Survival of patients with advanced metastatic melanoma: The impact of novel therapies

Ugurel, Selma; Röhmel, Joachim; Ascierto, Paolo A.; Flaherty, Keith T.; Grob, Jean-Jacques; Hauschild, Axel; Larkin, James; Long, Georgina V.; Lorigan, Paul; McArthur, Grant A.; Ribas, Antoni; Robert, Caroline; Schadendorf, Dirk; Garbe, Claus

doi:10.1016/j.ejca.2015.09.013

Cited by 148 publications

(115 citation statements)

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“…1,2 Since then, checkpoint inhibitors have supplanted dacarbazine and quadrupled long-term survival. 3–6 Although checkpoint inhibitors have garnered much attention, 1,2,7 other biotherapetics have been approved including immunostimulatory cytokines, 8 monoclonal antibodies, 9 cancer vaccines, 10 oncolytic virotherapy 11,12 and chimeric antigen receptor (CAR) T-cell therapy. 13 All these approaches invoke immunity through non-redundant mechanisms of action.…”

Section: Introductionmentioning

confidence: 99%

Preclinical evaluation of a MAGE-A3 vaccination utilizing the oncolytic Maraba virus currently in first-in-human trials

et al. 2018

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Multiple immunotherapeutics have been approved for cancer patients, however advanced solid tumors are frequently refractory to treatment. We evaluated the safety and immunogenicity of a vaccination approach with multimodal oncolytic potential in non-human primates (NHP) (Macaca fascicularis). Primates received a replication-deficient adenoviral prime, boosted by the oncolytic Maraba MG1 rhabdovirus. Both vectors expressed the human MAGE-A3. No severe adverse events were observed. Boosting with MG1-MAGEA3 induced an expansion of hMAGE-A3-specific CD4+ and CD8+ T-cells with the latter peaking at remarkable levels and persisting for several months. T-cells reacting against epitopes fully conserved between simian and human MAGE-A3 were identified. Humoral immunity was demonstrated by the detection of circulating MAGE-A3 antibodies. These preclinical data establish the capacity for the Ad:MG1 vaccination to engage multiple effector immune cell populations without causing significant toxicity in outbred NHPs. Clinical investigations utilizing this program for the treatment of MAGE-A3-positive solid malignancies are underway (NCT02285816, NCT02879760).

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Section: Introductionmentioning

confidence: 99%

Preclinical evaluation of a MAGE-A3 vaccination utilizing the oncolytic Maraba virus currently in first-in-human trials

et al. 2018

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“…Methode : In dieser Studie erfolgte eine 2-fache externe Validierung des GRS, (i) prognostisch durch in silico -Analysen mit Hilfe des SurvExpress Web Tools (1), und (ii) technisch durch externe in vitro -Duplikatanalysen.…”

Section: In Silico Und In Vitro -Validierung Eines Genexpressionsbasiunclassified

“…10% der Patienten zu Schilddrüs-enauffälligkeiten im Sinne einer immunvermittelten Hyperthyreose, bzw. Autoimmunthyreoiditis, die in der Regel milde verlaufen und gut medikamentös einstellbar sind [1,2]. Dennoch sollten die Zeichen einer thyreotoxischen Krise bei Einsatz von Immuncheckpointinhibitoren bekannt sein, um diese frühzeitig zu erkennen und erforderliche Maßnahmen einleiten zu können [3].…”

Section: P23unclassified

“…Einleitung : In der Behandlung des fortgeschrittenen metastasierten Melanoms nehmen kombinierte Immuntherapien eine herausragende Rolle ein [1]. Die Bestimmung des S100-β-Titers im Serum gilt als guter Biomarker bei Patienten mit metastasiertem malignem Melanom [2].…”

Section: P23unclassified

“…In order to achieve these results allografts are commonly required. Patients and Methods : 106 patients with scin cancer penetrating nasal alar defects were closed in one step via the use of a fi brous renicapsule allograft, produced by the Russian tissue establishment "Alloplant" (Ufa) (fi g. 1, 3d) [1][2][3][4][5][6]. …”

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2017

J Deutsche Derma Gesell

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Question : Lymphangiogenesis is a crucial step in the progression of cancer. Formation of new lymphatic vessels provides an additional route for tumor cells to metastasize. Therefore, infl uencing lymphangiogenesis is an interesting target in cancer therapy. Signaling via the vascular endothelial growth factor receptor-2/-3 (VEGFR-2/3), Lyve-1 and Tie-2 pathways are critical for lymphangiogenic responses. Arsenic trioxide (As 2 O 3 ), which is used as an effective treatment against relapsed acute promyelocytic leukemia, is characterized by low cytotoxicity. As As 2 O 3 promotes anti-angiogenic effects on endothelial cells, we hypothesized that As 2 O 3 may have impact on lymphangiogenesis. Therefore, we explored whether the known anti-tumorigenic properties of As 2 O 3 might be additionally mediated in part by anti-lymphangiogenic effects through the reduction in VEGFR-2/3, Lyve-1 and Tie-2 expressions in primary human lymphatic endothelial cells.Methods : Human lymphatic endothelial cells (LEC) were cultured in vitro and treated with or without As 2 O 3 . Effects of As 2 O 3 on proliferation, apoptosis and expression of the important endothelial receptors VEGFR-2/3, Lyve-1and Tie-2 were analyzed mainly by BrdU-Assay, cell death assay, caspase-9 activity assay, cytochrome c assay and immunoblotting. In vitro angiogenesis was investigated using the matrigel tube formation assay.Results : As 2 O 3 inhibited cell proliferation in a concentration-dependent manner. In our study we found that As2O3 induced apoptosis by activating caspase-9, cytochrome c release and down-regulating the anti-apoptotic proteins cIAP-2 and survivin. Furthermore, we could demonstrate an inhibition of the formation of lymphatic capillary like structures by As 2 O 3 treatment. In addition, we demonstrated that As 2 O 3 signifi cantly inhibited VEGFR-3 and Lyve-1 protein expression whereas VEGFR-2 and Tie-2 expression was unaffected after treatment with As 2 O 3 .Conclusion : In conclusion, our results provide for the fi rst time clear evidence, that As 2 O 3 has distinct anti-lymphangiogenic effects mainly by inhibition of the endothelial VEGFR-3 and Lyve-1 and activating the intrinsic apoptotic pathway. P2CD200 expression in Merkel cell carcinoma: a way to evade the immune system? Background : Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine skin cancer of the elderly with an increasing incidence and a very poor prognosis. Recently, treatments with anti-PD1 or anti-PD-L1 immune check-point inhibitors have shown promising results for metastatic MCC. CD200 is another immune check-point modulator whose receptor is found on tumor promoting M2 macrophages. In preliminary mRNA microarray gene expression analyses we found that CD200 is highly expressed on MCC tumors. Objectives : We sought to investigate the potential of CD200 as a target for novel immune-check-point modulation in MCC.Methods and Results : CD200 protein expression was demonstrated by immunohistochemistry on 82 of 89 MCC tumor samples of 62 patients including 55 ...

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Long-Term Survival in Patients With Advanced Melanoma

van Not,

van den Eertwegh,

Jalving

et al. 2024

JAMA Netw Open

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IMPORTANCELong-term survival data from clinical trials show that survival curves of patients with advanced melanoma treated with immune checkpoint inhibitors (ICIs) gradually reach a plateau, suggesting that patients have a chance of achieving long-term survival.OBJECTIVETo investigate long-term survival in patients with advanced melanoma treated with ICIs outside clinical trials.DESIGN, SETTING, AND PARTICIPANTSCohort study using prospectively collected data from the nationwide Dutch Melanoma Treatment Registry, including patients in the Netherlands with advanced melanoma treated with first-line ICIs from 2012 to 2019. Data were analyzed from January to September 2023.EXPOSURESPatients were treated with first-line ipilimumab-nivolumab, antibodies that target programmed cell death (anti–PD-1), or ipilimumab.MAIN OUTCOMES AND MEASURESProgression-free survival (PFS) and melanoma-specific survival were analyzed, and a Cox proportional hazards model was used to investigate factors associated with PFS after reaching partial response (PR) or complete response (CR).RESULTSA total of 2490 patients treated with first-line ICIs were included (median [IQR] age, 65.0 [55.3-73.0] years; 1561 male patients [62.7%]). Most patients had an Eastern Cooperative Oncology Group Performance Status of 1 or lower (2202 patients [88.5%]) and normal lactate dehydrogenase levels (1715 patients [68.9%]). PFS for all patients was 23.4% (95% CI, 21.7%-25.2%) after 3 years and 19.7% (95% CI, 18.0%-21.4%) after 5 years. Overall survival for all patients was 44.0% (95% CI, 42.1%-46.1%) after 3 years and 35.9% (95% CI, 33.9%-38.0%) after 5 years. Patients with metastases in 3 or more organ sites had a significantly higher hazard of progression after reaching PR or CR (adjusted hazard ratio, 1.37; 95% CI, 1.11-1.69).CONCLUSIONS AND RELEVANCEThis cohort study of patients with advanced melanoma treated with ICIs in clinical practice showed that their survival reached a plateau, comparable with patients participating in clinical trials. These findings can be used in daily clinical practice to guide long-term surveillance strategies and inform both physicians and patients regarding long-term treatment outcomes.

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Survival of patients with advanced metastatic melanoma: The impact of novel therapies

Cited by 148 publications

References 25 publications

Preclinical evaluation of a MAGE-A3 vaccination utilizing the oncolytic Maraba virus currently in first-in-human trials

Preclinical evaluation of a MAGE-A3 vaccination utilizing the oncolytic Maraba virus currently in first-in-human trials

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Long-Term Survival in Patients With Advanced Melanoma

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