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1.
The Role of Calcium Signaling in Melanoma.
Zhang, H, Chen, Z, Zhang, A, Gupte, AA, Hamilton, DJ
International journal of molecular sciences. 2022;(3)
Abstract
Calcium signaling plays important roles in physiological and pathological conditions, including cutaneous melanoma, the most lethal type of skin cancer. Intracellular calcium concentration ([Ca2+]i), cell membrane calcium channels, calcium related proteins (S100 family, E-cadherin, and calpain), and Wnt/Ca2+ pathways are related to melanogenesis and melanoma tumorigenesis and progression. Calcium signaling influences the melanoma microenvironment, including immune cells, extracellular matrix (ECM), the vascular network, and chemical and physical surroundings. Other ionic channels, such as sodium and potassium channels, are engaged in calcium-mediated pathways in melanoma. Calcium signaling serves as a promising pharmacological target in melanoma treatment, and its dysregulation might serve as a marker for melanoma prediction. We documented calcium-dependent endoplasmic reticulum (ER) stress and mitochondria dysfunction, by targeting calcium channels and influencing [Ca2+]i and calcium homeostasis, and attenuated drug resistance in melanoma management.
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2.
Combined presentation and immunogenicity analysis reveals a recurrent RAS.Q61K neoantigen in melanoma.
Peri, A, Greenstein, E, Alon, M, Pai, JA, Dingjan, T, Reich-Zeliger, S, Barnea, E, Barbolin, C, Levy, R, Arnedo-Pac, C, et al
The Journal of clinical investigation. 2021;(20)
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Abstract
Neoantigens are now recognized drivers of the antitumor immune response. Recurrent neoantigens, shared among groups of patients, have thus become increasingly coveted therapeutic targets. Here, we report on the data-driven identification of a robustly presented, immunogenic neoantigen that is derived from the combination of HLA-A*01:01 and RAS.Q61K. Analysis of large patient cohorts indicated that this combination applies to 3% of patients with melanoma. Using HLA peptidomics, we were able to demonstrate robust endogenous presentation of the neoantigen in 10 tumor samples. We detected specific reactivity to the mutated peptide within tumor-infiltrating lymphocytes (TILs) from 2 unrelated patients, thus confirming its natural immunogenicity. We further investigated the neoantigen-specific clones and their T cell receptors (TCRs) via a combination of TCR sequencing, TCR overexpression, functional assays, and single-cell transcriptomics. Our analysis revealed a diverse repertoire of neoantigen-specific clones with both intra- and interpatient TCR similarities. Moreover, 1 dominant clone proved to cross-react with the highly prevalent RAS.Q61R variant. Transcriptome analysis revealed a high association of TCR clones with specific T cell phenotypes in response to cognate melanoma, with neoantigen-specific cells showing an activated and dysfunctional phenotype. Identification of recurrent neoantigens and their reactive TCRs can promote "off-the-shelf" precision immunotherapies, alleviating limitations of personalized treatments.
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3.
Dermatomyositis in a patient undergoing nivolumab therapy for metastatic melanoma: a case report and review of the literature.
Kosche, C, Stout, M, Sosman, J, Lukas, RV, Choi, JN
Melanoma research. 2020;(3):313-316
Abstract
Checkpoint inhibitor immunotherapy is a transformative treatment for advanced malignancies, but can be associated with numerous immune-related adverse events (irAEs). The majority of irAEs include those that closely resemble known cutaneous and neurocutaneous autoimmune or autoinflammatory diseases, such as scleroderma, psoriasis, and dermatomyositis. We present the case of a 63-year-old man with metastatic melanoma undergoing treatment with nivolumab who developed significant motor weakness, paresthesias of both hands, swollen fingers, and a pruritic rash over the face, chest, and upper back after two cycles. Creatine kinase was elevated. Electromyography revealed a myopathic pattern, muscle biopsy of the deltoid revealed an inflammatory myopathy, and skin biopsy showed interface dermatitis. There were no detectable autoantibodies except positive antinuclear antibody. He was diagnosed with immunotherapy-induced dermatomyositis, nivolumab was held, and he was treated with oral prednisone and intravenous immunoglobulin with overall improvement in myopathic and cutaneous symptoms. Dermatomyositis is an inflammatory myopathy with a characteristic dermatologic presentation that can occur spontaneously, as a paraneoplastic phenomenon, or as a drug reaction. This is the second known case of nivolumab-induced dermatomyositis. A review of the literature revealed seven total cases of immunotherapy-induced dermatomyositis. Functionally disabling autoimmune adverse effects of this severity would frequently persuade providers to discontinue immunotherapy in patients with metastatic disease.
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4.
Plasma-activated medium triggers cell death and the presentation of immune activating danger signals in melanoma and pancreatic cancer cells.
Azzariti, A, Iacobazzi, RM, Di Fonte, R, Porcelli, L, Gristina, R, Favia, P, Fracassi, F, Trizio, I, Silvestris, N, Guida, G, et al
Scientific reports. 2019;(1):4099
Abstract
Over the past decade, cold atmospheric plasmas have shown promising application in cancer therapy. The therapeutic use of plasma-activated media is a topic addressed in an emerging field known as plasma pharmacy. In oncology, plasma-activated media are used to harness the therapeutic effects of oxidant species when they come in contact with cancer cells. Among several factors that contribute to the anticancer effect of plasma-activated liquid media (PALM), H2O2 and NO derivatives likely play a key role in the apoptotic pathway. Despite the significant amount of literature produced in recent years, a full understanding of the mechanisms by which PALM exert their activity against cancer cells is limited. In this paper, a sealed dielectric-barrier discharge was used to disentangle the effect of reactive nitrogen species (RNS) from that of reactive oxygen species (ROS) on cancer cells. Two cancers characterized by poor prognosis have been investigated: metastatic melanoma and pancreatic cancer. Both tumour models exposed to PALM rich in H2O2 showed a reduction in proliferation and an increase in calreticulin exposure and ATP release, suggesting the potential use of activated media as an inducer of immunogenic cell death via activation of the innate immune system.
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5.
Molecular and immune correlates of TIM-3 (HAVCR2) and galectin 9 (LGALS9) mRNA expression and DNA methylation in melanoma.
Holderried, TAW, de Vos, L, Bawden, EG, Vogt, TJ, Dietrich, J, Zarbl, R, Bootz, F, Kristiansen, G, Brossart, P, Landsberg, J, et al
Clinical epigenetics. 2019;(1):161
Abstract
BACKGROUND The T cell immunoglobulin and mucin-domain containing-3 receptor TIM-3 (also known as hepatitis A virus cellular receptor 2, encoded by HAVCR2) and its ligand galectin 9 (LGALS9) are promising targets for immune checkpoint inhibition immunotherapies. However, little is known about epigenetic regulation of the encoding genes. This study aimed to investigate the association of TIM-3 and LGALS9 DNA methylation with gene expression, patients' survival, as well as molecular and immune correlates in malignant melanoma. RESULTS Methylation of all six TIM-3 CpGs correlated significantly with TIM-3 mRNA levels (P ≤ 0.05). A strong inverse correlation (Spearman's ρ = - 0.49) was found in promoter regions, while a strong positive correlation (ρ = 0.63) was present in the gene body of TIM-3. High TIM-3 mRNA expression (hazard ratio (HR) = 0.88, 95% confidence interval (CI) [0.81-0.97], P = 0.007) was significantly associated with better overall survival. Seven of the eight LGALS9 CpG sites correlated significantly with LGALS9 mRNA levels (P ≤ 0.003). Methylation at five CpG sites showed a strong inverse correlation (Spearman's ρ = - 0.67) and at two sites a weak positive correlation (Spearman's ρ = 0.15). High LGALS9 mRNA expression was significantly associated with increased overall survival (HR = 0.83, 95%CI [0.75-0.93], P = 0.001). In addition, we found significant correlations between TIM-3 and LGALS9 methylation and mRNA expression with immune cell infiltrates and significant differences among distinct immune cell subsets. CONCLUSIONS Our study points toward an epigenetic regulation of TIM-3 and LGALS9 via DNA methylation and might provide an avenue for the development of a predictive biomarker for response to immune checkpoint blockade.
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Immunotherapy and targeted therapies in older patients with advanced melanoma; Young International Society of Geriatric Oncology review paper.
Bastiaannet, E, Battisti, N, Loh, KP, de Glas, N, Soto-Perez-de-Celis, E, Baldini, C, Kapiteijn, E, Lichtman, S
Journal of geriatric oncology. 2019;(3):389-397
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Abstract
Malignant melanoma is an aggressive cancer associated with a poor prognosis in patients with metastatic disease. As in many other cancers, the incidence of melanoma rises with age; and combined with the longer life expectancy, this led to an increasing prevalence of melanoma in the older population. Recently, immune checkpoint inhibitors significantly improved the treatment of melanoma given their efficacy and tolerability profile. Two major classes of agents include the anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) inhibitors, such as ipilimumab, and the anti-programmed death-ligand 1 (PD-1) inhibitors, such as nivolumab and pembrolizumab. Treatment of metastatic disease with immune checkpoint inhibitors demonstrated improved efficacy and better safety profiles compared to cytotoxic drugs and appears to be an attractive treatment option. Nevertheless, there is a need for tools designed to better predict which older patients will benefit from its use and who will experience toxicities related to the treatment. Current data do not show a major increase in toxicity rates in older patients. However, patients above 75 are often under-represented and those who are included are not representative of the general population of older patients, thereby also stressing the need for real-life data. Ongoing research is aiming at maximizing the potential treatment efficacy and developing novel immune-targeting modalities. Future studies should include older patients and assess geriatric domains in these older patients to better guide decision-making. This review discusses published clinical trials and where known, the efficacy and toxicity in older patients. Moreover, the clinical implications and future perspectives are discussed, with current recommendations for older patients, management of toxicities, and a proposal for an initial approach to the treatment of older patients with metastatic melanoma.
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7.
Vitamin D in melanoma: Controversies and potential role in combination with immune check-point inhibitors.
Stucci, LS, D'Oronzo, S, Tucci, M, Macerollo, A, Ribero, S, Spagnolo, F, Marra, E, Picasso, V, Orgiano, L, Marconcini, R, et al
Cancer treatment reviews. 2018;:21-28
Abstract
The role of vitamin D in melanoma is still controversial. Although several Authors described a correlation between vitamin D deficiency and poor survival in metastatic melanoma patients, clinical trials exploring the effects of vitamin D supplementation in this clinical setting were mostly inconclusive. However, recent evidence suggests that vitamin D exerts both anti-proliferative effects on tumor cells and immune-modulating activities, that have been widely explored in auto-immune disorders. On the one hand, vitamin D has been shown to inhibit T-helper17 lymphocytes, notoriously involved in the pathogenesis of immune-related adverse events (iAEs) which complicate immune-checkpoint inhibitor (ICI) treatment. On the other hand, vitamin D up-regulates PDL-1 expression on both epithelial and immune cells, suggesting a synergic effect in combination with ICIs, for which further investigation is needed.
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Autoimmune diabetes induced by PD-1 inhibitor-retrospective analysis and pathogenesis: a case report and literature review.
Gauci, ML, Laly, P, Vidal-Trecan, T, Baroudjian, B, Gottlieb, J, Madjlessi-Ezra, N, Da Meda, L, Madelaine-Chambrin, I, Bagot, M, Basset-Seguin, N, et al
Cancer immunology, immunotherapy : CII. 2017;(11):1399-1410
Abstract
Anti-PD-1 antibody treatment is approved in advanced melanoma and provides median overall survival over 24 months. The main treatment-related side effects are immune-related adverse events, which include rash, pruritus, vitiligo, thyroiditis, diarrhoea, hepatitis and pneumonitis. We report a case of autoimmune diabetes related to nivolumab treatment. A 73-year-old man was treated in second line with nivolumab at 3 mg/kg every two weeks for metastatic melanoma. At 6 weeks of treatment, he displayed diabetic ketoacidosis. Nivolumab was withheld 3.5 weeks and insulin therapy was initiated, enabling a normalization of glycaemia and the disappearance of symptoms. Laboratory investigations demonstrated the presence of islet cell autoantibodies, while C-peptide was undetectable. Retrospective explorations on serum banked at week 0 and 3 months before the start of nivolumab, already showed the presence of autoantibodies, but normal insulin, C-peptide secretion and glycaemia. Partial response was obtained at month 3, and nivolumab was then resumed at the same dose. The clinical context and biological investigations before, at and after nivolumab initiation suggest the autoimmune origin of this diabetes, most likely induced by anti-PD-1 antibody in a predisposed patient. The role of PD-1/PD-L1 binding is well known in the pathogenesis of type 1 diabetes. Therefore, this rare side effect can be expected in a context of anti-PD-1 treatment. Glycaemia should be monitored during PD-1/PD-L1 blockade. The presence of autoantibodies before treatment could identify individuals at risk of developing diabetes, but systematic titration may not be relevant considering the rarity of this side effect.
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A phase II study of REOLYSIN® (pelareorep) in combination with carboplatin and paclitaxel for patients with advanced malignant melanoma.
Mahalingam, D, Fountzilas, C, Moseley, J, Noronha, N, Tran, H, Chakrabarty, R, Selvaggi, G, Coffey, M, Thompson, B, Sarantopoulos, J
Cancer chemotherapy and pharmacology. 2017;(4):697-703
Abstract
REOLYSIN® (pelareorep) is an investigational new drug, consisting of a live, replication-competent, Reovirus Type 3 Dearing strain in a proprietary formulation. Several preclinical and clinical trials with REOLYSIN® on a wide range of cancer indications have demonstrated antineoplastic activity on cells with activated RAS-signaling pathway. Furthermore, long-term survival benefits were evident in post-treatment patients indicating a potential antitumor immune response triggered by REOLYSIN®. Numerous mono and/or combination therapy studies with the agent showed a consistent safety profile. The current study is a phase II, single-arm, open label trial of REOLYSIN® in combination with carboplatin and paclitaxel for patients with advanced melanoma. Results from the 14 patients enrolled in the study exhibited no grade 4 adverse events or deaths but manageable grade-3 toxicities commonly attributed to REOLYSIN®, including pyrexia, chills, myalgia, pain, fatigue, and nausea. The number of treatment cycles ranged from 2 to 20 with a median of 6 cycles. The study met its treatment and efficacy goal for the first stage with three partial responses (ORR was 21%). No complete responses were noted. The median PFS and OS were 5.2 and 10.9 months, respectively. The 1-year OS was 43% with a disease control rate of 85%. In conclusion, REOLYSIN® combined with carboplatin and paclitaxel is a safe and potentially efficacious therapy for patients with advanced malignant melanoma. Additional combination studies using REOLYSIN® with chemo/immunotherapy drugs may support more favorable outcomes for patients in this indication.
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10.
Nicotinamide for skin cancer chemoprevention.
Damian, DL
The Australasian journal of dermatology. 2017;(3):174-180
Abstract
Nicotinamide (vitamin B3 ) has a range of photoprotective effects in vitro and in vivo; it enhances DNA repair, reduces UV radiation-induced suppression of skin immune responses, modulates inflammatory cytokine production and skin barrier function and restores cellular energy levels after UV exposure. Pharmacological doses of nicotinamide have been shown to reduce actinic keratoses and nonmelanoma skin cancer incidence in high-risk individuals, making this a nontoxic and accessible option for skin cancer chemoprevention in this population.