Immunotherapy for metastatic melanoma

Zito, Christopher R.; Kluger, Harriet M.

doi:10.1002/jcb.23402

Cited by 16 publications

(23 citation statements)

References 71 publications

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“…Another strategy to treat melanoma that has received significant attention relies on immunotherapy 6 . Most recently, the blockade if immune checkpoints with the monoclonal antibody ipilimumab has been approved by the Food and Drug Administration (FDA) for the treatment of metastatic melanoma patients 7 .…”

Section: Introductionmentioning

confidence: 99%

“…Most recently, the blockade if immune checkpoints with the monoclonal antibody ipilimumab has been approved by the Food and Drug Administration (FDA) for the treatment of metastatic melanoma patients 7 . Other immunotherapeutic approaches being used or evaluated to treat melanoma include the use of cytokines including Type I interferons and interleukin (IL)-2, vaccines and adoptive T-cell transfer 6 , 8 . Various combinations of these strategies have also been evaluated and have shown encouraging results 9 .…”

Section: Introductionmentioning

confidence: 99%

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Vemurafenib enhances MHC induction inBRAF^V600Ehomozygous melanoma cells

2013

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To optimally integrate targeted kinase inhibitors and immunotherapies in the treatment of melanoma, it will be critical to understand how BRAFV600E mutational status and BRAFV600E inhibition influence the expression of genes that govern antitumor immune responses. Because major histocompatibility complex (MHC) molecules are critical for interactions between tumor cells and lymphocytes, we investigated the impact of BRAFV600E-selective inhibitors on the expression of MHC molecules. We found that the treatment of A375 melanoma cells with vemurafenib enhances the induction of MHC Class I and Class II molecules by interferon γ and IFNα2b. Consistent with these findings, we observed that the forced overexpression of BRAFV600E has the opposite effect and can repress the baseline expression of MHC Class I molecules in A375 cells. Further studies utilizing eight other melanoma cell lines revealed that the vemurafenib-mediated enhancement of MHC induction by IFNγ only occurs in the context of homozygous, but not heterozygous, BRAFV600E mutation. These findings suggest that BRAFV600Eactivity directly influences the expression of MHC molecules and the response to Type I and Type II IFNs. Furthermore, our data suggest that the effect of vemurafenib on the expression of immune system-relevant genes may depend on the zygosity of the BRAFV600E mutation, which is not routinely assessed in melanoma patients.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Vemurafenib enhances MHC induction inBRAF^V600Ehomozygous melanoma cells

2013

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“…IL-2, the first cytokine permitted for use in patients with metastatic melanoma, has elicited sustained responses in a small subgroup of patients, providing hope that immunotherapy might be useful for this disease (3). Ipilimumab, a monoclonal antibody to CTLA-4, also has recently been approved by the FDA (37). The discovery of the BRAF mutation, following a genomewide analysis, revealed that 80% of BRAF mutations are V600E and this mutation is predominant in melanoma (5).…”

Section: Discussionmentioning

confidence: 99%

Gossypin as a Novel Selective Dual Inhibitor of v-raf Murine Sarcoma Viral Oncogene Homolog B1 and Cyclin-Dependent Kinase 4 for Melanoma

Bhaskaran

Dileep

Deepa

et al. 2013

Molecular Cancer Therapeutics

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Mutation in the BRAF gene (BRAFV600E) exists in nearly 70% of human melanomas. Targeted therapy against BRAFV600E kinase using a recently identified RAF-selective inhibitor, PLX4032, has been successful in early clinical trials. However, in patients with the normal BRAF allele (wild-type), PLX4032 is protumorigenic. This conundrum identifies the unmet need for novel therapeutic agents to target BRAFV600E kinase that are not counterproductive. We have identified gossypin, a pentahydroxy flavone, as a potent antimelanoma agent. Gossypin inhibited human melanoma cell proliferation, in vitro, in melanoma cell lines that harbor both BRAFV600E kinase and cyclin-dependent kinase 4 (CDK4) as well as in cells with BRAF wild-type allele. Gossypin inhibited kinase activities of BRAFV600E and CDK4, in vitro, possibly through direct binding of gossypin with these kinases, as confirmed by molecular docking studies. For cells harboring the BRAFV600E, gossypin inhibited cell proliferation through abrogation of the MEK-ERK-cyclin D1 pathway and in cells with BRAF wild-type allele, through attenuation of the retinoblastoma-cyclin D1 pathway. Furthermore, gossypin significantly inhibited melanoma growth in an organotypic three-dimensional skin culture mimicking human skin. Gossypin (10 and 100 mg/kg) treatment for 10 days in human melanoma (A375) cell xenograft tumors harboring BRAFV600E significantly reduced tumor volume through induction of apoptosis and increased survival rate in mice, and the effect was significantly superior to that of PLX4032 (10 mg/kg) or roscovitine 10 mg/kg. In summary, this study identified gossypin as a novel agent with dual inhibitory effects for BRAFV600E kinase and CDK4 for treatment of melanoma.

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“…Additional immune-modulatory molecules that have gained scientific attention and are now under clinical development are OX40 (CD134), CD40, GITR, and 4-1BB (CD137) (http://www.clinicaltrials.gov/) (Table 1, also reviewed in [85]).…”

Section: Anti-melanoma Immunotherapiesmentioning

confidence: 99%

Novel Anti-Melanoma Immunotherapies: Disarming Tumor Escape Mechanisms

Sapoznik

Hammer²,

Ortenberg

et al. 2012

Clinical and Developmental Immunology

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The immune system fights cancer and sometimes temporarily eliminates it or reaches an equilibrium stage of tumor growth. However, continuous immunological pressure also selects poorly immunogenic tumor variants that eventually escape the immune control system. Here, we focus on metastatic melanoma, a highly immunogenic tumor, and on anti-melanoma immunotherapies, which recently, especially following the FDA approval of Ipilimumab, gained interest from drug development companies. We describe new immunomodulatory approaches currently in the development pipeline, focus on the novel CEACAM1 immune checkpoint, and compare its potential to the extensively described targets, CTLA4 and PD1. This paper combines multi-disciplinary approaches and describes anti-melanoma immunotherapies from molecular, medical, and business angles.

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Immunotherapy for metastatic melanoma

Cited by 16 publications

References 71 publications

Vemurafenib enhances MHC induction inBRAF^V600Ehomozygous melanoma cells

Vemurafenib enhances MHC induction inBRAF^V600Ehomozygous melanoma cells

Gossypin as a Novel Selective Dual Inhibitor of v-raf Murine Sarcoma Viral Oncogene Homolog B1 and Cyclin-Dependent Kinase 4 for Melanoma

Novel Anti-Melanoma Immunotherapies: Disarming Tumor Escape Mechanisms

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Immunotherapy for metastatic melanoma

Cited by 16 publications

References 71 publications

Vemurafenib enhances MHC induction inBRAFV600Ehomozygous melanoma cells

Vemurafenib enhances MHC induction inBRAFV600Ehomozygous melanoma cells

Gossypin as a Novel Selective Dual Inhibitor of v-raf Murine Sarcoma Viral Oncogene Homolog B1 and Cyclin-Dependent Kinase 4 for Melanoma

Novel Anti-Melanoma Immunotherapies: Disarming Tumor Escape Mechanisms

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Vemurafenib enhances MHC induction inBRAF^V600Ehomozygous melanoma cells

Vemurafenib enhances MHC induction inBRAF^V600Ehomozygous melanoma cells