Immune Checkpoint Blockade and Interferon-α in Melanoma

Rafique, Imran; Kirkwood, John M.; Tarhini, Ahmad A.

doi:10.1053/j.seminoncol.2015.02.012

Cited by 36 publications

(28 citation statements)

References 88 publications

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“…Encouraging results from combinations with CTLA4 or PD1/PDL1 inhibitors have been reported from multiple clinical studies, including combinations with cytotoxic chemotherapy (Antonia et al, 2014), radiotherapy (Sharabi et al, 2015;Twyman-Saint Victor et al, 2015), or small-molecule inhibitors (Prieto et al, 2016). Ongoing trials are testing the anti-PD1 antibody pembrolizumab plus IFN-a in both metastatic disease and the neoadjuvant setting (Rafique et al, 2015). In this context, the use of epigenetic modifiers to boost immunotherapy is a promising frontier for multimodal therapeutic approaches in the management of clinical melanoma, and at least seven clinical trials are underway to test combinations of immune checkpoints and epigenetic therapies in solid tumors (Weintraub, 2016).…”

Section: Discussionmentioning

confidence: 99%

Combining Type I Interferons and 5-Aza-2′-Deoxycitidine to Improve Anti-Tumor Response against Melanoma

Lucarini

Buccione

Ziccheddu

et al. 2017

Journal of Investigative Dermatology

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Resistance to IFN-I-induced antineoplastic effects has been reported in many tumors and arises, in part, from epigenetic silencing of IFN-stimulated genes by DNA methylation. We hypothesized that restoration of IFN-stimulated genes by co-administration of the demethylating drug 5-aza-2'-deoxycitidine (decitabine [DAC]) may enhance the susceptibility to IFN-I-mediated antitumoral effects in melanoma. We show that combined administration of IFN-I and DAC significantly inhibits the growth of murine and human melanoma cells, both in vitro and in vivo. Compared with controls, DAC/IFN-I-treated melanoma cells exhibited reduced cell growth, augmented apoptosis, and diminished migration. Moreover, IFN-I and DAC synergized to suppress the growth of three-dimensional human melanoma spheroids, altering tumor architecture. These direct antitumor effects correlated with induction of the IFN-stimulated gene Mx1. In vivo, DAC/IFN-I significantly reduced melanoma growth via stimulation of adaptive immunity, promoting tumor-infiltrating CD8 T cells while inhibiting the homing of immunosuppressive CD11b myeloid cells and regulatory T cells. Accordingly, exposure of human melanoma cells to DAC/IFN-I induced the recruitment of immune cells toward the tumor in a Matrigel (Corning Life Sciences, Kennebunkport, ME)-based microfluidic device. Our findings underscore a beneficial effect of DAC plus IFN-I combined treatment against melanoma through both direct and immune-mediated anti-tumor effects.

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Section: Discussionmentioning

confidence: 99%

Combining Type I Interferons and 5-Aza-2′-Deoxycitidine to Improve Anti-Tumor Response against Melanoma

Lucarini

Buccione

Ziccheddu

et al. 2017

Journal of Investigative Dermatology

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“…Type I IFNs can be critical to the innate immune recognition of a growing tumor in animal studies (48). Clinical studies have also suggested that IFNα has significant immunomodulatory and antitumor activity in metastatic melanoma and may have additive or synergistic effects in promoting tumor elimination with anti–CTLA-4 (49). …”

Section: Discussionmentioning

confidence: 99%

VEGF Neutralization Plus CTLA-4 Blockade Alters Soluble and Cellular Factors Associated with Enhancing Lymphocyte Infiltration and Humoral Recognition in Melanoma

Giobbie‐Hurder

Liao

et al. 2016

Cancer Immunology Research

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Immune recognition of tumor targets by specific cytotoxic lymphocytes is essential for the effective rejection of tumors. A phase I clinical trial of ipilimumab (an antibody that blocks CTLA-4 function) in combination with bevacizumab (an antibody that inhibits angiogenesis) in patients with metastatic melanoma found favorable clinical outcomes were associated with increased tumor endothelial activation and lymphocyte infiltration. To better understand the underlying mechanisms, we sought features and factors that changed as a function of treatment in patients. Ipilimumab plus bevacizumab (Ipi-Bev) increased tumor vascular expression of ICAM-1 and VCAM-1. Treatment also altered concentrations of many circulating cytokines and chemokines, including increases of IP-10, IL1α, TNFα, GRO, IFNα2, and IL8, with decreases in VEGF-A in most patients. IL1α and TNFα induced expression of E-selectin, ICAM-1, and VCAM-1 on melanoma tumor-associated endothelial cells (TEC) in vitro and promoted adhesion of activated T cells onto TEC. VEGF-A inhibited TNFα-induced expression of ICAM-1 and VCAM-1 and T-cell adhesion, which was blocked by bevacizumab. IP-10 promoted T-cell migration across TEC in vitro, was frequently expressed by melanoma cells, and was upregulated in a subset of tumors in treated patients. Robust upregulation of IP-10 in tumors was accompanied by increased T-cell infiltration. Ipi-Bev also augmented humoral immune responses recognizing targets in melanoma, tumor endothelial, and tumor mesenchymal stem cells. Our findings suggest that Ipi-Bev therapy augments immune recognition in the tumor microenvironment through enhancing lymphocyte infiltration and antibody responses. IL1α, TNFα, and IP-10, together with VEGF neutralization, contribute to Ipi-Bev–induced melanoma immune recognition.

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“…This has been well reviewed by Bellardelli and colleagues [57,58]. More recently, accumulative data from the clinic and preclinical studies indicate new relevance of type I IFN in tumor immunology, particularly in the context of the tumor microenvironment [59,60] and the recent development of T-cell checkpoint inhibitors [61,62].…”

Section: New Relevance Of Type I Ifn In Tumor Immunotherapymentioning

confidence: 99%

“…Promising preliminary data suggested that such combinations may improve the clinical management of advanced melanoma beyond checkpoint inhibitor monotherapy [61]. An overall response rate of 24% with durable responses and downregulation of host immune suppressor mechanisms has been reported in Phase II trials in which advanced melanoma patients were treated with a combination of IFN-α and the anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) antibody, tremelimumab [73,74].…”

Section: New Relevance Of Type I Ifn In Tumor Immunotherapymentioning

confidence: 99%

IFN-λ Cancer Immunotherapy: New Kid on the Block

et al. 2016

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Interferon-lambda (IFN-λ) is a new IFN type, related to IFN-α, that is commonly used in the clinic. However, significant side effects accompanying IFN-α treatment limit enthusiasm for IFN-α. In this review, we discuss the current landscape of IFN-α use in oncology and describe the biologic characteristics of IFN-λ. IFN-λ offers unique advantages, including a more tumor cell selective targeting, lower off-target binding and an ability to generate both innate and adaptive immune responses. IFN-λ has also demonstrated therapeutic benefit in murine cancer models. IFN-λ may be used in clinic as a single agent or in combination with other immunotherapy agents, such as immune checkpoint inhibitors. Further clinical trials will be needed to fully elucidate the potential of this novel agent in oncology.

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Immune Checkpoint Blockade and Interferon-α in Melanoma

Cited by 36 publications

References 88 publications

Combining Type I Interferons and 5-Aza-2′-Deoxycitidine to Improve Anti-Tumor Response against Melanoma

Combining Type I Interferons and 5-Aza-2′-Deoxycitidine to Improve Anti-Tumor Response against Melanoma

VEGF Neutralization Plus CTLA-4 Blockade Alters Soluble and Cellular Factors Associated with Enhancing Lymphocyte Infiltration and Humoral Recognition in Melanoma

IFN-λ Cancer Immunotherapy: New Kid on the Block

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