Survival follow-up and ipilimumab retreatment of patients with advanced melanoma who received ipilimumab in prior phase II studies

Lebbe, Célèste; Weber, Jeffrey S.; Maio, Michele; Neyns, Bart; Harmankaya, Kaan; Hamid, Omid; O’Day, Steven; Konto, Cyril; Cykowski, L.; McHenry, M. Brent; Wolchok, Jedd D.

doi:10.1093/annonc/mdu441

Cited by 128 publications

(95 citation statements)

References 22 publications

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“…Some evidence supports the former possibility: a trial immunotherapy consisting of ipilimumab (in combination with irradiated, GM-CSF-expressing, autologous tumor cells) provokes a humoral response resulting in the elicitation of clinically relevant anti-MIF autoantibodies (12). Given that the targeting of CTLA-4 with ipilimumab is efficacious in patients with metastatic melanoma (45,46), it is possible that combinatorial targeting of adaptive immune suppressive mechanisms (anti-CTLA-4) and innate immune suppressive mechanisms (anti-MIF) may provide synergistic clinical responses in patients with advanced stage melanoma.…”

Section: Discussionmentioning

confidence: 99%

MIF Is Necessary for Late-Stage Melanoma Patient MDSC Immune Suppression and Differentiation

Yaddanapudi

Rendon

Lamont

et al. 2016

Cancer Immunology Research

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Highly aggressive cancers “entrain” innate and adaptive immune cells to suppress anti-tumor lymphocyte responses. Circulating myeloid-derived suppressor cells (MDSCs) constitute the bulk of monocytic immunosuppressive activity in late stage melanoma patients. Previous studies revealed that monocyte-derived macrophage migration inhibitory factor (MIF) is necessary for the immune suppressive function of tumor-associated macrophages (TAMs) and MDSCs in mouse models of melanoma. In the current study we sought to determine whether MIF contributes to human melanoma MDSC induction and T-cell immunosuppression using melanoma patient-derived MDSCs and an ex vivo co-culture model of human melanoma-induced MDSC. We now report that circulating MDSCs isolated from late stage melanoma patients are reliant upon MIF for suppression of antigen-independent T-cell activation and that MIF is necessary for maximal reactive oxygen species (ROS) generation in these cells. Moreover, inhibition of MIF results in a functional reversion from immune suppressive MDSC to an immunostimulatory dendritic cell (DC)-like phenotype that is at least partly due to reductions in MDSC prostaglandin E2 (PGE2). These findings indicate that monocyte-derived MIF is centrally involved in human monocytic MDSC induction/immune suppressive function and that therapeutic targeting of MIF may provide a novel means of inducing anti-tumor DC responses in late stage melanoma patients.

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Section: Discussionmentioning

confidence: 99%

MIF Is Necessary for Late-Stage Melanoma Patient MDSC Immune Suppression and Differentiation

Yaddanapudi

Rendon

Lamont

et al. 2016

Cancer Immunology Research

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“…Ipilimumab, an anticytotoxic T-lymphocyte antigen (CTLA)-4 monoclonal antibody, improved overall survival compared with chemotherapy for advanced melanoma with 22% of treated patients alive at 3-year follow-up (1,2). Additional immune checkpoint inhibitors, pembrolizumab and nivolumab, targeting programmed cell death-1 (PD-1) were approved by the FDA in 2014, and these inhibitors also unleashed the suppressed antitumor immune responses (3,4).…”

Section: Introductionmentioning

confidence: 99%

Ipilimumab-Induced Encephalopathy with a Reversible Splenial Lesion

Conry

Sullivan

Nabors

2015

Cancer Immunology Research

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Ipilimumab, an anticytotoxic T-lymphocyte antigen (CTLA)-4 monoclonal antibody, is a first-line therapy for stage IV melanoma. Although high-grade immune-related adverse events occur in 25% of patients receiving ipilimumab, serious neurologic toxicity, primarily consisting of transient sensory and motor neuropathies, affects less than 1% of patients. We present a case report of a patient with melanoma who received highdose ipilimumab at 10 mg/kg as first-line therapy for metastatic disease. After the third dose, the patient developed "mild" encephalopathy with a reversible splenial lesion (MERS) of the corpus callosum by MRI and neurogenic bladder, two novel immune-related adverse events during checkpoint inhibition. In addition to headache, delirium, and altered consciousness commonly seen with MERS, the patient also developed tremor, gait instability, paresthesias, and neurogenic bladder. The latter two symptoms were thought to represent sensory and autonomic neuropathies, respectively. The syndrome gradually resolved following intravenous methylprednisolone at 2 mg/kg divided twice daily for 5 days and a slow taper of oral prednisone over 8 weeks. Cancer Immunol Res; 3(6); 598-601. Ó2015 AACR.

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“…Elucidation of the cellular and molecular mechanisms underlying the activating and suppressive immunological checkpoints has led to much more promising results [4,5]. Ipilimumab is a fully humanised monoclonal anti-Cytotoxic T-Lymphocyte Antigen 4 antibody that demonstrated a significant improvement of MM patient survival [6], with 5-year survival rates up to 16.5% and 17.0% in pre-treated and treatment-naïve patients, respectively, who were administered with ipilimumab 3 mg/kg q3w in phase II clinical trials [7,8]. However, treatment with ipilimumab may be associated with severe immunological toxicity, usually according to a time pattern that presents consistent risk of delayed adverse events [9].…”

Section: Introductionmentioning

confidence: 99%

Personalised medicine: Development and external validation of a prognostic model for metastatic melanoma patients treated with ipilimumab

Valpione¹,

Martinoli²,

Fava³

et al. 2015

European Journal of Cancer

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Survival follow-up and ipilimumab retreatment of patients with advanced melanoma who received ipilimumab in prior phase II studies

Cited by 128 publications

References 22 publications

MIF Is Necessary for Late-Stage Melanoma Patient MDSC Immune Suppression and Differentiation

MIF Is Necessary for Late-Stage Melanoma Patient MDSC Immune Suppression and Differentiation

Ipilimumab-Induced Encephalopathy with a Reversible Splenial Lesion

Personalised medicine: Development and external validation of a prognostic model for metastatic melanoma patients treated with ipilimumab

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