Pilot Trial of FANG Immunotherapy in Ewing's Sarcoma

Ghisoli, Maurizio; Barve, Minal; Schneider, Reva; Mennel, Robert G.; Lenarsky, Carl; Wallraven, Gladice; Pappen, Beena O.; LaNoue, John; Kumar, Padmasini; Nemunaitis, Derek; Roth, A; Nemunaitis, J.; Whiting, Sam; Senzer, Neil; Fletcher, Frederick A.; Nemunaitis, John

doi:10.1038/mt.2015.43

Cited by 48 publications

(34 citation statements)

References 61 publications

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“…Silencing of furin is employed to inhibit maturation of the immunosuppressive cytokine TGFβ1. Safety of the FANG vaccine and efficacy of the immune response were confirmed and benefits of treatment were suggested by phase I and II trials in patients with advanced cancers including Ewing sarcoma, hepatocellular carcinoma and ovarian cancer …”

Section: Furin Is a Tool For Cancer Cell‐specific Therapeutic Approachesmentioning

confidence: 91%

The proprotein convertase furin in tumour progression

Jaaks

Bernasconi

2017

Intl Journal of Cancer

115

113

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Proprotein convertases are proteases that have been implicated in the activation of a wide variety of proteins. These proteins are generally synthesised as precursor proteins and require limited proteolysis for conversion into their mature bioactive counterparts. Many of these proteins, including metalloproteases, growth factors and their receptors or adhesion molecules, have been shown to facilitate tumour formation and progression. Hence, this review will focus on the proprotein convertase furin and its role in cancer. The expression of furin has been confirmed in a large spectrum of cancers such as head and neck squamous cell carcinoma, breast cancer and rhabdomyosarcoma. Functional studies modulating furin activity uncovered its importance for the processing of many cancer-related substrates and strongly indicate that high furin activity promotes the malignant phenotype of cancer cells. In this review, we summarise the expression and function of furin in different cancer types, discuss its role in processing cancer-related proproteins and give examples of potential therapeutic approaches that take advantage of the proteolytic activity of furin in cancer cells.

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Section: Furin Is a Tool For Cancer Cell‐specific Therapeutic Approachesmentioning

confidence: 91%

The proprotein convertase furin in tumour progression

Jaaks

Bernasconi

2017

Intl Journal of Cancer

115

113

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“…Elevated levels of GMCSF also resulted in increased activation of bone marrow-derived dendritic cells, facilitating the elimination of tumor cells. In a phase I trial, Nemunaitis et al [84–86] produced vaccines from a wide variety of tumor sources, including, small cell lung cancer, breast cancer, colon cancer, liposarcoma, and ovarian cancer [84] This approach is still underway, but anticipates positive outcomes in decreasing the relapse in patients diagnosed with hepatocellular carcinoma [84], metastatic advanced Ewing’s sarcoma [87, 88], advanced stage ovarian cancer [89]. …”

Section: Furin Silencing: Strengthening the Immune Responsementioning

confidence: 99%

Proprotein convertase inhibition: Paralyzing the cell’s master switches

Klein‐Szanto

Bassi

2017

Biochemical Pharmacology

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Proprotein convertases are serine proteases responsible for the cleavage and subsequent activation of protein substrates, many of them relevant for the development of an ample variety of diseases. Seven of the PCs, including furin and PACE4, recognize and hydrolyze the C-terminal end of the general sequence RXRR/KXR, whereas PCSK-9 recognizes a series of non-basic amino acids. In some systems, PC-mediated substrate activation results in the development of pathological processes, such as cancer, endocrinopathies, and cardiovascular and infectious diseases. After establishing PCs as relevant contributors to disease processes, research efforts were directed towards the development of inhibition strategies, including small and large molecules, anti-sense therapies, and antibody-based therapies. Most of these inhibitors mimic the consensus sequence of PCs, blocking the active site in a competitive manner. The most promising inhibitors were designed as bioengineered proteins; however, some non-protein and peptidomimetic agents has also proved to be effective. These efforts led to the design of pre-clinical studies and clinical trials utilizing inhibitors to PCs. Although the initial studies were performed using non-selective PCs inhibitors, such as CMK, the search for more specific, and compartmentalized selective inhibitors resulted in specific activities ascribed to some, but not all of the PCs. For instance, PACE4 inhibitors were effective in decreasing prostate cancer cell proliferation, and neovascularization. Decreased metastatic ovarian cancer utilizing furin inhibitors represents one of the major endeavors, currently in a phase II trial stage. Antibodies targeting PCSK-9 decreased significantly the levels of HDL-cholesterol, in a phase III trial. The study of Proprotein convertases has reached a stage of maturity. New strategies based on the alteration of their activity at the cellular and clinical level represent a promising experimental pharmacology field. The development of allosteric inhibitors, or specific agents directed against individual PCs is one of the challenges to be unraveled in the future.

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“…Recent data demonstrated a 75% OS at one year with FANG immunotherapy in adolescent patients with Ewing’s sarcoma. The treatment was well tolerated with a favorable OS[41]. A seemingly interesting phase I trial designed for the treatment of pediatric patients with relapsed high-risk Ewing sarcoma, osteogenic sarcoma, rhabdomyosarcoma, synovial sarcoma, and neuroblastoma is using a combination of Decitabine demethylating agent and a cancer vaccine composed of dendritic cells pulsed with overlapping peptides of NY-ESO-1, MAGE-A1, and MAGE-A3 (NCT0 1241162).…”

Section: Immunotherapeutic Modalities Evaluated In Sarcomasmentioning

confidence: 99%

Immunotherapies in sarcoma: Updates and future perspectives

Ghosn

Rassy

Kourié

2017

WJCO

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Sarcomas are malignant tumors that are characterized by a wide diversity of subtypes with various cytogenetic profiles. Despite major treatment breakthroughs, standard treatment modalities combining chemotherapy, radiotherapy, and surgery failed to improve overall survival. Therefore, high expectations are foreseen with immunotherapy upon its maturation and better understanding of its mechanism of action. This paper presents a targeted review of the published data and ongoing clinical trials in immunotherapies of sarcomas, mainly adoptive cell therapies, cancer vaccines and immune checkpoint inhibitors.

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Pilot Trial of FANG Immunotherapy in Ewing's Sarcoma

Cited by 48 publications

References 61 publications

The proprotein convertase furin in tumour progression

The proprotein convertase furin in tumour progression

Proprotein convertase inhibition: Paralyzing the cell’s master switches

Immunotherapies in sarcoma: Updates and future perspectives

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