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2015 ; 3
(ä): 24
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Immune modulating effects of cyclophosphamide and treatment with tumor lysate/CpG
synergize to eliminate murine neuroblastoma
#MMPMID26082836
Gershan JA
; Barr KM
; Weber JJ
; Jing W
; Johnson BD
J Immunother Cancer
2015[]; 3
(ä): 24
PMID26082836
show ga
BACKGROUND: Neuroblastoma is a pediatric cancer of neural crest origin. Despite
aggressive treatment, mortality remains at 40 % for patients with high-risk
disseminated disease, underscoring the need to test new combinations of
therapies. In murine tumor models, our laboratory previously showed that T
cell-mediated anti-tumor immune responses improve in the context of lymphopenia.
The goal of this study was to incorporate lymphodepletion into an effective
immune therapy that can be easily translated into neuroblastoma standard of care.
Based on the lymphodepleting effects of cyclophosphamide, we hypothesized that
cyclophosphamide would synergize with the TLR9 agonist, CpG oligodeoxynucleotide
(ODN), to produce a T cell-mediated anti-neuroblastoma effect. METHODS: To test
this hypothesis, we used the AgN2a aggressive murine model of neuroblastoma. Mice
bearing subcutaneous tumors were treated with cyclophosphamide followed by
treatment with tumor cell lysate mixed with CpG ODN injected at the tumor site.
RESULTS: Subcutaneous neuroblastoma regressed only in mice that were treated with
100 mg/kg cyclophosphamide prior to receiving treatments of tumor lysate mixed
with CpG ODN. The anti-neuroblastoma response was T cell-mediated. Synergy
between cyclophosphamide and the tumor lysate/CpG ODN treatment influenced the
production of anti-tumor CD8 T cell effectors, and dendritic cell homeostasis.
For clinical consideration, an allogeneic tumor lysate was used effectively with
this protocol to eliminate AgN2a tumor in vivo. CONCLUSION: Synergistic immune
modulating effects of cyclophosphamide and a treatment containing tumor cell
lysate and CpG ODN provide T cell-mediated anti-tumor activity against murine
neuroblastoma.