A phase I study of zoledronic acid and low‐dose cyclophosphamide in recurrent/refractory neuroblastoma: A new approaches to neuroblastoma therapy (NANT) study

Russell, Heidi V.; Groshen, Susan; Ara, Tasnim; DeClerck, Yves A.; Hawkins, Randy; Jackson, Hollie A.; Daldrup-Link, Heike E.; Marachelian, Araz; Skerjanec, Andrej; Park, Julie R.; Katzenstein, Howard M.; Matthay, Katherine K.; Blaney, Susan M.; Villablanca, Judith G.

doi:10.1002/pbc.22821

Cited by 40 publications

(47 citation statements)

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“…The data (Figure 6B) demonstrated an increase in pSTAT3 activation in the presence of 10 ng/mL of sIL-6R and above but not at lower concentrations (0.1 and 1.0 ng/mL). These sIL-6R concentrations are found the blood of cancer patients (35). Because neuroblastoma cells do not produce sIL-6R and are thus dependent of a paracrine source (16), we examined whether it was produced by normal cells in the tumor microenvironment.…”

Section: Resultsmentioning

confidence: 91%

“…To test this hypothesis, we examined whether the addition of sIL-6R at a concentration of 25 ng/mL, which is within the range of the levels detected in the blood of patients with neuroblastoma (10–90 ng/mL; Ref. 34, 35), would result in STAT3 activation in the presence of concentrations of IL-6 in the (0.1 to 10) ng/mL range. These experiments demonstrated that when IL-6 was used alone, a concentration of 10 ng/mL was necessary to activate STAT3 whereas when used in combination with sIL-6R (25 ng/mL), a concentration of 0.1 ng/mL of IL-6 was sufficient for STAT3 activation (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Critical Role of STAT3 in IL-6–Mediated Drug Resistance in Human Neuroblastoma

Ara

Nakata

Sheard³

et al. 2013

Cancer Research

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Drug resistance is a major cause of treatment failure in cancer. Here we have evaluated the role of STAT3 in environment-mediated drug resistance (EMDR) in human neuroblastoma. We determined that STAT3 was not constitutively active in most neuroblastoma cell lines but was rapidly activated upon treatment with interleukin-6 (IL-6) alone and in combination with the soluble IL-6 receptor (sIL-6R). Treatment of neuroblastoma cells with IL-6 protected them from drug-induced apoptosis in a STAT3-dependent manner because the protective effect of IL-6 was abrogated in the presence of a STAT3 inhibitor and upon STAT3 knockdown. STAT3 was necessary for the upregulation of several survival factors such as survivin (BIRC5) and Bcl-xL (BCL2L1) when cells were exposed to IL-6. Importantly, IL-6-mediated STAT3 activation was enhanced by sIL-6R produced by human monocytes, pointing to an important function of monocytes in promoting IL-6-mediated EMDR. Our data also point to the presence of reciprocal activation of STAT3 between tumor cells and bone marrow stromal cells including not only monocytes but also Treg cells and non-myeloid stromal cells. Thus, the data identify an IL-6/sIL-6R/STAT3 interactive pathway between neuroblastoma cells and their microenvironment that contributes to drug resistance.

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Section: Resultsmentioning

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Critical Role of STAT3 in IL-6–Mediated Drug Resistance in Human Neuroblastoma

Ara

Nakata

Sheard³

et al. 2013

Cancer Research

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116

114

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“…Targeting osteoclasts with bisphosphonates like zoledronic acid has been tested in patients with bone metastasis and the results of a Phase I trial completed by the New Advances in Neuroblastoma Therapy (NANT) consortium demonstrated the safety and efficacy of zoledronic acid [142]. This agent is now tested with cyclophosphamide in a Phase I clinical trial by Baylor College of Medicine (NCT00206388) and in combination with Interleukin-2 in refractory neuroblastoma by University of Alabama at Birmingham (NCT01404702).…”

Section: Therapeutic Considerationmentioning

confidence: 99%

More than the genes, the tumor microenvironment in neuroblastoma

et al. 2016

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Neuroblastoma is the second most common solid tumor in children. Since the seminal discovery of the role of amplification of the MYCN oncogene in the pathogenesis of neuroblastoma in the 1980s, much focus has been on the contribution of genetic alterations in the progression of this cancer. However it is now clear that not only genetic events play a role but that the tumor microenvironment (TME) substantially contributes to the biology of neuroblastoma. In this article, we present a comprehensive review of the literature on the contribution of the TME to the ten hallmarks of cancer in neuroblastoma and discuss the mechanisms of communication between neuroblastoma cells and the TME that underlie the influence of the TME on neuroblastoma progression. We end our review by discussing how the knowledge acquired over the last two decades in this field is now leading to new clinical trials targeting the TME.

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“…[18] A similar approach has been assessed in a recent New Advances to Neuroblastoma Therapy trial of ZOL in combination with oral cyclophosphamide in refractory NB patients, although this trial did not study γδ T cell expansion. [19] …”

Section: Discussionmentioning

confidence: 99%

In vivo expansion and activation of γδ T cells as immunotherapy for refractory neuroblastoma

Pressey

Adams²,

Harkins³

et al. 2016

Medicine

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Introduction:CD3+ γδ+ T cells comprise 2% to 5% of circulating T cells with Vγ9Vδ2+ cells the dominant circulating subtype. Vγ9Vδ2+ cells recognize non-peptide phosphoantigens and stress-associated NKG2D ligands expressed on malignant cells. Strategies that incorporate the tumoricidal properties of γδ T cells represent a promising immunotherapeutic strategy for treatment of solid malignancies including neuroblastoma (NB). In this prospective, non-randomized Phase I trial, we assessed whether circulating Vγ9Vδ2+ cells could be safely expanded using intravenous ZOL (Zoledronate [Zometa®]) and subcutaneous Interleukin-2 (IL-2) in patients with refractory NB.Methods:Patients 2 to 21 years of age with refractory neuroblastoma with no known curative therapeutic options received ZOL on day 1, and IL-2 on days 1 to 5 and 15 to 19 of each 28-day cycle (n = 4). Lymphocyte immunophenotyping was assessed weekly. Immunophenotyping studies from the treatment group were compared with healthy pediatric controls (n = 16; range, 5y–15y) and of untreated NB disease controls (n = 9; range, 4m–18y).Results:Treatment was well tolerated with no unexpected grade 3 and 4 toxicities. Lymphocyte subset counts did not differ significantly between volunteers and disease controls with the exception of γδ+ T cell counts that were significantly higher in healthy volunteers (212 + 93 vs. 89 + 42, P = 0.05). Study patients showed increases in circulating γδ+ T cell count (3–10 fold) after the first week, increasing into the range seen in healthy volunteers (125 + 37, P = 0.1940). Interestingly, all ZOL + IL-2 treated patients showed significant increases in CD3+CD4+CD27hiCD127dim T cells that rose weekly in 2 patients throughout the 4 weeks of observation (maximum 41% and 24% of total CD3+CD4+ T cells, respectively).Conclusions:In summary, combined ZOL and IL-2 is well tolerated and restored γδ+ T cell counts to the normal range with a moderate expansion of Natural Killer cells. Progressive increases in circulating CD4+ T cells with a regulatory phenotype cells may offset beneficial effects of this therapy.

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A phase I study of zoledronic acid and low‐dose cyclophosphamide in recurrent/refractory neuroblastoma: A new approaches to neuroblastoma therapy (NANT) study

Cited by 40 publications

References 46 publications

Critical Role of STAT3 in IL-6–Mediated Drug Resistance in Human Neuroblastoma

Critical Role of STAT3 in IL-6–Mediated Drug Resistance in Human Neuroblastoma

More than the genes, the tumor microenvironment in neuroblastoma

In vivo expansion and activation of γδ T cells as immunotherapy for refractory neuroblastoma

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