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PURPOSE: The choice of threshold and reliability of high tumor mutational burden (TMB) to predict outcomes and guide treatment choice for patients with metastatic melanoma receiving first-line immune checkpoint inhibitor (ICI) therapy in the real world is not well known. METHODS: Using a deidentified nationwide (US-based) melanoma clinicogenomic database, we identified a real-world cohort of patients with metastatic melanoma (N = 497) who received first-line monotherapy anti-PD-1 (n = 240) or dual anti-PD-1 and anti-CTLA-4 ICI (n = 257) and had a tissue-based comprehensive genomic profiling test TMB score. RESULTS: TMB-high (TMB-H; ≥10 mutations per megabase [muts/Mb], n = 352, 71%) was independently predictive of superior real-world progression-free survival and overall survival versus TMB-low (<10 mut/Mb, n = 145, 29%) in both mono ICI (hazard ratio [HR], 0.45 [95% CI, 0.32 to 0.63]; P < .001; HR, 0.61 [95% CI, 0.41 to 0.90]; P = .01, respectively) and dual ICI (HR, 0.67 [95% CI, 0.49 to 0.90]; P = .009; HR, 0.61 [95% CI, 0.42 to 0.88]; P = .007, respectively) patients. Dual ICI offered no significant advantage in BRAFwt patients and unexpectedly demonstrated greatest benefit in the TMB 10-19 mut/Mb group, identifying a TMB-very high (≥20 mut/Mb, n = 247, 50%) BRAFmut patient subgroup for whom mono ICI may be preferable. CONCLUSION: TMB-H predicts superior outcomes on ICI while coassessment of BRAF status and TMB may inform first-line regimen choice.
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Inibidores de Checkpoint Imunológico , Melanoma , Mutação , Humanos , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/secundário , Melanoma/mortalidade , Inibidores de Checkpoint Imunológico/uso terapêutico , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Adulto , Idoso de 80 Anos ou mais , Resultado do TratamentoRESUMO
Objectives: Despite the success of immune checkpoint blockade, most metastatic melanoma patients fail to respond to therapy or experience severe toxicity. Assessment of biomarkers and immunophenotypes before or early into treatment will help to understand favourable responses and improve therapeutic outcomes. Methods: We present a high-dimensional approach for blood T-cell profiling using three multi-parameter cytometry panels: (1) a TruCount panel for absolute cell counts, (2) a 27-colour spectral panel assessing T-cell markers and (3) a 20-colour spectral panel evaluating intracellular cytokine expression. Pre-treatment blood mononuclear cells from patients and healthy controls were cryopreserved before staining across 11 batches. Batch effects were tracked using a single-donor control and the suitability of normalisation was assessed. The data were analysed using manual gating and high-dimensional strategies. Results: Batch-to-batch variation was minimal, as demonstrated by the dimensionality reduction of batch-control samples, and normalisation did not improve manual or high-dimensional analysis. Application of the workflow demonstrated the capacity of the panels and showed that patients had fewer lymphocytes than controls (P = 0.0027), due to lower naive CD4+ (P = 0.015) and CD8+ (P = 0.011) T cells and follicular helper T cells (P = 0.00076). Patients showed trends for higher proportions of Ki67 and IL-2-expressing cells within CD4+ and CD8+ memory subsets, and increased CD57 and EOMES expression within TCRγδ+ T cells. Conclusion: Our optimised high-parameter spectral cytometry approach provided in-depth profiling of blood T cells and found differences in patient immunophenotype at baseline. The robustness of our workflow, as demonstrated by minimal batch effects, makes this approach highly suitable for the longitudinal evaluation of immunotherapy effects.
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BACKGROUND: Immunotherapy has reshaped the prognoses for many cancers and is increasingly used in both metastatic and adjuvant settings. There is a high prevalence of immunotherapy side effects, or immune-related adverse events (irAEs), which can affect any organ. Some irAEs can cause permanent or prolonged morbidity and, in rare cases, may be fatal. irAEs can present with mild, non-specific symptoms, resulting in delays to identification and management. OBJECTIVE: We aim to provide a general overview of immunotherapy and irAEs, highlighting common clinical scenarios and general principles of management. DISCUSSION: Cancer immunotherapy toxicity is an important clinical problem that is increasingly relevant to general practice, where patients with adverse events may first present. Early diagnosis and timely intervention are important in limiting the severity and morbidity of these toxicities. The management of irAEs should follow treatment guidelines, in consultation with patients' treating oncology teams.
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Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Medicina Geral , Neoplasias , Humanos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/terapia , Imunoterapia/efeitos adversos , Imunoterapia/métodos , Neoplasias/tratamento farmacológicoRESUMO
Cellular heterogeneity in cancer is linked to disease progression and therapy response, although mechanisms regulating distinct cellular states within tumors are not well understood. We identified melanin pigment content as a major source of cellular heterogeneity in melanoma and compared RNAseq data from high-pigmented (HPCs) and low-pigmented melanoma cells (LPCs), suggesting EZH2 as a master regulator of these states. EZH2 protein was found to be upregulated in LPCs and inversely correlated with melanin deposition in pigmented patient melanomas. Surprisingly, conventional EZH2 methyltransferase inhibitors, GSK126 and EPZ6438, had no effect on LPC survival, clonogenicity and pigmentation, despite fully inhibiting methyltransferase activity. In contrast, EZH2 silencing by siRNA or degradation by DZNep or MS1943 inhibited growth of LPCs and induced HPCs. As the proteasomal inhibitor MG132 induced EZH2 protein in HPCs, we evaluated ubiquitin pathway proteins in HPC vs LPCs. Biochemical assays and animal studies demonstrated that in LPCs, the E2-conjugating enzyme UBE2L6 depletes EZH2 protein in cooperation with UBR4, an E3 ligase, via ubiquitination at EZH2's K381 residue, and is downregulated in LPCs by UHRF1-mediated CpG methylation. Targeting UHRF1/UBE2L6/UBR4-mediated regulation of EZH2 offers potential for modulating the activity of this oncoprotein in contexts in which conventional EZH2 methyltransferase inhibitors are ineffective.
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Melaninas , Melanoma , Animais , Melaninas/metabolismo , Ubiquitinação , Melanoma/genética , Fenótipo , Diferenciação Celular , Pigmentação , Metiltransferases/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismoRESUMO
Immune checkpoint blockade (ICB) has revolutionized cancer treatment. However, many patients fail to respond to this therapy or experience side effects. Recently, gut microbiota have emerged as a key determinant of ICB efficacy and toxicity, making manipulation of the microbiome a novel therapeutic strategy with which to improve ICB outcomes.
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Microbioma Gastrointestinal , Microbiota , Neoplasias , Humanos , Neoplasias/tratamento farmacológico , Imunoterapia/efeitos adversosRESUMO
BACKGROUND: Immune checkpoint inhibitors (ICI) are associated with immune-mediated adverse effects, potentially involving any organ. ICI has also been associated with an increased risk of cardiovascular disease in cancer populations. OBJECTIVE: To characterize the incidence and risk of major atherosclerotic cardiovascular events associated with ICI use in a high-risk and advanced melanoma population. METHODS: We conducted a retrospective cohort study of patients with high-risk or advanced melanoma (AJCC stage II, III or IV) presenting to an academic tertiary hospital between 2015-2020. The main outcome was major atherosclerotic cardiovascular events (MACE) including acute myocardial infarction, ischemic stroke, acute limb ischemia and coronary revascularization. RESULTS: The study cohort consisted of 646 patients, including 289 who had been treated with ICI. The incidence of MACE was higher in the ICI treated group (3.6 vs. 0.9 events per 100-person years). After adjusting for age, sex, smoking history and prior BRAF and/or MEK inhibitor use, ICI treatment was associated with an increased risk of MACE (HRadj 2.8, 95% CI 1.1-6.9, p = 0.03). Elevated risk was especially pronounced in patients with a past history of MACE (HR 14.4, 95% CI 1.9-112.3, p = 0.01). CONCLUSION: Patients with high-risk or advanced melanoma are at an increased risk of atherosclerotic cardiovascular events following ICI treatment, particularly those with a history of cardiovascular disease.
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Melanoma cells display distinct intrinsic phenotypic states. Here, we seek to characterize the molecular regulation of these states using multi-omic analyses of whole exome, transcriptome, microRNA, long non-coding RNA and DNA methylation data together with reverse-phase protein array data on a panel of 68 highly annotated early passage melanoma cell lines. We demonstrate that clearly defined cancer cell intrinsic transcriptomic programs are maintained in melanoma cells ex vivo and remain highly conserved within melanoma tumors, are associated with distinct immune features within tumors, and differentially correlate with checkpoint inhibitor and adoptive T cell therapy efficacy. Through integrative analyses we demonstrate highly complex multi-omic regulation of melanoma cell intrinsic programs that provide key insights into the molecular maintenance of phenotypic states. These findings have implications for cancer biology and the identification of new therapeutic strategies. Further, these deeply characterized cell lines will serve as an invaluable resource for future research in the field.
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Melanoma , MicroRNAs , RNA Longo não Codificante , Metilação de DNA , Humanos , Melanoma/metabolismo , Melanoma/patologia , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , TranscriptomaRESUMO
Treatment with therapy targeting BRAF and MEK (BRAF/MEK) has revolutionized care in melanoma and other cancers; however, therapeutic resistance is common and innovative treatment strategies are needed1,2. Here we studied a group of patients with melanoma who were treated with neoadjuvant BRAF/MEK-targeted therapy ( NCT02231775 , n = 51) and observed significantly higher rates of major pathological response (MPR; ≤10% viable tumour at resection) and improved recurrence-free survival (RFS) in female versus male patients (MPR, 66% versus 14%, P = 0.001; RFS, 64% versus 32% at 2 years, P = 0.021). The findings were validated in several additional cohorts2-4 of patients with unresectable metastatic melanoma who were treated with BRAF- and/or MEK-targeted therapy (n = 664 patients in total), demonstrating improved progression-free survival and overall survival in female versus male patients in several of these studies. Studies in preclinical models demonstrated significantly impaired anti-tumour activity in male versus female mice after BRAF/MEK-targeted therapy (P = 0.006), with significantly higher expression of the androgen receptor in tumours of male and female BRAF/MEK-treated mice versus the control (P = 0.0006 and P = 0.0025). Pharmacological inhibition of androgen receptor signalling improved responses to BRAF/MEK-targeted therapy in male and female mice (P = 0.018 and P = 0.003), whereas induction of androgen receptor signalling (through testosterone administration) was associated with a significantly impaired response to BRAF/MEK-targeted therapy in male and female patients (P = 0.021 and P < 0.0001). Together, these results have important implications for therapy.
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Antagonistas de Receptores de Andrógenos , Melanoma , Quinases de Proteína Quinase Ativadas por Mitógeno , Terapia de Alvo Molecular , Proteínas Proto-Oncogênicas B-raf , Receptores Androgênicos , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Feminino , Humanos , Masculino , Melanoma/tratamento farmacológico , Melanoma/patologia , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Receptores Androgênicos/metabolismo , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Análise de SobrevidaRESUMO
BACKGROUND: Patients with BRAF-mutant and wild-type melanoma have different response rates to immune checkpoint blockade therapy. However, the reasons for this remain unknown. To address this issue, we investigated the precise immune composition resulting from BRAF mutation in treatment-naive melanoma to determine whether this may be a driver for different response to immunotherapy. METHODS: In this study, we characterized the treatment-naive immune context in patients with BRAF-mutant and BRAF wild-type (BRAF-wt) melanoma using data from single-cell RNA sequencing, bulk RNA sequencing, flow cytometry and immunohistochemistry (IHC). RESULTS: In single-cell data, BRAF-mutant melanoma displayed a significantly reduced infiltration of CD8+ T cells and macrophages but also increased B cells, natural killer (NK) cells and NKT cells. We then validated this finding using bulk RNA-seq data from the skin cutaneous melanoma cohort in The Cancer Genome Atlas and deconvoluted the data using seven different algorithms. Interestingly, BRAF-mutant tumors had more CD4+ T cells than BRAF-wt samples in both primary and metastatic cohorts. In the metastatic cohort, BRAF-mutant melanoma demonstrated more B cells but less CD8+ T cell infiltration when compared with BRAF-wt samples. In addition, we further investigated the immune cell infiltrate using flow cytometry and multiplex IHC techniques. We confirmed that BRAF-mutant melanoma metastases were enriched for CD4+ T cells and B cells and had a co-existing decrease in CD8+ T cells. Furthermore, we then identified B cells were associated with a trend for improved survival (p=0.078) in the BRAF-mutant samples and Th2 cells were associated with prolonged survival in the BRAF-wt samples. CONCLUSIONS: In conclusion, treatment-naive BRAF-mutant melanoma has a distinct immune context compared with BRAF-wt melanoma, with significantly decreased CD8+ T cells and increased B cells and CD4+ T cells in the tumor microenvironment. These findings indicate that further mechanistic studies are warranted to reveal how this difference in immune context leads to improved outcome to combination immune checkpoint blockade in BRAF-mutant melanoma.
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Melanoma , Proteínas Proto-Oncogênicas B-raf , Neoplasias Cutâneas , Linfócitos B , Linfócitos T CD8-Positivos , Humanos , Células Matadoras Naturais , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/imunologia , Mutação , Células T Matadoras Naturais , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologia , Microambiente Tumoral/genéticaRESUMO
Gut bacteria modulate the response to immune checkpoint blockade (ICB) treatment in cancer, but the effect of diet and supplements on this interaction is not well studied. We assessed fecal microbiota profiles, dietary habits, and commercially available probiotic supplement use in melanoma patients and performed parallel preclinical studies. Higher dietary fiber was associated with significantly improved progression-free survival in 128 patients on ICB, with the most pronounced benefit observed in patients with sufficient dietary fiber intake and no probiotic use. Findings were recapitulated in preclinical models, which demonstrated impaired treatment response to antiprogrammed cell death 1 (antiPD-1)based therapy in mice receiving a low-fiber diet or probiotics, with a lower frequency of interferon-γpositive cytotoxic T cells in the tumor microenvironment. Together, these data have clinical implications for patients receiving ICB for cancer.
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Fibras na Dieta , Microbioma Gastrointestinal , Inibidores de Checkpoint Imunológico/uso terapêutico , Melanoma/terapia , Probióticos , Animais , Estudos de Coortes , Ácidos Graxos Voláteis/análise , Transplante de Microbiota Fecal , Fezes/química , Fezes/microbiologia , Feminino , Humanos , Imunoterapia , Masculino , Melanoma/imunologia , Melanoma/microbiologia , Melanoma Experimental/imunologia , Melanoma Experimental/microbiologia , Melanoma Experimental/terapia , Camundongos , Camundongos Endogâmicos C57BL , Intervalo Livre de Progressão , Linfócitos TRESUMO
Targeted and immunotherapy regimens have revolutionized the treatment of advanced melanoma patients. Despite this, only a subset of patients respond durably. Recently, combination strategies of BRAF/MEK inhibitors with immune checkpoint inhibitor monotherapy (α-CTLA-4 or α-PD-1) have increased the rate of durable responses. Based on evidence from our group and others, these therapies appear synergistic, but at the cost of significant toxicity. We know from other treatment paradigms (e.g. hematologic malignancies) that combination strategies with multi-drug regimens (>4 drugs) are associated with more durable disease control. To better understand the mechanism of these improved outcomes, and to identify and prioritize new strategies for testing, we studied several multi-drug regimens combining BRAF/MEK targeted therapy and immunotherapy combinations in a Braf-mutant murine melanoma model (BrafV600E/Pten-/- ). Short-term treatment with α-PD-1 and α-CTLA-4 monotherapies were relatively ineffective, while treatment with α-OX40 demonstrated some efficacy [17% of mice with no evidence of disease, (NED), at 60-days]. Outcomes were improved in the combined α-OX40/α-PD-1 group (42% NED). Short-term treatment with quadruplet therapy of immunotherapy doublets in combination with targeted therapy [dabrafenib and trametinib (DT)] was associated with excellent tumor control, with 100% of mice having NED after combined DT/α-CTLA-4/α-PD-1 or DT/α-OX40/α-PD-1. Notably, tumors from mice in these groups demonstrated a high proportion of effector memory T cells, and immunologic memory was maintained with tumor re-challenge. Together, these data provide important evidence regarding the potential utility of multi-drug therapy in treating advanced melanoma and suggest these models can be used to guide and prioritize combinatorial treatment strategies.
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Melanoma , Preparações Farmacêuticas , Animais , Humanos , Imunoterapia , Melanoma/tratamento farmacológico , Melanoma/genética , Células T de Memória , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno , Proteínas Proto-Oncogênicas B-raf/genéticaRESUMO
Metastatic melanoma is a deadly malignancy with poor outcomes historically. Immuno-oncology (IO) agents, targeting immune checkpoint molecules such as cytotoxic T-lymphocyte associated protein-4 (CTLA-4) and programmed cell death-1 (PD-1), have revolutionized melanoma treatment and outcomes, achieving significant response rates and remarkable long-term survival. Despite these vast improvements, roughly half of melanoma patients do not achieve long-term clinical benefit from IO therapies and there is an urgent need to understand and mitigate mechanisms of resistance. MicroRNAs are key post-transcriptional regulators of gene expression that regulate many aspects of cancer biology, including immune evasion. We used network analysis to define two core microRNA-mRNA networks in melanoma tissues and cell lines corresponding to 'MITF-low' and 'Keratin' transcriptomic subsets of melanoma. We then evaluated expression of these core microRNAs in pre-PD-1-inhibitor-treated melanoma patients and observed that higher expression of miR-100-5p and miR-125b-5p were associated with significantly improved overall survival. These findings suggest that miR-100-5p and 125b-5p are potential markers of response to PD-1 inhibitors, and further evaluation of these microRNA-mRNA interactions may yield further insight into melanoma resistance to PD-1 inhibitors.
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Treatment with combined immune checkpoint blockade (CICB) targeting CTLA-4 and PD-1 is associated with clinical benefit across tumor types, but also a high rate of immune-related adverse events. Insights into biomarkers and mechanisms of response and toxicity to CICB are needed. To address this, we profiled the blood, tumor and gut microbiome of 77 patients with advanced melanoma treated with CICB, with a high rate of any ≥grade 3 immune-related adverse events (49%) with parallel studies in pre-clinical models. Tumor-associated immune and genomic biomarkers of response to CICB were similar to those identified for ICB monotherapy, and toxicity from CICB was associated with a more diverse peripheral T-cell repertoire. Profiling of gut microbiota demonstrated a significantly higher abundance of Bacteroides intestinalis in patients with toxicity, with upregulation of mucosal IL-1ß in patient samples of colitis and in pre-clinical models. Together, these data offer potential new therapeutic angles for targeting toxicity to CICB.
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Antígeno CTLA-4/imunologia , Microbioma Gastrointestinal , Receptor de Morte Celular Programada 1/imunologia , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Interleucina-1beta/imunologia , Melanoma , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Complex tumor microenvironmental (TME) features influence the outcome of cancer immunotherapy (IO). Here we perform immunogenomic analyses on 67 intratumor sub-regions of a PD-1 inhibitor-resistant melanoma tumor and 2 additional metastases arising over 8 years, to characterize TME interactions. We identify spatially distinct evolution of copy number alterations influencing local immune composition. Sub-regions with chromosome 7 gain display a relative lack of leukocyte infiltrate but evidence of neutrophil activation, recapitulated in The Cancer Genome Atlas (TCGA) samples, and associated with lack of response to IO across three clinical cohorts. Whether neutrophil activation represents cause or consequence of local tumor necrosis requires further study. Analyses of T-cell clonotypes reveal the presence of recurrent priming events manifesting in a dominant T-cell clonotype over many years. Our findings highlight the links between marked levels of genomic and immune heterogeneity within the physical space of a tumor, with implications for biomarker evaluation and immunotherapy response.
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Genômica/métodos , Melanoma/metabolismo , Biomarcadores Tumorais/genética , Variações do Número de Cópias de DNA/genética , Humanos , Melanoma/genética , Mutação/genética , Ativação de Neutrófilo/genética , Ativação de Neutrófilo/fisiologia , Microambiente Tumoral/genética , Microambiente Tumoral/fisiologiaRESUMO
Although immune checkpoint inhibitors (ICIs) have achieved unprecedented results in melanoma, the biological features of the durable responses initiated by these drugs remain unknown. Here we show the genetic and phenotypic changes induced by treatment with programmed cell death-1 (PD-1) blockade in a genetically engineered mouse model of melanoma driven by oncogenic BRAF. In this controlled system anti-PD-1 treatment yields responses in ~35% of the tumors, and prolongs survival in ~27% of the animals. We identify increased stroma remodeling and reduced expression of proliferation markers as features associated with prolonged response. These traits are corroborated in two independent early on-treatment anti-PD-1 melanoma patient cohorts. These insights into the biological responses of tumors to ICI provide a strategy for identification of durable response early during the course of treatment and could improve patient stratification for checkpoint inhibitory drugs.
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Divisão Celular/fisiologia , Melanoma/metabolismo , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Células Estromais/metabolismo , Animais , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Proliferação de Células , Modelos Animais de Doenças , Exoma/genética , Feminino , Humanos , Imunoterapia , CamundongosRESUMO
Immune checkpoint blockade therapy targets T cell-negative costimulatory molecules such as cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed cell death-1 (PD-1). Combination anti-CTLA-4 and anti-PD-1 blockade therapy has enhanced efficacy, but it remains unclear through what mechanisms such effects are mediated. A critical question is whether combination therapy targets and modulates the same T cell populations as monotherapies. Using a mass cytometry-based systems approach, we comprehensively profiled the response of T cell populations to monotherapy and combination anti-CTLA-4 plus anti-PD-1 therapy in syngeneic murine tumors and clinical samples. Most effects of monotherapies were additive in the context of combination therapy; however, multiple combination therapy-specific effects were observed. Highly phenotypically exhausted cluster of differentiation 8 (CD8) T cells expand in frequency following anti-PD-1 monotherapy but not combination therapy, while activated terminally differentiated effector CD8 T cells expand only following combination therapy. Combination therapy also led to further increased frequency of T helper type 1 (Th1)-like CD4 effector T cells even though anti-PD-1 monotherapy is not sufficient to do so. Mass cytometry analyses of peripheral blood from melanoma patients treated with immune checkpoint blockade therapies similarly revealed mostly additive effects on the frequencies of T cell subsets along with unique modulation of terminally differentiated effector CD8 T cells by combination ipilimumab plus nivolumab therapy. Together, these findings indicate that dual blockade of CTLA-4 and PD-1 therapy is sufficient to induce unique cellular responses compared with either monotherapy.
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Antígeno CTLA-4/imunologia , Imunoterapia/métodos , Neoplasias/terapia , Receptor de Morte Celular Programada 1/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Linfócitos do Interstício Tumoral/imunologia , Camundongos , Neoplasias/imunologia , Subpopulações de Linfócitos TRESUMO
PD-1 blockade represents a major therapeutic avenue in anticancer immunotherapy. Delineating mechanisms of secondary resistance to this strategy is increasingly important. Here, we identified the deleterious role of signaling via the type I interferon (IFN) receptor in tumor and antigen presenting cells, that induced the expression of nitric oxide synthase 2 (NOS2), associated with intratumor accumulation of regulatory T cells (Treg) and myeloid cells and acquired resistance to anti-PD-1 monoclonal antibody (mAb). Sustained IFNß transcription was observed in resistant tumors, in turn inducing PD-L1 and NOS2 expression in both tumor and dendritic cells (DC). Whereas PD-L1 was not involved in secondary resistance to anti-PD-1 mAb, pharmacological or genetic inhibition of NOS2 maintained long-term control of tumors by PD-1 blockade, through reduction of Treg and DC activation. Resistance to immunotherapies, including anti-PD-1 mAb in melanoma patients, was also correlated with the induction of a type I IFN signature. Hence, the role of type I IFN in response to PD-1 blockade should be revisited as sustained type I IFN signaling may contribute to resistance to therapy.
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Anticorpos Monoclonais/farmacologia , Interferon Tipo I/metabolismo , Receptor de Morte Celular Programada 1/imunologia , Transdução de Sinais/efeitos dos fármacos , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Antígeno B7-H1/metabolismo , Linhagem Celular Tumoral , Células Dendríticas/citologia , Células Dendríticas/metabolismo , Resistencia a Medicamentos Antineoplásicos , Humanos , Estimativa de Kaplan-Meier , Melanoma/tratamento farmacológico , Melanoma/mortalidade , Melanoma/patologia , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias/tratamento farmacológico , Neoplasias/mortalidade , Neoplasias/patologia , Óxido Nítrico Sintase Tipo II/metabolismo , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismoRESUMO
BACKGROUND: Metastatic uveal melanoma is a highly aggressive disease with no standard of care treatment option. A large proportion of patients have liver-only metastatic disease which raises the question if liver-directed therapy can be efficacious in this subpopulation. AIMS: The study aims to evaluate the safety and efficacy of radiosensitizing chemotherapy in combination with yttrium-90 microspheres in patients with uveal melanoma with liver-only metastases. METHODS AND RESULTS: This single arm, open labeled, non-randomized study enrolled 10 patients with liver-only metastatic uveal melanoma between November 2012 and January 2018. Eligible patients received intrahepatic yttrium-90 microspheres followed by intravenous cisplatin (20 mg/m2) for 5 days. Ten patients were enrolled, but nine patients received treatment who were included in the final analysis with a median follow-up of 30 months (range 7 to 44). Five (50%) were female, five (50%) had an elevated lactate dehydrogenase (LDH), and one (10%) had prior anti-PD-1 therapy. The combination was well tolerated with no greater than or equal to grade 3 toxicity observed. The liver objective response rate (ORR) was 33% (3/9), the median progression-free survival (PFS) in the liver was 3 months (95% CI, 3-NA), and the extrahepatic PFS was 3 months (95% CI, 3-NA). Seventy-eight percent (7/9) received an immune checkpoint inhibitor on disease progression, with no responses seen. The median overall survival (OS) was 10 months (95% CI, 7-NA). CONCLUSION: The combination of cisplatin with yttrium-90 microspheres was well tolerated; however, it was associated with intrahepatic disease control of relatively short duration. No responses were seen in patients treated with immune checkpoint inhibitors post radioembolization.
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Quimiorradioterapia/métodos , Embolização Terapêutica/métodos , Neoplasias Hepáticas/terapia , Melanoma/terapia , Neoplasias Uveais/terapia , Radioisótopos de Ítrio/administração & dosagem , Idoso , Quimiorradioterapia/efeitos adversos , Cisplatino/administração & dosagem , Imagem de Difusão por Ressonância Magnética , Embolização Terapêutica/efeitos adversos , Feminino , Seguimentos , Humanos , Fígado/irrigação sanguínea , Fígado/diagnóstico por imagem , Fígado/efeitos dos fármacos , Fígado/patologia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Masculino , Melanoma/mortalidade , Melanoma/secundário , Pessoa de Meia-Idade , Projetos Piloto , Intervalo Livre de Progressão , Neoplasias Uveais/mortalidade , Neoplasias Uveais/secundárioRESUMO
In the version of this article originally published, there was an error in Fig. 2b. RECIST ORR and pCR were both listed as 25%. RECIST ORR was actually 73%, and pCR was 45%. Also, an author's name was incorrect in the author list. Danny K. Wells should have been listed as Daniel K. Wells. The errors have been corrected in the print, HTML and PDF versions of this article.