnění. Kombinace nivolumabu a ipilimumabu je v současnosti považována za nejúčinnější režim. Hlavním problémem je však jeho vysoká toxicita, která může být pro řadu pacientů limitující. Zvýšit účinnost, případně snížit toxicitu léčby je motivací k dalšímu výzkumu a vývoji nových checkpoint inhibitorů, jako jsou například anti-LAG-3 protilátky. Ve studii RELATIVITY-047 byla testována první anti-LAG-3 protilátka relatlimab v kombinaci s anti-PD-1 protilátkou nivolumabem versus samotný nivolumab. Studie ukázala, že kombinace významně prodlužuje přežití bez progrese onemocnění ve srovnání s monoterapií nivolumabem (10,1 měsíce vs. 4,6 měsíce), a navíc bez výrazného navýšení toxicity ve srovnání s nivolumabem a ipilimumabem. Nivolumab + relatlimab tak představují novou potenciálně účinnou variantu kombinované léčby pokročilého melanomu. Výběr vhodného léčebného režimu však dále musí být individualizovaný na základě charakteristik onemocnění a konkrétních potřeb pacienta.

In the last decade, significant advances have been made in the treatment of metastatic malignant melanoma, mainly thanks to immunotherapy, which has significantly increased the number of patients with long-term disease control. The combination of nivolumab and ipilimumab is currently considered the most effective regimen. However, the main problem is its high toxicity, which can be limiting for many patients. Increasing the effectiveness or reducing the toxicity of the treatment is the motivation for further research and development of new checkpoint inhibitors, such as anti-LAG-3 antibodies. In the RELATIVITY-047 study, the first anti-LAG-3 antibody relatlimab was tested in combination with the anti-PD-1 antibody nivolumab versus nivolumab alone. The study showed that the combination significantly prolonged progression-free survival compared to nivolumab monotherapy (10.1 vs 4.6 months), and in addition, without a significant increase in toxicity compared to nivolumab and ipilimumab. Nivolumab plus relatlimab thus represents a new potentially effective combination treatment option for advanced melanoma. However, the selection of an appropriate treatment regimen must be individualized based on the characteristics of the disease and the specific needs of the patient.

V posledním desetiletí byly dosaženy značné pokroky v léčbě metastazujícího maligního melanomu, a to především díky imunoterapii, která významně zvýšila počet pacientů s dlouhodobou kontrolou onemocnění. Kombinace nivolumabu a ipilimumabu je v současnosti považována za nejúčinnější režim. Hlavním problémem je však jeho vysoká toxicita, která může být pro řadu pacientů limitující. Zvýšit účinnost, případně snížit toxicitu léčby je motivací k dalšímu výzkumu a vývoji nových checkpoint inhibitorů, jako jsou například anti-LAG-3 protilátky. Ve studii RELATIVITY-047 byla testována první anti-LAG-3 protilátka relatlimab v kombinaci s protilátkou proti receptoru programované buněčné smrti 1 (programmed cell death protein 1, PD-1) nivolumabem versus samotný nivolumab. Studie ukázala, že kombinace významně prodlužuje přežití bez progrese onemocnění ve srovnání s monoterapií nivolumabem (10,1 měsíce vs. 4,6 měsíce), a navíc bez výrazného navýšení toxicity ve srovnání s nivolumabem a ipilimumabem. Nivolumab + relatlimab tak představuje novou potenciálně účinnou variantu kombinované léčby pokročilého melanomu. Výběr vhodného léčebného režimu však dále musí být individualizovaný na základě charakteristik onemocnění a konkrétních potřeb pacienta.

In the last decade, significant advances have been made in the treatment of metastatic malignant melanoma, mainly thanks to immunotherapy, which has significantly increased the number of patients with long-term disease control. The combination of nivolumab and ipilimumab is currently considered the most effective regimen. However, the main problem is its high toxicity, which can be limiting for many patients. Increasing the effectiveness or reducing the toxicity of the treatment is the motivation for further research and development of new checkpoint inhibitors, such as anti-LAG-3 antibodies. In the RELATIVITY-047 study, the first anti-LAG-3 antibody relatlimab was tested in combination with the programmed cell death protein 1 (PD-1) antibody nivolumab versus nivolumab alone. The study showed that the combination significantly prolonged progression free survival compared to nivolumab monotherapy (10.1 months vs. 4.6 months), and in addition, without a significant increase in toxicity compared to nivolumab and ipilimumab. Nivolumab + relatlimab thus represents a new potentially effective combination treatment option for advanced melanoma. However, the selection of an appropriate treatment regimen must be individualized based on the characteristics of the disease and the specific needs of the patient.

• Keywords
• studie RELATIVITY-047, Nivolumab, relatlimab,
• MeSH
• Progression-Free Survival MeSH
• Tumor Necrosis Factor Inhibitors MeSH
• Combined Antibody Therapeutics * adverse effects   toxicity   MeSH
• Humans MeSH
• Melanoma * drug therapy   immunology   MeSH
• Neoplasm Metastasis MeSH
• Antibodies, Monoclonal MeSH
• Randomized Controlled Trials as Topic MeSH
• Check Tag
• Humans MeSH
• Publication type
• Research Support, Non-U.S. Gov't MeSH