Although the role of the tumor microenvironment in the process of cancer progression has been extensively investigated, the contribution of different stromal components to tumor growth and/or evasion ...from immune surveillance is still only partially defined. In this study we analyzed fibroblasts derived from metastatic melanomas and provide evidence for their strong immunosuppressive activity. In coculture experiments, melanoma-derived fibroblasts sharply interfered with NK cell functions including cytotoxicity and cytokine production. Thus, both the IL-2-induced up-regulation of the surface expression of NKp44, NKp30, and DNAM-1 triggering receptors and the acquisition of cytolytic granules were inhibited in NK cells. This resulted in an impairment of the NK cell-mediated killing of melanoma target cells. Transwell cocultures and the use of specific inhibitors suggested that cell-to-cell contact was required for inducing DNAM-1 modulation. In contrast, modulation of NKp44 and NKp30 was due to PGE₂ released by fibroblasts during coculture. Normal skin fibroblasts could also partially affect NK cell phenotype and function. However, the inhibitory effect of tumor-derived fibroblasts was far stronger and directly correlated with their ability to produce PGE₂ either constitutively or upon induction by NK cells.
Experimental and clinical data suggest that tumours harbour a cell population retaining stem cell characteristics that can drive tumorigenesis. CD133 is considered an important cancer stem cells ...(CSC)-associated marker. In a large variety of human malignancies, including melanoma, CD133+ cells have been reported to comprise CSC. In this study, we show that melanoma cell lines are highly heterogeneous for the expression of several stem cell-associated markers including CD133, c-kit/CD117 and p75 neurotrophin receptor/CD271. Since no information is available on the ability of NK cells to recognize and lyse melanoma stem cells, we assessed whether melanoma cell lines, characterized by stem cell-like features, were susceptible to lysis by IL-2-activated NK cells. We show that activated NK cells efficiently kill malignant melanoma cell lines that were enriched in putative CSC by the use of different selection methods (i.e. CD133 expression, radioresistance or the ability to form melanospheres in stem cell-supportive medium). NK cell-mediated recognition and lysis of melanoma cells involved different combinations of activating NK receptors. Since CSC have been reported to be both drug resistant and radioresistant, our present data suggest that NK-based adoptive immunotherapy could represent a novel therapeutic approach to possibly eradicate metastatic melanoma.
Summary Background Ipilimumab improves survival of patients with metastatic melanoma, many of whom develop brain metastases. Chemotherapy-induced release of tumour antigens might amplify ipilimumab's ...antitumour activity. We aimed to investigate the efficacy and safety of ipilimumab plus fotemustine in patients with metastatic melanoma with or without asymptomatic brain metastases. Methods In our open-label, single-arm phase 2 trial, we enrolled patients 18 years or older with measurable, locally advanced, unresectable stage III or stage IV melanoma between July 6, 2010, and April 14, 2011. Eligible patients had a life expectancy of 16 weeks or more and an Eastern Cooperative Oncology Group performance status of 1 or less, and could have received a maximum of one previous line of chemotherapy. Participants received induction treatment of 10 mg/kg intravenous ipilimumab every 3 weeks to a total of four doses, and 100 mg/m2 intravenous fotemustine weekly for 3 weeks and then every 3 weeks from week 9 to week 24. Patients with a confirmed clinical response were eligible for maintenance treatment from week 24, with ipilimumab every 12 weeks and fotemustine every 3 weeks. The primary endpoint was the proportion of patients with immune-related disease control as established with immune-related response criteria. Analyses were done per protocol. This trial is registered with EudraCT, number 2010-019356-50, and with ClinicalTrials.gov , number NCT01654692. Findings 86 patients were eligible for treatment, of whom 20 had asymptomatic brain metastases at baseline. 40 patients in the study population achieved disease control (46·5%, 95% CI 35·7–57·6), as did ten with brain metastases (50·0%, 27·2–72·8). 47 patients (55%) had grade 3 or 4 treatment-related adverse events, of which the most common was myelotoxicity (thrombocytopenia in 21 24% patients and neutropenia in 16 19%). The most common grade 3 or 4 immune-related adverse events were hepatic: 21 patients (24%) had grade 3 or 4 increases in concentrations of alanine aminotransferase or aspartate aminotransferase. Interpretation The combination of ipilimumab plus fotemustine has clinical activity in patients with metastatic melanoma, including those with brain metastases. Funding Bristol-Myers Squibb.
Cutaneous squamous cell carcinoma (CSCC) accounts for approximately 20% of all keratinocytic tumors. In most cases, the diagnosis and treatments are made on small, low-risk lesions. However, in about ...5% of cases, CSCC may present as either locally advanced or metastatic (i.e. with locoregional lymph nodes metastases or distant localizations). Prior to the introduction of immunotherapy in clinical practice, the standard treatment of advanced CSCC was not clearly defined, and up to 60% of patients received no systemic therapy. Thanks to a strong pre-clinical rationale, clinical trials led to the FDA (Food and Drug Administration) and EMA (European Medicines Agency) registration of cemiplimab, a PD-1 inhibitor that achieved encouraging results in terms of objective response, overall survival, and quality of life. Subsequently, the anti-PD-1 pembrolizumab received the approval for the treatment of advanced CSCC by the FDA only. In this review, we will focus on the definition of advanced CSCC and on the current and future therapeutic options, with a particular regard for immunotherapy.
As for all types of cancer, the incidence of melanoma increases with age. However, naevus counts (the principal risk factor for melanoma) decrease with age; hence the relationship between ageing and ...melanoma is complex. Subjects who maintain a high naevus count after the age of 50 years are more likely to be affected by melanoma, as their lesions do not senesce. Longer telomere length, which is strongly related to age, is linked to high naevus counts/melanoma risk; thus melanoma biology is influenced by factors that slow down ageing. Age is also an important prognostic factor in melanoma. Increasing age leads to worse survival in stages I, II and III. Sentinel lymph node (SLN) status, which is a strong predictor of melanoma survival, is also affected by age, as SLN positivity decreases with age. However, the prognostic predictive value of SLN status on survival increases with age, so, again, these relationships are complex. In patients with stage IV melanoma, age impacts on survival because it affects responses to treatment. This review examines the effects of age on melanoma risk, prognostic factors and responses to treatment.
•Atypical responses to anti-PD-1 therapy were evaluated in 19 clinical trials.•151 responses after initial progression were observed in 2400 patients (6%).•Some patients may derive benefit from ...extended anti-PD-1 therapy beyond progression.
Anti-programmed death receptor 1 (PD-1) drugs nivolumab and pembrolizumab were recently approved for the treatment of advanced melanoma and other solid tumors. Atypical patterns of response (i.e. tumor shrinkage or stabilization after initial progression) were observed in about 10% of metastatic melanoma patients treated with anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) drug ipilimumab and were associated with improved survival; however, the rate of atypical response patterns to anti-PD-1 therapy is not clear. An electronic search was performed to identify clinical trials evaluating response to anti-PD-1 therapy with nivolumab and pembrolizumab in patients with advanced solid tumors.
Thirty-eight studies were included in our analysis for a total of 7069 patients with advanced cancer treated with anti-PD-1 therapy. Responses were evaluated by unconventional response criteria in 19 trials and were observed for all cancer types but tumors with mismatch-repair deficiency and head and neck squamous cell carcinoma. Overall, 151 atypical responses were observed in 2400 patients (6%) evaluated by unconventional response criteria.
The results of our systematic review highlight the clinical relevance of unconventional responses to anti-PD-1 therapy and support further investigation into the development of tools that may assist evaluation of the antitumor activity of immunotherapy.
Metastatic melanoma was the first malignancy in which immune checkpoint inhibitors demonstrated their successful efficacy. Currently, the knowledge on the interaction between the immune system and ...malignant disease is steadily increasing and new drugs and therapeutic strategies are overlooking in the clinical scenario. To provide a comprehensive overview of immune modulating drugs currently available in the treatment of melanoma as well as to discuss of possible future strategies in the metastatic melanoma setting, the present review aims at analyzing controversial aspects about the optimal immunomodulating treatment sequences, the search for biomarkers of efficacy of immunocheckpoint inhibitors, and innovative combinations of drugs currently under investigation.
Conventional melanoma serum biomarkers (S100 and lactate dehydrogenase LDH) perform poorly in patients with uveal melanoma, and the search for new biomarkers is needed. A high expression of the ...oncoprotein c-Met in primary uveal melanoma is associated with metastatic progression, and c-Met is released as a soluble ectodomain through ADAM10- and ADAM17-mediated cleavage, suggesting a possible role as biomarker.
To determine the potential role of soluble c-Met (sc-Met) as a biomarker of uveal melanoma progression in comparison with S100 and LDH.
Soluble c-Met was studied in the conditioned medium of 9 uveal melanoma cell lines and in the blood serum samples of 24 mice with uveal melanoma xenografts, 57 patients with uveal melanoma (17 patients whose tumors metastasized and 40 patients whose tumors did not metastasize), and 37 healthy donors. We collected blood samples for as long as 5 years after treatment of the primary tumor. The concentration of sc-Met was measured using enzyme-linked immunosorbent assays, and the receiver operating characteristic curve was used to evaluate sensitivity and specificity in the identification of metastatic uveal melanoma. The study began on May 2, 2011, and the last samples were collected in January 2015.
Levels of sc-Met in uveal melanoma cell cultures and in the blood serum samples of xenotransplanted mice, of healthy donors, and of patients with uveal melanoma during follow-up.
The conditioned medium of uveal melanoma cell lines and the blood serum samples of mice with uveal melanoma xenografts contained significant levels of sc-Met. Patients with metastatic disease had significantly higher serum levels of sc-Met (median level, 590 ng/mL range, 246-12,856 ng/mL) than did patients without metastatic disease (median level, 296 ng/mL range, 201-469 ng/mL) (P < .001) and healthy donors (median level, 285 ng/mL range, 65-463 ng/mL) (P < .001). Analysis of receiver operating characteristic curves for sc-Met levels in patients with nonmetastatic uveal melanoma vs patients with metastatic uveal melanoma yielded an area under the curve of 0.82 (95% CI, 0.68-0.95) (P < .001), which was superior to the areas under the curve achieved with S100 or LDH markers. Patients with progressive metastatic disease showed further increases in sc-Met level, whereas stable patients did not.
The present pilot study suggests that sc-Met should be further exploited as a biomarker for monitoring of uveal melanoma.
Background. Brain metastases are one of the leading causes of death in melanoma patients. This systematic review and meta-analysis aimed to look at the variables that affect melanoma patients’ ...intracranial treatment responses to immunotherapy and targeted therapy. Methods. A systematic search of PubMed and Scopus up to December 2023 was conducted to identify trials investigating treatment response of melanoma brain metastasis. This meta-analysis presents summary estimates (SEs) of treatment response and odd ratios (ORs) for the comparison between symptomatic and asymptomatic metastases. Generalised linear mixed models were used for the SE of the proportion of clinical responses and 95% CIs are reported. We investigated between-study heterogeneity using meta-regression. Results. We included 19 independent clinical trials for a total of 1074 patients with brain metastases. The SE of the overall response was 36% 95%CI 27%; 47%, I2 = 84%, similar to the SE for symptomatic metastases: SE = 29% 95%CI 16%; 47%, I2 = 80%. A significantly higher response of symptomatic metastases was observed between patients who had previously received immunotherapy compared to those who had not (47% vs. 9%, p-value = 0.001). The SE was greater for asymptomatic metastases (38% 95%CI 29%; 49%, I2 = 80%), and among these, patients that received the combo-immunotherapy importantly responded more than those who had received monotherapy (45% vs. 26.1%, p-value = 0.002). The major limit of our analysis is the absence of data about the specific intracranial response separately in asymptomatic and symptomatic patients in seven studies. Conclusions. This study shows the importance of starting immunotherapy as early as possible in asymptomatic patients. Randomised trials with greater statistical power are needed to find the best strategies for symptomatic and asymptomatic brain metastases.
Merkel cell carcinoma (MCC) is a rare, highly aggressive, neuroendocrine cutaneous tumor. The incidence of MCC is growing worldwide, and the disease-related mortality is about three-fold higher than ...melanoma. Since a few years ago, very little has been known about this disease, and chemotherapy has been the standard of care. Nowadays, new discoveries about the pathophysiology of this neoplasm and the introduction of immunotherapy allowed to completely rewrite the history of these patients. In this review, we provide a summary of the most important changes in the management of Merkel cell carcinoma, with a focus on immunotherapy and a landscape of future treatment strategies.
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