RESUMO
Although clonal neo-antigen burden is associated with improved response to immune therapy, the functional basis for this remains unclear. Here we study this question in a novel controlled mouse melanoma model that enables us to explore the effects of intra-tumor heterogeneity (ITH) on tumor aggressiveness and immunity independent of tumor mutational burden. Induction of UVB-derived mutations yields highly aggressive tumors with decreased anti-tumor activity. However, single-cell-derived tumors with reduced ITH are swiftly rejected. Their rejection is accompanied by increased T cell reactivity and a less suppressive microenvironment. Using phylogenetic analyses and mixing experiments of single-cell clones, we dissect two characteristics of ITH: the number of clones forming the tumor and their clonal diversity. Our analysis of melanoma patient tumor data recapitulates our results in terms of overall survival and response to immune checkpoint therapy. These findings highlight the importance of clonal mutations in robust immune surveillance and the need to quantify patient ITH to determine the response to checkpoint blockade.
Assuntos
Heterogeneidade Genética/efeitos da radiação , Melanoma/genética , Melanoma/imunologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologia , Raios Ultravioleta/efeitos adversos , Animais , Carcinogênese/genética , Linhagem Celular Tumoral , Estudos de Coortes , Modelos Animais de Doenças , Feminino , Humanos , Linfócitos do Interstício Tumoral , Melanoma/mortalidade , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout , Mutação/efeitos da radiação , Filogenia , Neoplasias Cutâneas/mortalidade , Taxa de Sobrevida , Linfócitos T/imunologia , Microambiente Tumoral/imunologia , Microambiente Tumoral/efeitos da radiaçãoRESUMO
Although the pathological significance of tumor-associated macrophage (TAM) heterogeneity is still poorly understood, TAM reprogramming is viewed as a promising anticancer therapy. Here we show that a distinct subset of TAMs (F4/80hiCD115hiC3aRhiCD88hi), endowed with high rates of heme catabolism by the stress-responsive enzyme heme oxygenase-1 (HO-1), plays a critical role in shaping a prometastatic tumor microenvironment favoring immunosuppression, angiogenesis and epithelial-to-mesenchymal transition. This population originates from F4/80+HO-1+ bone marrow (BM) precursors, accumulates in the blood of tumor bearers and preferentially localizes at the invasive margin through a mechanism dependent on the activation of Nrf2 and coordinated by the NF-κB1-CSF1R-C3aR axis. Inhibition of F4/80+HO-1+ TAM recruitment or myeloid-specific deletion of HO-1 blocks metastasis formation and improves anticancer immunotherapy. Relative expression of HO-1 in peripheral monocyte subsets, as well as in tumor lesions, discriminates survival among metastatic melanoma patients. Overall, these results identify a distinct cancer-induced HO-1+ myeloid subgroup as a new antimetastatic target and prognostic blood marker.
Assuntos
Biomarcadores Tumorais/metabolismo , Heme Oxigenase-1/metabolismo , Neoplasias Pulmonares/imunologia , Melanoma/imunologia , Neoplasias Cutâneas/imunologia , Macrófagos Associados a Tumor/imunologia , Animais , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/sangue , Linhagem Celular Tumoral/transplante , Quimioterapia Adjuvante/métodos , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/imunologia , Feminino , Heme/metabolismo , Heme Oxigenase-1/antagonistas & inibidores , Heme Oxigenase-1/sangue , Heme Oxigenase-1/genética , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/terapia , Masculino , Melanoma/mortalidade , Melanoma/secundário , Melanoma/terapia , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Transgênicos , Células Progenitoras Mieloides/imunologia , Células Progenitoras Mieloides/metabolismo , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapia , Evasão Tumoral/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Macrófagos Associados a Tumor/metabolismoRESUMO
Immune checkpoint blockade therapy has shifted the paradigm for cancer treatment. However, the majority of patients lack effective responses due to insufficient T cell infiltration in tumors. Here we show that expression of mitochondrial uncoupling protein 2 (UCP2) in tumor cells determines the immunostimulatory feature of the tumor microenvironment (TME) and is positively associated with prolonged survival. UCP2 reprograms the immune state of the TME by altering its cytokine milieu in an interferon regulatory factor 5-dependent manner. Consequently, UCP2 boosts the conventional type 1 dendritic cell- and CD8+ T cell-dependent anti-tumor immune cycle and normalizes the tumor vasculature. Finally we show, using either a genetic or pharmacological approach, that induction of UCP2 sensitizes melanomas to programmed cell death protein-1 blockade treatment and elicits effective anti-tumor responses. Together, this study demonstrates that targeting the UCP2 pathway is a potent strategy for alleviating the immunosuppressive TME and overcoming the primary resistance of programmed cell death protein-1 blockade.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Melanoma Experimental/imunologia , Neoplasias Cutâneas/imunologia , Microambiente Tumoral/imunologia , Proteína Desacopladora 2/imunologia , Animais , Antineoplásicos Imunológicos/farmacologia , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Células Dendríticas/imunologia , Resistencia a Medicamentos Antineoplásicos/imunologia , Feminino , Humanos , Imunoterapia/métodos , Fatores Reguladores de Interferon/imunologia , Fatores Reguladores de Interferon/metabolismo , Melanoma Experimental/irrigação sanguínea , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/mortalidade , Camundongos Endogâmicos C57BL , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Neoplasias Cutâneas/irrigação sanguínea , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/mortalidade , Análise de Sobrevida , Resultado do Tratamento , Proteína Desacopladora 2/genética , Proteína Desacopladora 2/metabolismoRESUMO
Cytolytic activity by CD8(+) cytotoxic T lymphocytes (CTLs) is a powerful strategy for the elimination of intracellular pathogens and tumor cells. The destructive capacity of CTLs is progressively dampened during chronic infection, yet the environmental cues and molecular pathways that influence immunological 'exhaustion' remain unclear. Here we found that CTL immunity was regulated by the central transcriptional response to hypoxia, which is controlled in part by hypoxia-inducible factors (HIFs) and the von Hippel-Lindau tumor suppressor VHL. Loss of VHL, the main negative regulator of HIFs, led to lethal CTL-mediated immunopathology during chronic infection, and VHL-deficient CTLs displayed enhanced control of persistent viral infection and neoplastic growth. We found that HIFs and oxygen influenced the expression of pivotal transcription, effector and costimulatory-inhibitory molecules of CTLs, which was relevant to strategies that promote the clearance of viruses and tumors.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/imunologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/imunologia , Melanoma Experimental/imunologia , Neoplasias Cutâneas/imunologia , Linfócitos T Citotóxicos/imunologia , Proteína Supressora de Tumor Von Hippel-Lindau/imunologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/deficiência , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Hipóxia Celular/imunologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/deficiência , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Coriomeningite Linfocítica/imunologia , Coriomeningite Linfocítica/patologia , Coriomeningite Linfocítica/virologia , Vírus da Coriomeningite Linfocítica/imunologia , Melanoma Experimental/mortalidade , Melanoma Experimental/patologia , Melanoma Experimental/virologia , Camundongos , Camundongos Knockout , Oxigênio/farmacologia , Transdução de Sinais/efeitos dos fármacos , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/virologia , Análise de Sobrevida , Linfócitos T Citotóxicos/patologia , Transcrição Gênica/efeitos dos fármacos , Proteína Supressora de Tumor Von Hippel-Lindau/genéticaRESUMO
BACKGROUND: In the European Organisation for Research and Treatment of Cancer (EORTC) 1325-MG/KEYNOTE-054 study, adjuvant pembrolizumab improved recurrence-free survival and distant-metastasis-free survival in patients with resected stage III melanoma. Earlier results showed no effect of pembrolizumab on health-related quality of life (HRQOL). Little is known about HRQOL after completion of treatment with pembrolizumab, an important research area concerning patients who are likely to become long-term survivors. This study reports long-term HRQOL results. METHODS: This double-blind, randomised, controlled, phase 3 trial compared adjuvant pembrolizumab with placebo in patients aged 18 years or older with previously untreated stage IIIA, IIIB, or IIIC resected cutaneous melanoma and an Eastern Cooperative Oncology Group performance status score of 1 or 0, recruited from 123 academic centres and community hospitals in 23 countries. Patients were randomly assigned (1:1) with a minimisation technique stratified for stage and geographical region to receive 200 mg of intravenous pembrolizumab or placebo every 3 weeks for up to 18 doses. Investigators, patients, and those collecting or analysing data were masked to group assignment. The primary endpoint of the trial was recurrence-free survival (reported elsewhere). HRQOL was a prespecified exploratory endpoint, measured with the EORTC Quality of Life Questionnaire-Core 30. All patients with a baseline HRQOL evaluation available who were alive 108 weeks from randomisation were included in this analysis of long-term HRQOL. Long-term HRQOL included assessments measured every 6 months between 108 weeks and 48 months after randomisation. The threshold of clinical relevance for all HRQOL scales used was an average change of 5 points. The trial is ongoing, recruitment is completed, and HRQOL data collection is finalised. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37. FINDINGS: Between Aug 26, 2015, and Nov 14, 2016, 1019 patients were randomly assigned to pembrolizumab (n=514) or placebo (n=505). Completion of the HRQOL evaluation at baseline exceeded 90% (481 [94%] patients in the pembrolizumab group and 467 [92%] in the placebo group), and ranged between 60% and 90% for post-baseline timepoints. Among patients with a baseline HRQOL evaluation, 365 (39%) were female and 583 (61%) were male. The mean change from baseline to long-term HRQOL was -0·56 (95% CI -2·33 to 1·22) in the pembrolizumab group and 1·63 (-0·12 to 3·38) in the placebo group. The difference between the two groups was -2·19 (-4·65 to 0·27, p=0·081). Differences for all other scales were smaller than 5 and not statistically significant. INTERPRETATION: Adjuvant pembrolizumab did not have a significant impact on long-term HRQOL compared with placebo in patients with resected stage III melanoma. These findings, together with earlier results on efficacy and HRQOL, support the use of pembrolizumab in this setting. FUNDING: Merck Sharp & Dohme.
Assuntos
Anticorpos Monoclonais Humanizados , Melanoma , Estadiamento de Neoplasias , Qualidade de Vida , Neoplasias Cutâneas , Humanos , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Melanoma/tratamento farmacológico , Melanoma/patologia , Melanoma/cirurgia , Feminino , Masculino , Método Duplo-Cego , Pessoa de Meia-Idade , Idoso , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/cirurgia , Neoplasias Cutâneas/mortalidade , Quimioterapia Adjuvante , Antineoplásicos Imunológicos/uso terapêutico , Antineoplásicos Imunológicos/efeitos adversos , Adulto , Fatores de TempoRESUMO
Tumor-stroma ratio (TSR) has been recognized as a valuable prognostic indicator in various solid tumors. This study aimed to examine the clinicopathologic relevance of TSR in Merkel cell carcinoma (MCC) using artificial intelligence (AI)-based parameterization of the stromal landscape and validate TSR scores generated by our AI model against those assessed by humans. One hundred twelve MCC cases with whole-slide images were collected from 4 different institutions. Whole-slide images were first partitioned into 128 × 128-pixel "mini-patches," then classified using a novel framework, termed pre-tumor and stroma (Pre-TOAST) and TOAST, whose output equaled the probability of the minipatch representing tumor cells rather than stroma. Hierarchical random samplings of 50 minipatches per region were performed throughout 50 regions per slide. TSR and tumor-stroma landscape (TSL) parameters were estimated using the maximum-likelihood algorithm. Receiver operating characteristic curves showed that the area under the curve value of Pre-TOAST in discriminating classes of interest including tumor cells, collagenous stroma, and lymphocytes from nonclasses of interest including hemorrhage, space, and necrosis was 1.00. The area under the curve value of TOAST in differentiating tumor cells from related stroma was 0.93. MCC stroma was categorized into TSR high (TSR ≥ 50%) and TSR low (TSR < 50%) using both AI- and human pathology-based methods. The AI-based TSR-high subgroup exhibited notably shorter metastasis-free survival (MFS) with a statistical significance of P = .029. Interestingly, pathologist-determined TSR subgroups lacked statistical significance in recurrence-free survival, MFS, and overall survival (P > .05). Density-based spatial clustering of applications with noise analysis identified the following 2 distinct TSL clusters: TSL1 and TSL2. TSL2 showed significantly shorter recurrence-free survival (P = .045) and markedly reduced MFS (P < .001) compared with TSL1. TSL classification appears to offer better prognostic discrimination than traditional TSR evaluation in MCC. TSL can be reliably calculated using an AI-based classification framework and predict various prognostic features of MCC.
Assuntos
Inteligência Artificial , Carcinoma de Célula de Merkel , Neoplasias Cutâneas , Humanos , Carcinoma de Célula de Merkel/patologia , Carcinoma de Célula de Merkel/mortalidade , Feminino , Masculino , Idoso , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/mortalidade , Idoso de 80 Anos ou mais , Células Estromais/patologia , Pessoa de Meia-Idade , PrognósticoRESUMO
Previous studies demonstrated limited efficacy of immune checkpoint inhibitors in unresectable acral melanoma (AM); it remains unclear how this translates to the adjuvant setting. This study investigates clinical outcomes of acral compared to cutaneous melanoma (CM) patients treated with adjuvant anti-PD-1 after complete resection. All stages III-IV AM and CM patients receiving adjuvant anti-PD-1 after complete resection between 2018 and 2022 were included from the prospective nationwide Dutch Melanoma Treatment Registry. We analyzed recurrence-free survival (RFS), distant metastasis-free survival (DMFS), and overall survival (OS). A multivariable Cox regression analysis of RFS was performed to adjust for potential confounders. We included 1958 (86 AM and 1872 CM) patients. At baseline, AM patients more frequently had KIT mutations, higher disease stages, and Eastern Cooperative Oncology Group Performance Status, and fewer BRAF and NRAS mutations. Median RFS was 14.8 months (95% confidence interval [CI]: 11.5-29.3) in AM and 37.4 months (95% CI: 34.6 to not reached) in CM (p = .002). After correcting for potential confounders, AM remained associated with a higher risk of recurrence (HRadj 1.53; 95% CI: 1.07-2.17; p = .019). Two-year DMFS tended to be worse for AM than for CM: 64.5% versus 79.7% (p = .050). Two-year OS was significantly lower in AM (71.5% vs. 84.3%; p = .027). The results of this study suggest a poorer outcome of adjuvant-treated AM compared to CM. Studies assessing the added value of adjuvant treatment in AM are needed. Future research should investigate alternative treatment strategies to improve outcomes of high-risk AM.
Assuntos
Inibidores de Checkpoint Imunológico , Melanoma , Neoplasias Cutâneas , Humanos , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/mortalidade , Melanoma/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/mortalidade , Idoso , Quimioterapia Adjuvante/métodos , Estudos Prospectivos , Adulto , Mutação , Países Baixos/epidemiologia , Idoso de 80 Anos ou mais , Melanoma Maligno Cutâneo , Sistema de Registros , Receptor de Morte Celular Programada 1/antagonistas & inibidoresRESUMO
Cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer and the metastatic disease is associated with poor prognosis. Cancer-associated fibroblasts (CAFs) promote progression of cancer, but their role in cSCC is largely unknown. We examined the potential of CAF markers in the assessment of metastasis risk and prognosis of primary cSCC. We utilized multiplexed fluorescence immunohistochemistry for profiling CAF landscape in metastatic and non-metastatic primary human cSCCs, in metastases, and in premalignant epidermal lesions. Quantitative high-resolution image analysis was performed with two separate panels of antibodies for CAF markers and results were correlated with clinical and histopathological parameters including disease-specific mortality. Increased stromal expression of fibroblast activation protein (FAP), α-smooth muscle actin, and secreted protein acidic and rich in cysteine (SPARC) were associated with progression to invasive cSCC. Elevation of FAP and platelet-derived growth factor receptor-ß (PDGFRß) expression was associated with metastasis risk of primary cSCCs. High expression of PDGFRß and periostin correlated with poor prognosis. Multimarker combination defined CAF subset, PDGFRα-/PDGFRß+/FAP+, was associated with invasion and metastasis, and independently predicted poor disease-specific survival. These results identify high PDGFRß expression alone and multimarker combination PDGFRα-/PDGFRß+/FAP+ by CAFs as potential biomarkers for risk of metastasis and poor prognosis.
Assuntos
Fibroblastos Associados a Câncer , Carcinoma de Células Escamosas , Progressão da Doença , Proteínas de Membrana , Receptor beta de Fator de Crescimento Derivado de Plaquetas , Serina Endopeptidases , Neoplasias Cutâneas , Humanos , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/mortalidade , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/metabolismo , Prognóstico , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Serina Endopeptidases/metabolismo , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Proteínas de Membrana/metabolismo , Feminino , Masculino , Biomarcadores Tumorais/metabolismo , Gelatinases/metabolismo , Endopeptidases , Moléculas de Adesão Celular/metabolismo , Osteonectina/metabolismo , Metástase Neoplásica , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Idoso , Actinas/metabolismo , Pessoa de Meia-IdadeRESUMO
Metastatic melanoma is still a difficult-to-treat cancer type owing to its frequent resistance mechanisms to targeted and immunotherapy. Therefore, we aimed to unravel novel therapeutic strategies for melanoma patients. Preclinical and clinical studies show that melanoma patients may benefit from a treatment with poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi). In this study, we focus on PARP1 as a potential biomarker to predict the response of melanoma cells to PARPi therapy. We found that melanoma cells with high basal PARP1 expression exhibit significantly increased cell death after PARPi treatment owing to higher PARP1 trapping compared with melanoma cells with low PARP1 expression. In addition, we could demonstrate that PARP1 expression levels are low in nonmalignant skin cells, and metastatic melanomas show considerably higher PARP1 levels compared with primary melanomas. Most strikingly, we found that high PARP1 levels correlate with worse overall survival of late stage metastasized melanoma patients. In conclusion, we show that PARP1 might act as a biomarker to predict the response to PARPi therapy, and that in particular the late stage metastasized melanoma patients are especially sensitive to PARPi therapy owing to elevated PARP1 expression. Our data suggest that the PARPi cytotoxicity primarily will affect the high PARP1 expressing melanoma cells, rather than the low PARP1 expressing nonmalignant skin cells resulting in only low side effects.
Assuntos
Melanoma , Poli(ADP-Ribose) Polimerase-1 , Inibidores de Poli(ADP-Ribose) Polimerases , Neoplasias Cutâneas , Feminino , Humanos , Masculino , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Melanoma/tratamento farmacológico , Melanoma/mortalidade , Melanoma/genética , Melanoma/patologia , Melanoma/metabolismo , Metástase Neoplásica , Poli(ADP-Ribose) Polimerase-1/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Poli(ADP-Ribose) Polimerases/metabolismo , Prognóstico , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismoRESUMO
BACKGROUND: Neoadjuvant-adjuvant therapy for locally advanced or potentially resectable metastatic melanoma was expected to improve operability and clinical outcomes over upfront surgery and adjuvant treatment only. METHODS: Forty-seven consecutive patients were treated with neoadjuvant-adjuvant BRAF inhibitors (BRAFi)/MEK inhibitors (MEKi) and surgery. RESULTS: Twelve (26%) patients achieved a pathological complete response and 10 (21%) patients achieved a near-complete response. In the whole group, median recurrence-free survival was 19.4 months and median distant metastasis-free survival (mDMFS) was 21.9 months. In patients with a pathological complete response (pCR)/near-pCR median recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) were significantly longer than in patients with minor pathological response with hazard ratio (HR) = 0.37 (p = .005) for RFS and HR = 0.33 (p = .002) for DMFS. After median follow-up of 52.5 months, median progression-free survival since BRAFi/MEKi therapy initiation was 25.1 months. The median time-to-treatment-failure since initiation of neoadjuvant therapy was 22.2 months and was significantly longer in patients with pCR/near-pCR (HR = 0.45; p = .022). Neoadjuvant therapy did not result in any new specific complications of surgery. After 48 months, RFS and overall survival were 36.3% and 64.8% or 20% and 37.4% in patients with pCR/near-pCR and pathological partial response/pathological nonresponse, respectively. CONCLUSIONS: The authors confirmed that BRAFi/MEKi combination is an effective and safe regimen in the perioperative treatment of stage III/IV melanoma. Major pathological response to neoadjuvant treatment is a surrogate marker of recurrence including DMFS in these patients. PLAIN LANGUAGE SUMMARY: Our study presents a large comprehensive analysis of neoadjuvant-adjuvant systemic therapy in patients diagnosed with marginally resectable stage III or IV melanoma. Neoadjuvant therapy effectively reduced the volume of the disease, which facilitated subsequent surgical resection. After median follow-up of 52.5 months, median progression-free survival since therapy initiation was 25.1 months. Twelve patients had complete pathological response and 10 patients had a near-complete pathological response-and together they had median recurrence-free survival and distant metastasis-free survival significantly longer than in patients with pathological partial response or nonresponse. Complete/near-complete pathological response to neoadjuvant treatment is a surrogate marker of recurrence-free, including distant metastasis-free, survival in these patients.
Assuntos
Melanoma , Terapia Neoadjuvante , Estadiamento de Neoplasias , Proteínas Proto-Oncogênicas B-raf , Humanos , Melanoma/tratamento farmacológico , Melanoma/patologia , Melanoma/mortalidade , Melanoma/terapia , Terapia Neoadjuvante/métodos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Adulto , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/terapia , Neoplasias Cutâneas/cirurgia , Quimioterapia Adjuvante , Inibidores de Proteínas Quinases/uso terapêutico , Idoso de 80 Anos ou mais , Terapia de Alvo Molecular/métodos , Resultado do TratamentoRESUMO
BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive cancer with often poor outcomes. Limited biomarkers exist for predicting clinical outcomes. The Merkel cell polyomavirus (MCPyV) serum antibody test (AMERK) has shown potential for indicating better recurrence-free survival in a single-institution study. The study aimed to evaluate the link between initial AMERK serostatus and survival. Secondary objectives included examining the relationship between initial AMERK titer levels and tumor burden. METHODS: A retrospective cohort study across two institutions analyzed patients tested with AMERK within 90 days of MCC diagnosis. Regression models assessed the association of survival outcomes with serostatus, considering various factors. The relationship between AMERK titer and tumor burden indicators was evaluated using ANOVA. Significance testing was exploratory, without a fixed significance level. RESULTS: Of 261 MCC patients tested, 49.4% were initially seropositive (titer ≥75). Multivariable analysis showed that seropositivity improved recurrence, event-free, overall, and MCC-specific survival rates. Strong associations were found between initial AMERK titer and clinical, tumor, and nodal stages, tumor size, and disease extent. Notably, improved survival with seropositivity was observed only in patients with localized disease at initial presentation. CONCLUSION: Circulating antibodies to MCPyV oncoproteins, as indicated by the AMERK test, are linked with better survival in MCC patients with localized disease at presentation. This could enhance patient risk profiling and treatment personalization. The study's retrospective nature and exploratory analysis are key limitations. PLAIN LANGUAGE SUMMARY: Merkel cell carcinoma (MCC) is a potentially aggressive skin cancer, and tools to predict patient outcomes are limited. A blood test called anti-Merkel cell panel (AMERK), which checks for specific antibodies related to this cancer, might give us some clues. In this study, we looked at 261 MCC patients who took the AMERK test within 90 days of diagnosis. We found that patients with an initial positive AMERK result tended to have better outcomes, especially if their cancer was in the early stages. However, it is important to note that this study has limitations, including using retrospective data and exploratory analyses.
Assuntos
Anticorpos Antivirais , Carcinoma de Célula de Merkel , Poliomavírus das Células de Merkel , Neoplasias Cutâneas , Humanos , Carcinoma de Célula de Merkel/virologia , Carcinoma de Célula de Merkel/sangue , Carcinoma de Célula de Merkel/mortalidade , Carcinoma de Célula de Merkel/diagnóstico , Carcinoma de Célula de Merkel/imunologia , Poliomavírus das Células de Merkel/imunologia , Poliomavírus das Células de Merkel/isolamento & purificação , Feminino , Masculino , Estudos Retrospectivos , Idoso , Prognóstico , Pessoa de Meia-Idade , Neoplasias Cutâneas/sangue , Neoplasias Cutâneas/virologia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Anticorpos Antivirais/sangue , Idoso de 80 Anos ou mais , Infecções Tumorais por Vírus/virologia , Infecções por Polyomavirus/sangue , Infecções por Polyomavirus/diagnóstico , Infecções por Polyomavirus/virologia , Infecções por Polyomavirus/imunologiaRESUMO
Melanoma causes significant morbidity in solid organ transplant recipients (SOTRs). Melanomas diagnosed before transplantation can recur with intensive immunosuppression, but outcomes have not been well studied. We evaluated 901 non-Hispanic White SOTRs with a pretransplant melanoma identified using linked transplant and cancer registry data in the United States. Most pretransplant melanomas were invasive (60.7%), and the median time from diagnosis to transplantation was 5.1 years. After transplantation, 41 SOTRs developed a new invasive melanoma, corresponding to 9-fold increased risk compared with the general population (standardized incidence ratio, 9.2; 95% confidence interval [CI], 6.6-12). Twenty-two SOTRs died from melanoma after transplantation, corresponding to 52-fold increased risk (standardized mortality ratio, 52; 95% CI, 33-79). Risk factors for posttransplant melanoma included age at transplantation (adjusted hazard ratio [HR], 2.86; 95% CI, 1.24-6.60; for age 55+ vs <55 years) and maintenance immunosuppression with cyclosporine/azathioprine (adjusted HR, 2.53; 95% CI, 1.08-5.90). Melanoma mortality was strongly elevated after a posttransplant melanoma diagnosis (HR, 35.6; 95% CI, 14.0-90.4; adjusted for cyclosporine/azathioprine maintenance therapy and calendar year of transplantation). In conclusion, SOTRs with a pretransplant melanoma are at risk of adverse melanoma-related outcomes after transplantation. These findings support thorough dermatologic evaluation prior to transplantation and frequent posttransplant surveillance.
Assuntos
Melanoma , Transplante de Órgãos , Neoplasias Cutâneas , Transplantados , Humanos , Melanoma/diagnóstico , Melanoma/mortalidade , Masculino , Feminino , Pessoa de Meia-Idade , Transplante de Órgãos/efeitos adversos , Adulto , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/etiologia , Fatores de Risco , Seguimentos , Incidência , Prognóstico , Idoso , Sistema de Registros , Adulto Jovem , Adolescente , Taxa de Sobrevida , Estados Unidos/epidemiologia , Imunossupressores/uso terapêutico , Complicações Pós-Operatórias/diagnósticoRESUMO
BACKGROUND: Currently, treatment options for patients with advanced melanoma who experience failed immunotherapy or targeted therapy are lacking. Recent studies suggest the antitumor activity of combined pembrolizumab and lenvatinib in patients with advanced melanoma progressing on immunotherapy. Herein, we report the clinical outcomes of combined lenvatinib and a programmed cell death protein-1 inhibitor (PD-1) in this population. MATERIALS AND METHODS: This French multicenter real-world study was conducted between September 2020 and July 2023. The primary endpoint was the objective response rate (ORR) according to the Response Evaluation Criteria in Solid Tumours (version 1.1). Secondary variables were treatment-related adverse events (TRAEs), progression-free survival (PFS), overall survival (OS), and duration of response (DOR). RESULTS: Of the 67 patients included (median age, 69 years; median follow-up, 5.0 months), 85% had stage IV-M1c or M1d disease. The overall ORR was 28.4% (95% CI, 18%-41%), including 3 complete (4.5%) and 16 partial (23.9%) responses. Median DOR was 3.1 (interquartile range, 1.3-4.3) months. Median PFS and OS were 3.1 (95% CI, 2.5-3.7) and 9.8 (95% CI, 5.6-13.9) months, respectively. Grades 3-5 TRAEs occurred in 16 (24%) patients; common TRAEs were fatigue (43.3%), nausea/vomiting (26.8%), diarrhea (20.9%), and hypertension (20.9%). No treatment-related deaths occurred. CONCLUSION: Our real-world study demonstrates an interesting response rate and acceptable safety profile in a population with poor prognostic factors. Our data support this treatment option for refractory melanoma, as it is not approved by the Food and Drug Administration or European Medicines Agency, and highlight the need for new strategies.
Assuntos
Melanoma , Compostos de Fenilureia , Quinolinas , Humanos , Quinolinas/uso terapêutico , Quinolinas/efeitos adversos , Melanoma/tratamento farmacológico , Melanoma/patologia , Melanoma/mortalidade , Masculino , Feminino , Idoso , Estudos Retrospectivos , Pessoa de Meia-Idade , Compostos de Fenilureia/uso terapêutico , Compostos de Fenilureia/efeitos adversos , Idoso de 80 Anos ou mais , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/mortalidade , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , França , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/farmacologia , Anticorpos Monoclonais HumanizadosRESUMO
BACKGROUND: Adoptive cell therapy with tumor-infiltrating lymphocytes (TIL-ACT) has consistently shown efficacy in advanced melanoma. New results in the field provide now the opportunity to assess overall survival (OS) after TIL-ACT and to examine the effect of prior anti-programmed cell death protein 1/programmed death-ligand 1 [anti-PD-(L)1] therapy on its efficacy. METHODS: A comprehensive search was conducted in PubMed up to 29 February 2024. Ιn this meta-analysis we focused on studies including high-dose interleukin 2, doubling the patient numbers from our previous meta-analysis conducted up to December 2018 and using OS as the primary endpoint. Objective response rate (ORR), complete response rate (CRR), and duration of response were secondary endpoints. Findings are synthesized using tables, Kaplan-Meier plots, and forest plots. Pooled estimates for ORR and CRR were derived from fixed or random effects models. RESULTS: A total of 13 high-dose interleukin 2 studies were included in this updated meta-analysis, with OS information available for 617 patients. No difference was found in median OS between studies with prior anti-PD-(L)1 treatment {n = 238; 17.5 months [95% confidence interval (CI) 13.8-20.5 months]} and without [n = 379; 16.3 months (95% CI 14.2-20.6 months)] (log-rank P = 0.53). ORR was estimated to be 34% (95% CI 16%-52%) and 44% (95% CI 37%-51%), for the studies with and without prior anti-PD-(L)1, respectively. The pooled estimate for CRR was 10% for both groups. No statistically significant difference was observed between the two groups, either for ORR (P = 0.15) or CRR (P = 0.45). CONCLUSIONS: Prior anti-PD-(L)1 treatment has no effect on the clinical response or survival benefit from TIL-ACT in advanced cutaneous melanoma. The benefit of TIL therapy in the second-line setting is also present after anti-PD-(L)1 treatment. Our data reinforce the evidence that TIL-ACT should be considered as a treatment of choice in second line for metastatic melanoma patients failing anti-PD-(L)1 therapy.
Assuntos
Linfócitos do Interstício Tumoral , Melanoma , Neoplasias Cutâneas , Humanos , Melanoma/tratamento farmacológico , Melanoma/imunologia , Melanoma/patologia , Melanoma/terapia , Melanoma/mortalidade , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapia , Neoplasias Cutâneas/mortalidade , Linfócitos do Interstício Tumoral/imunologia , Melanoma Maligno Cutâneo , Imunoterapia Adotiva/métodos , Inibidores de Checkpoint Imunológico/uso terapêutico , Interleucina-2/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: Neoadjuvant dabrafenib plus trametinib has a high pathological response rate and impressive short-term survival in patients with resectable stage III melanoma. We report 5-year outcomes from the phase II NeoCombi trial. PATIENTS AND METHODS: NeoCombi (NCT01972347) was a single-arm, open-label, single-centre, phase II trial. Eligible patients were adults (aged ≥18 years) with histologically confirmed, resectable, RECIST-measurable, American Joint Committee on Cancer seventh edition clinical stage IIIB-C BRAF V600E/K-mutant melanoma and Eastern Cooperative Oncology Group performance status ≤1. Patients received 52 weeks of treatment with dabrafenib 150 mg (orally twice per day) plus trametinib 2 mg (orally once per day), with complete resection of the pre-therapy tumour bed at week 12. RESULTS: Between 20 August 2014 and 19 April 2017, 35 patients were enrolled. At data cut-off (17 August 2021), the median follow-up was 60 months [95% confidence interval (CI) 56-72 months]. Overall, 21 of 35 (60%) patients recurred, including 12 (57%) with first recurrence in locoregional sites (followed by later distant recurrence in 6) and 9 (43%) with first recurrence in distant sites, including 3 in the brain. Most recurrences occurred within 2 years, with no recurrences beyond 3 years. At 5 years, recurrence-free survival (RFS) was 40% (95% CI 27% to 60%), distant metastasis-free survival (DMFS) was 57% (95% CI 42% to 76%), and overall survival was 80% (95% CI 67% to 94%). Five-year survival outcomes were stratified by pathological response: RFS was 53% with pathological complete response (pCR) versus 28% with non-pCR (P = 0.087), DMFS was 59% versus 55% (P = 0.647), and overall survival was 88% versus 71% (P = 0.205), respectively. CONCLUSIONS: Neoadjuvant dabrafenib plus trametinib has high pathological response rates in clinical stage III melanoma, but low rates of RFS, similar to those achieved with adjuvant targeted therapy alone. Patients with a pCR to dabrafenib plus trametinib still had a high risk of recurrence, unlike that seen with immunotherapy where recurrences are rare.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Imidazóis , Melanoma , Terapia Neoadjuvante , Estadiamento de Neoplasias , Oximas , Piridonas , Pirimidinonas , Humanos , Oximas/administração & dosagem , Melanoma/tratamento farmacológico , Melanoma/patologia , Melanoma/mortalidade , Pirimidinonas/administração & dosagem , Piridonas/administração & dosagem , Imidazóis/administração & dosagem , Feminino , Masculino , Pessoa de Meia-Idade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Idoso , Adulto , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/mortalidade , SeguimentosRESUMO
BACKGROUND: Melanoma is a highly aggressive tumor, predominantly found in the skin, recognized as skin cutaneous melanoma (SKCM). Lymph node metastasis is commonly used as the route of metastasis in SKCM, necessitating the discovery of prognostic genes associated with this process for improved prognosis. METHODS: The prognostic significance of lymph node metastasis in SKCM was assessed through Kaplan-Meier analysis in SEER and TCGA-SKCM datasets. Prognostic genes were identified and a prognostic risk model was constructed Enrichment analysis and immune cell infiltration analysis were also carried out.Moreover, a validation in vitro and in vivo were conducted by CCK8,flow cytometry, transwell and animal study. RESULTS: The Kaplan-Meier survival curve revealed that patients with lymph node metastasis had a worse prognosis compared to those without. FCGR3B and PRF1 were screened by TCGA analysis.Additionally, significant differences in nine immune cell types were observed between the two risk groups. Notably, a strong positive association with CD8 T cells and a negative relationship with M2 macrophages were exhibited by PRF1. The validation of our nomogram were conducted in vitro and in vivo, and the results showed the correlations between CD8+ T cell and PRF1. CONCLUSION: In summary, two prognostic genes (FCGR3B and PRF1) were identified, and a prognostic risk model was developed for SKCM. These findings provide a novel approach for the diagnosis and treatment of SKCM.
Assuntos
Metástase Linfática , Melanoma , Perforina , Neoplasias Cutâneas , Humanos , Melanoma/genética , Melanoma/patologia , Melanoma/mortalidade , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/mortalidade , Prognóstico , Metástase Linfática/genética , Perforina/genética , Perforina/metabolismo , Animais , Melanoma Maligno Cutâneo , Linhagem Celular Tumoral , Masculino , Feminino , Biomarcadores Tumorais/genética , Camundongos , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Regulação Neoplásica da Expressão Gênica , Estimativa de Kaplan-MeierRESUMO
OBJECTIVES: Nivolumab is approved as adjuvant therapy for resected stage III/IV melanoma based on the phase 3 CheckMate 238 trial. This analysis compared outcomes from CheckMate 238 with those from the real-world Flatiron Health electronic health record-derived de-identified database in patients with resected stage III melanoma (per AJCC-8) treated with adjuvant nivolumab. MATERIALS: Outcomes included baseline characteristics, overall survival (OS) in the CheckMate 238 cohort (randomization until death or last known alive), and real-world overall survival (rwOS) in the Flatiron Health cohort (nivolumab initiation until death or data cutoff). rwOS was compared with OS using unadjusted and adjusted Cox proportional hazards models. Inverse probability of treatment weighting (IPTW) was combined with the adjusted model to reduce baseline discrepancies. RESULTS: The CheckMate 238 and real-world cohorts included 369 and 452 patients, respectively (median age, 56.0 and 63.0 years; median follow-up, 61.4 vs. 25.5 months). rwOS was not different from OS in the unadjusted (hazard ratio [HR] 1.27; 95% CI 0.92-1.74), adjusted (HR 1.01; 95% CI 0.67-1.54), and adjusted IPTW (HR 1.07; 95% CI 0.70-1.63) analyses. In the adjusted analysis, 2-year OS and rwOS rates were 84%. Median OS and rwOS were not reached. After IPTW, OS and rwOS were not different (HR 1.07; 95% CI 0.70-1.64). CONCLUSIONS: In this comparative analysis, OS in the CheckMate 238 trial was similar to rwOS in the Flatiron Health database after adjustments in patients with resected stage III melanoma (per AJCC-8) treated with adjuvant nivolumab, validating the trial results.
Assuntos
Melanoma , Estadiamento de Neoplasias , Nivolumabe , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antineoplásicos Imunológicos/uso terapêutico , Quimioterapia Adjuvante/métodos , Melanoma/tratamento farmacológico , Melanoma/mortalidade , Melanoma/patologia , Melanoma/cirurgia , Nivolumabe/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/cirurgia , Resultado do TratamentoRESUMO
BACKGROUND: In a princeps study we conducted in patients with advanced cutaneous squamous cell carcinoma treated with concomitant anti-Programmed cell death protein 1 (PD-1) and radiotherapy, we demonstrated a clinico radiological response to cemiplimab that appeared to persist over time, 1 year after treatment discontinuation. METHOD: We conducted a single-center descriptive study at Caen Hospital from September 1, 2021 to September 2023, in 14 patients with advanced carcinoma treated with cemiplimab until September 1, 2021. The aim of this update is to examine clinical and radiological follow-up 2 years after discontinuation of cemiplimab. RESULTS: Of the 12 patients with a partial or complete response, we report 8 (66.7%) persistent responses 2 years after stopping cemiplimab, with only 2 patients progressing to distant disease, one lost to follow-up, and one death a priori unrelated to the disease. CONCLUSION: Our study confirms a long-term and persistent effect despite discontinuation of cemiplimab at least up to 2 years later.
Assuntos
Anticorpos Monoclonais Humanizados , Carcinoma de Células Escamosas , Neoplasias Cutâneas , Humanos , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/radioterapia , Masculino , Feminino , Idoso , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/radioterapia , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/terapia , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Inibidores de Checkpoint Imunológico/uso terapêutico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Seguimentos , Quimiorradioterapia/métodosRESUMO
Treatment duration with checkpoint inhibitors must be optimized to prevent unjustified toxicity, but evidence for the management of cutaneous squamous cell carcinoma is lacking. A retrospective study was performed to evaluate the survival of patients with cutaneous squamous cell carcinoma (CSCC) who discontinued cemiplimab due to different causes and without progression. Among 95 patients with CSCC who received cemiplimab, 22 (23%) patients discontinued immunotherapy due to causes other than progression, such as comorbidities, toxicity, complete response or lack of compliance (group that discontinued before censoring [DBC]), then 73 patients had standard treatment scheduled (STS). The overall survival was 25.2 months (95% CI: 8.9-29.4) in STS group and 28.3 months (95% CI: 12.7-28.3) in the DBC group; deaths for all causes were 11/22 (50%) in the DBC group and 34/73 (46.6%) in the STS group (p = 0.32). 10/22 (45.4%) subjects died due to CSCC in the DBC after discontinuation and 34/73 (46.6%) in the STS group, and the difference between groups was not significant (p = 0.230). Duration of treatment was significantly lower in subjects with stable disease versus those with complete or partial response (16.9, 30.6 and 34.9 months, respectively; p = 0.004). Among the 22 STS patients, 12 received cemiplimab for less than 12 months (10 [83%] died) and 10 for at least 12 months (1 [10%] died). Our observation, finding no outcome difference between DBC and STS groups, suggests that ICI treatment after one year might expose patients to further treatment related events without efficacy advantages.
Assuntos
Anticorpos Monoclonais Humanizados , Carcinoma de Células Escamosas , Neoplasias Cutâneas , Humanos , Masculino , Feminino , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/mortalidade , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/mortalidade , Idoso , Estudos Retrospectivos , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Resultado do Tratamento , Antineoplásicos Imunológicos/uso terapêutico , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Adulto , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/administração & dosagem , Inibidores de Checkpoint Imunológico/efeitos adversosRESUMO
BACKGROUND: Immune checkpoint inhibitors (ICI) applied in patients with melanoma in an adjuvant setting have proven safety and efficacy in several studies, but data on elderly patients aged 75 years or more is scarce. Aim of this study was to investigate efficacy and safety of adjuvant ICI in patients aged ≥ 75 years compared to patients < 75 years in a real-world setting. METHODS: We retrospectively analyzed clinical data, including occurrence of immune-related adverse events (irAE) and outcome of 456 patients that had been treated with adjuvant ICI between January 1st, 2018 and December 20th, 2022. We then compared patients aged ≥ 75 years (n = 117) to patients < 75 years (n = 339) in terms of safety and disease-free survival (DFS). RESULTS AND CONCLUSION: ICI were well tolerated in both groups, with no significant difference observed in the overall occurrence of irAE. However, within the elderly subgroup, there was a significantly higher proportion of skin or nephrological toxicity and colitis/diarrhea compared to the other group. In terms of efficacy, a significantly shorter DFS in patients aged ≥ 75 years was observed. Adjuvant ICI in patients ≥ 75 years was less effective and furthermore associated with an increased risk for skin, renal or bowel toxicity. Therefore, in elderly patients, adjuvant ICI should be used with precaution.