Ipilimumab

Cameron, Fiona; Whiteside, Glenn; Perry, Caroline

doi:10.2165/11594010-000000000-00000

Cited by 177 publications

(86 citation statements)

References 3 publications

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“…This including vemurafenib (a B-Raf enzyme inhibitor also known as PLX4032) [41] and ipilimumab (a fully human antibody that binds to cytotoxic T lymphocyte-associated inhibitor, which may in turn augment T-cell responses to melanoma cells) [42]. B-Raf knockdown leads to apoptosis in the melanoma cell line A375 [43], however it did not come up as the best option on the basis of our preliminary in vitro studies (see under Results).…”

Section: Discussionmentioning

confidence: 99%

Glutathione and Bcl-2 targeting facilitates elimination by chemoradiotherapy of human A375 melanoma xenografts overexpressing bcl-xl, bcl-2, and mcl-1

et al. 2012

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BackgroundBcl-2 is believed to contribute to melanoma chemoresistance. However, expression of Bcl-2 proteins may be different among melanomas. Thus correlations among expression of Bcl-2-related proteins and in vivo melanoma progression, and resistance to combination therapies, was investigated.MethodsHuman A375 melanoma was injected s.c. into immunodeficient nude mice. Protein expression was studied in tumor samples obtained by laser microdisection. Transfection of siRNA or ectopic overexpression were applied to manipulate proteins which are up- or down-regulated, preferentially, during melanoma progression. Anti-bcl-2 antisense oligonucleotides and chemoradiotherapy (glutathione-depleting agents, paclitaxel protein-binding particles, daunorubicin, X rays) were administered in combination.ResultsIn vivo A375 cells down-regulated pro-apoptotic bax expression; and up-regulated anti-apoptotic bcl-2, bcl-xl, and mcl-1, however only Bcl-2 appeared critical for long-term tumor cell survival and progression in vivo. Reduction of Bcl-2, combined with partial therapies, decreased melanoma growth. But only Bcl-2 targeting plus the full combination of chemoradiotherapy eradicated A375 melanoma, and led to long-term survival (> 120 days) without recurrence in 80% of mice. Tumor regression was not due to immune stimulation. Hematology and clinical chemistry data were within accepted clinical toxicities.ConclusionStrategies to target Bcl-2, may increase the effectiveness of antitumor therapies against melanomas overexpressing Bcl-2 and likely other Bcl-2-related antiapoptotic proteins.

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Section: Discussionmentioning

confidence: 99%

Glutathione and Bcl-2 targeting facilitates elimination by chemoradiotherapy of human A375 melanoma xenografts overexpressing bcl-xl, bcl-2, and mcl-1

et al. 2012

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“…The first anti-CTLA4 human monoclonal antibody (mAb), ipilimumab, was approved in 2011 by the FDA for use in metastatic melanoma (12). Following activity in phase II clinical trials, success for ipilimumab was reported in a large phase III clinical trial involving treatment of 676 patients with metastatic melanoma, who had undergone previous failed treatment (13).…”

Section: Negative Checkpoint Regulators New and Oldmentioning

confidence: 99%

VISTA Is a Novel Broad-Spectrum Negative Checkpoint Regulator for Cancer Immunotherapy

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Sempere

Broughton³

et al. 2014

Cancer Immunology Research

196

154

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In the past few years, the field of cancer immunotherapy has made great progress and is finally starting to change the way cancer is treated. We are now learning that multiple negative checkpoint regulators (NCR) restrict the ability of T-cell responses to effectively attack tumors. Releasing these brakes through antibody blockade, first with anti-CTLA4 and now followed by anti-PD1 and anti-PDL1, has emerged as an exciting strategy for cancer treatment. More recently, a new NCR has surfaced called V-domain immunoglobulin (Ig)-containing suppressor of T-cell activation (VISTA). This NCR is predominantly expressed on hematopoietic cells, and in multiple murine cancer models is found at particularly high levels on myeloid cells that infiltrated the tumors. Preclinical studies with VISTA blockade have shown promising improvement in antitumor T-cell responses, leading to impeded tumor growth and improved survival. Clinical trials support combined anti-PD1 and anti-CTLA4 as safe and effective against late-stage melanoma. In the future, treatment may involve combination therapy to target the multiple cell types and stages at which NCRs, including VISTA, act during adaptive immune responses.

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“…Each MEDI1873 monomer comprises three distinct domains (Fig. 1A): 1 a human immunoglobulin G1 (IgG1) fragment crystallizable (Fc) domain, 2 an isoleucine zipper trimerization domain from human coronin 1A, 3 and the hGITRL extracellular domain (ECD), with a point mutation (N161D) that eliminates the sole occupied glycosylation site. We demonstrate that MEDI1873 can be purified to homogeneity and is a significantly more potent agonist of hGITR than a monoclonal antibody.…”

Section: Introductionmentioning

confidence: 99%

MEDI1873, a potent, stabilized hexameric agonist of human GITR with regulatory T-cell targeting potential

et al. 2017

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Glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) is part of a system of signals involved in controlling T-cell activation. Targeting and agonizing GITR in mice promotes antitumor immunity by enhancing the function of effector T cells and inhibiting regulatory T cells. Here, we describe MEDI1873, a novel hexameric human GITR agonist comprising an IgG1 Fc domain, a coronin 1A trimerization domain and the human GITRL extracellular domain (ECD). MEDI1873 was optimized through systematic testing of different trimerization domains, aglycosylation of the GITRL ECD and comparison of different Fc isotypes. MEDI1873 exhibits oligomeric heterogeneity and superiority to an anti-GITR antibody with respect to evoking robust GITR agonism, T-cell activation and clustering of Fc gamma receptors. Further, it recapitulates, in vitro, several aspects of GITR targeting described in mice, including modulation of regulatory T-cell suppression and the ability to increase the CD8+:CD4+ T-cell ratio via antibody-dependent T-cell cytotoxicity. To support translation into a therapeutic setting, we demonstrate that MEDI1873 is a potent T-cell agonist in vivo in non-human primates, inducing marked enhancement of humoral and T-cell proliferative responses against protein antigen, and demonstrate the presence of GITR- and FoxP3-expressing infiltrating lymphocytes in a range of human tumors. Overall our data provide compelling evidence that MEDI1873 is a novel, potent GITR agonist with the ability to modulate T-cell responses, and suggest that previously described GITR biology in mice may translate to the human setting, reinforcing the potential of targeting the GITR pathway as a therapeutic approach to cancer.

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Ipilimumab

Cited by 177 publications

References 3 publications

Glutathione and Bcl-2 targeting facilitates elimination by chemoradiotherapy of human A375 melanoma xenografts overexpressing bcl-xl, bcl-2, and mcl-1

Glutathione and Bcl-2 targeting facilitates elimination by chemoradiotherapy of human A375 melanoma xenografts overexpressing bcl-xl, bcl-2, and mcl-1

VISTA Is a Novel Broad-Spectrum Negative Checkpoint Regulator for Cancer Immunotherapy

MEDI1873, a potent, stabilized hexameric agonist of human GITR with regulatory T-cell targeting potential

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