Enhanced Survival Associated with Vitiligo Expression during Maintenance Biotherapy for Metastatic Melanoma

Boasberg, Peter D.; Hoon, Dave S.B.; Piro, Lawrence D.; Martin, Mike; Fujimoto, Akhide; Kristedja, Timothy S.; Bhachu, Sandeep; Ye, Xing; Deck, Regina; O’Day, Steven

doi:10.1038/sj.jid.5700545

Cited by 93 publications

(80 citation statements)

References 23 publications

(36 reference statements)

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“…38 There are reports of vitiligo related with better survival in melanoma patients treated with biotherapies like interferon alfa -2b 39 or IL-2+ GM-CSF. 40 Rosenberg has previously reported vitiligo during treatment of melanoma patients with Il-2, but it was not observed in metastatic renal cell carcinoma 41 nor events of this type were reported by Kirkwood and colleagues with the GM2-KLH-QS21 (GMK) vaccine. 42 Vitiligo has also been observed in a clinical trial with an autologous GM-GSF transduced tumor cell vaccine.…”

Section: Discussionmentioning

confidence: 99%

Heterophilic NeuGcGM3 ganglioside cancer vaccine in advanced melanoma patients: Results of a phase Ib/IIa study

Osorio¹,

Gracia²,

Rodríguez³

et al. 2008

Cancer Biology & Therapy

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NeuGcGM3 ganglioside is especially attractive because it is expressed on melanoma cells but it is minimally or not expressed at all on most normal human tissues.A Phase Ib/IIa clinical trial was carried out in patients with advanced cutaneous and ocular malignant melanomas, to evaluate immunogenicity and toxicity of an intramuscularly administered cancer vaccine and composed by NeuGcGM3 in a proteoliposome of Neisseria meningitides with Montanide ISA 51 as adjuvant.Twenty two patients were included, twelve at dose level of 200 μg and 10 at 400 μg. The first five doses were administered every other week and then monthly until 9 doses. 12 patients received additional immunizations.Vaccination induced specific anti-NeuGcGM3 IgM, IgG and IgA antibodies responses. Titers of IgM were greater for the highest vaccine doses. Vaccination also elicited DTH response in 45.5% of patients in the lower doses and 77.8% in the higher doses. Toxicities were mostly grade 1 or 2, according CTC-NCI criteria. Interestingly, 3 patients developed vitiligo at the lower dose (none in the highest dose) although the nominal antigen NeuGcGM3 is not present in melanocytes. Survival analysis was not the goal of this Phase I trial; nevertheless, the fact that seven patients are alive for more than 2 years after inclusion is noteworthy.Safety and immunogenicity with NeuGcGM3 vaccine treatment in advanced melanoma patients were established. The prognostic value of autoimmunity and the possibilities of dissociating antitumor immunity from autoimmunity deserve further research.

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Section: Discussionmentioning

confidence: 99%

Heterophilic NeuGcGM3 ganglioside cancer vaccine in advanced melanoma patients: Results of a phase Ib/IIa study

Osorio¹,

Gracia²,

Rodríguez³

et al. 2008

Cancer Biology & Therapy

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“…Therefore, it is possible that areas of vitiligo could hide a primary melanoma in some patients. Noteworthy, in melanoma patients it has been shown that vitiligo has a positive prognostic role [26,27].…”

Section: Discussionmentioning

confidence: 99%

Melanoma of unknown primary site: a 33-year experience at the Turin Melanoma Centre

et al. 2010

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This is an author version of the contribution published on:Questa è la versione dell'autore dell'opera: AbstractUnknown melanoma occurs as metastasis to skin, nodes or viscera, without a detectable cutaneous primary tumour. We reviewed our database of 4881 melanoma patients, diagnosed and followed up prospectively for a 33-year period. We identified 93 cases of metastatic melanoma without evidence of primary; however, five of these patients had a history of a previous excision of a presumed benign lesion without histological examination and were excluded from analyses. At diagnosis, metastases were cutaneous in 35.3% of cases, nodal in 43.2% and visceral in 17% of cases; in 4.5% of patients, both skin and nodes were involved. In all cases, clinical inspection and staging procedures performed at diagnosis of metastatic disease failed to identify a primary melanoma. In 11 cases (11.8%), extensively regressed pigmented lesions (without evidence of melanoma cells at the histological examination) were documented; moreover, we identified in our series five patients with unknown primary affected by vitiligo. The 5-year and 10-year overall survival rates were 49.6 and 41.4%, respectively, with a median of 4.9 years. The 5-year and 10-year time to progression rates were 39.4 and 32.3%, respectively, with a median of 2.3 years. Survival was longer in females and showed significant differences among patients with skin, lymph node or visceral involvement at diagnosis. In melanoma patients, unknown primary represents a not so rare event, with an uncertain origin. We confirmed the relatively good prognosis of unknown primary melanoma patients, a fact that has to be taken into consideration for their management.

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“…Anecdotal spontaneous remissions, thought to be immune mediated, have been described by multiple investigators, and the appearance of vitiligo, an autoimmune response to melanocytes, is of good prognostic significance in patients with MM (10)(11)(12). Therapeutic strategies to augment the immune response, e.g., treatment with interferon and IL-2, demonstrate efficacy in certain clinical settings (5,6,8,13), and anti-CTLA4 antibodies, which enhance T cell activation, have been reported to possess promising single-agent activity in early clinical trials (14,15).…”

Section: Introductionmentioning

confidence: 99%

CD200 is induced by ERK and is a potential therapeutic target in melanoma

Petermann¹,

Rozenberg²,

Zedek³

et al. 2007

J. Clin. Invest.

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Immune-mediated antitumor responses occur in patients with metastatic melanoma (MM), and therapies designed to augment such responses are clinically beneficial. Despite the immunogenicity of melanoma, immunomodulatory therapies fail in the majority of patients with MM. An inability of DCs to sufficiently activate effector cells may, in part, underlie this failure of the antitumor response seen in most patients. In this work, we show that mutation of N-RAS or B-RAF, signature genetic lesions present in most MMs, potently induced the expression of cell-surface CD200, a repressor of DC function. Employing 2 independent, genomewide microarray analyses, we identified CD200 as a highly dynamic, downstream target of RAS/RAF/MEK/ ERK activation in melanoma. CD200 protein was similarly overexpressed in human melanoma cell lines and primary tumors. CD200 mRNA expression correlated with progression and was higher in melanoma than in other solid tumors or acute leukemia. Melanoma cell lines expressing endogenous CD200 repressed primary T cell activation by DCs, while knockdown of CD200 by shRNA abrogated this immunosuppressive effect. These data indicate that in addition to its effects on growth, survival, and motility, ERK activation in MM attenuates a host antitumor immune response, implicating CD200 and its interaction with the CD200 receptor as a potential therapeutic target for MM. IntroductionMelanoma, the most lethal form of skin cancer, has increased in incidence and mortality over the last 3 decades. Metastatic disease that is not amenable to surgery is generally refractory to therapy and, therefore, ultimately lethal. Standard chemotherapy typically produces response rates on the order of 10%, and radiotherapy plays only a limited role in disease palliation. Despite these sobering facts, some optimism has been engendered by recent advances in our molecular understanding of the disease, particularly the finding that approximately 80% of metastatic melanomas (MMs) harbor mutually exclusive activating mutations of either N-RAS or B-RAF (reviewed in ref. 1). These lesions lead to activation of the RAF/MEK/ERK/MAPK pathway, which in turn controls the transcription of hundreds if not thousands of genes related to cellular proliferation, survival, and motility (2). Although work in murine models and pharmacological approaches have suggested that RAS-RAF activation is required not only for tumor formation, but also for tumor maintenance (3, 4), the cell-biological effects of ERK activation that are most relevant for tumor formation and progression have not been fully established.Arguably, the evidence for a clinically valuable anticancer immune response is stronger in MM than any other human malignancy (reviewed in refs. 5-8). Functional T cells restricted to melanoma antigens can be readily recovered from patients with MM, establishing the tumor's immunogenicity in humans (5-7, 9).

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Enhanced Survival Associated with Vitiligo Expression during Maintenance Biotherapy for Metastatic Melanoma

Cited by 93 publications

References 23 publications

Heterophilic NeuGcGM3 ganglioside cancer vaccine in advanced melanoma patients: Results of a phase Ib/IIa study

Heterophilic NeuGcGM3 ganglioside cancer vaccine in advanced melanoma patients: Results of a phase Ib/IIa study

Melanoma of unknown primary site: a 33-year experience at the Turin Melanoma Centre

CD200 is induced by ERK and is a potential therapeutic target in melanoma

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