Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study

O’Day, Steven; Maio, Michele; Chiarion-Sileni, Vanna; Gajewski, Thomas F.; Pehamberger, Hubert; Bondarenko, Igor; Queirolo, Paola; Lundgren, Lotta; Михайлов, С. М.; Roman, L.; Verschraegen, Claire F.; Humphrey, Rachel; Ibrahim, Ramy; Pril, Veerle de; Hoos, Axel; Wolchok, Jedd D.

doi:10.1093/annonc/mdq013

Cited by 475 publications

(324 citation statements)

References 26 publications

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“…However, these modalities are still largely suboptimal and carry substantial immune toxic effects in the skin, gastrointestinal tract, and other syndromes such as uveitis or hypophysitis (31)(32)(33). This occurs because anti-CTLA4 and anti-PD1 target general immune checkpoints, which are not tumor-specific, although those caused by anti-PD1 seem to be milder (reviewed in ref.…”

Section: Discussionmentioning

confidence: 99%

Novel Immunotherapy for Malignant Melanoma with a Monoclonal Antibody That Blocks CEACAM1 Homophilic Interactions

Ortenberg

Sapir

Raz

et al. 2012

Molecular Cancer Therapeutics

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CEACAM1 (biliary glycoprotein-1, CD66a) was reported as a strong clinical predictor of poor prognosis in melanoma. We have previously identified CEACAM1 as a tumor escape mechanism from cytotoxic lymphocytes. Here, we present substantial evidence in vitro and in vivo that blocking of CEACAM1 function with a novel monoclonal antibody (MRG1) is a promising strategy for cancer immunotherapy. MRG1, a murine IgG1 monoclonal antibody, was raised against human CEACAM1. It recognizes the CEACAM1-specific N-domain with high affinity (K D $ 2 nmol/L). Furthermore, MRG1 is a potent inhibitor of CEACAM1 homophilic binding and does not induce any agonistic effect. We show using cytotoxicity assays that MRG1 renders multiple melanoma cell lines more vulnerable to T cells in a dose-dependent manner, only following antigen-restricted recognition. Accordingly, MRG1 significantly enhances the antitumor effect of adoptively transferred, melanoma-reactive human lymphocytes using human melanoma xenograft models in severe combined immunodeficient/nonobese diabetic (SCID/NOD) mice. A significant antibody-dependent cell cytotoxicity response was excluded. It is shown that MRG1 reaches the tumor and is cleared within a week. Importantly, approximately 90% of melanoma specimens are CEACAM1 þ , implying that the majority of patients with melanoma could be amenable to MRG1-based therapy. Normal human tissue microarray displays limited binding to luminal epithelial cells on some secretory ducts, which was weaker than the broad normal cell binding of other anticancer antibodies in clinical use. Importantly, MRG1 does not directly affect CEACAM1 þ cells. CEACAM1 blockade is different from other immunomodulatory approaches, as MRG1 targets inhibitory interactions between tumor cells and late effector lymphocytes, which is thus a more specific and compartmentalized immune stimulation with potentially superior safety profile.

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Section: Discussionmentioning

confidence: 99%

Novel Immunotherapy for Malignant Melanoma with a Monoclonal Antibody That Blocks CEACAM1 Homophilic Interactions

Ortenberg

Sapir

Raz

et al. 2012

Molecular Cancer Therapeutics

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“…Rare targets for autoimmunity include the joints and kidneys [14]. In Phase II studies less than 1 in 100 treated patients developed Grade 3 or 4 cough, dyspnea or pleural effusion [15]. There is only one previous report of autoimmune pulmonary toxicity related to ipilimumab administration [16].…”

Section: Discussionmentioning

confidence: 99%

Ipilimumab Associated Autoimmune Alveolitis Responding to Corticosteroids

Rao

2012

J Med Cases

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Malignant melanoma is increasing in incidence and metastatic melanoma is extremely challenging to treat, although new targeted and immunotherapeutic options for treatment are emerging. One of these is the anti CTLA4 antibody ipilimumab which releases the 'break' on endogenous anti-melanoma T-cell responses leading to improved survival. It is associated with autoimmune toxicity, typically in the liver, skin and colon. We report here the case of an ipilimumab treated patient who developed autoimmune alveolitis due to the drug, which is only very rarely reported in association with this form of immune-modulating therapy.

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“…In patients with unresectable Stage III or IV melanoma, administration of ipilimumab resulted in a 47.2% 1-year survival rate. 56 A long-term follow-up of 177 patients with metastatic melanoma treated with ipilimumab revealed an 88-month median duration of objective response, which suggests that complete remission is possible in some patients. 65 Additionally, Weber et al demonstrated that ipilimumab is considered safe for patients with metastatic melanoma in whom there was CNS involvement.…”

Section: Cytotoxic T-lymphocyte Antigen-4 Blockade With Ipilimumabmentioning

confidence: 99%

Stereotactic radiosurgery and immunotherapy for metastatic spinal melanoma

Caruso¹,

Cohen-Inbar

Bilsky

et al. 2015

FOC

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The management of metastatic spinal melanoma involves maximizing local control, preventing recurrence, and minimizing treatment-associated toxicity and spinal cord damage. Additionally, therapeutic measures should promote mechanical stability, facilitate rehabilitation, and promote quality of life. These objectives prove difficult to achieve given melanoma's elusive nature, radioresistant and chemoresistant histology, vascular character, and tendency for rapid and early metastasis. Different therapeutic modalities exist for metastatic spinal melanoma treatment, including resection (definitive, debulking, or stabilization procedures), stereotactic radiosurgery, and immunotherapeutic techniques, but no single treatment modality has proven fully effective. The authors present a conceptual overview and critique of these techniques, assessing their effectiveness, separately and combined, in the treatment of metastatic spinal melanoma. They provide an up-to-date guide for multidisciplinary treatment strategies. Protocols that incorporate specific, goal-defined surgery, immunotherapy, and stereotactic radiosurgery would be beneficial in efforts to maximize local control and minimize toxicity.

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Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study

Abstract: Ipilimumab demonstrated clinical activity with encouraging long-term survival in a previously treated advanced melanoma population.

Cited by 475 publications

References 26 publications

Novel Immunotherapy for Malignant Melanoma with a Monoclonal Antibody That Blocks CEACAM1 Homophilic Interactions

Novel Immunotherapy for Malignant Melanoma with a Monoclonal Antibody That Blocks CEACAM1 Homophilic Interactions

Ipilimumab Associated Autoimmune Alveolitis Responding to Corticosteroids

Stereotactic radiosurgery and immunotherapy for metastatic spinal melanoma

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