Our long-term goal is to develop immunotherapy for high-risk neuroblastoma that realizes the full potential of natural killer (NK) cells combined with antitumor monoclonal antibodies (e.g., anfi-GD2) to eradicate primary and metastatic disease. We hypothesize the following: 1) Anti-tumor efficacy of NK antibody dependent cellular cytotoxicity (ADCC) depends upon the quantity, persistence, and anti-tumor function of NK cells in tumor microenvironments. 2) Neuroblastoma cells and mononuclear phagocytes reciprocally cooperate to create a microenvironment milieu, which includes IL-6 and TGFB1, that is pro-tumor and immunosuppressive. Thus, therapeutic strategies must both maximize NK activation for ADCC and cytokine secretion (e.g., Ifni) and minimize microenvironment suppression (e.g., IL-6 and TGFB1).
Our Specific Aims are as follows: 1) Identify interactions between tumor cells and mononuclear phagocytes that promote tumor growth and/or suppress anti-tumor NK functions. 2) Develop combinatorial therapy for established and minimal disease by maximizing anti-tumor activities of NK cells while abrogating pro-tumor activities of mononuclear phagocytes. Research Design and Methods.
In Aim 1. we shall use our existing microarray database to gain further insight into inflammation-related gene expression of tumors from patients (e.g., IL- 6/STAT3 and TGFB pathways) and then validate findings with protein array analyses. Next, we shall use in vitro models to understand interactions between tumor cells and monocytes that increase growth of tumor cells and suppress activation of NK cells for ADCC and Ifni secretion. Finally we shall use In vivo models of local and disseminated disease in NOD/SCID mice that include bioluminescent imaging of tumor cells monocytes, and NK cells to further understand how monocytes promote tumor growth and to determine if they cause resistance to NK ADCC.
In Aim 2, we shall develop combinatorial therapy that maximizes antitumor NK ADCC while negating pro-tumor and immunosuppressive contributions from tumor cells and mononuclear phagocytes. Here, we shall use In vitro models to develop strategies with drugs such as the immune modulator lenalidomide for maximizing induction of NK ADCC and cytokine secretion while modulating the pro-tumor functions of monocytes.
This aim will include generating microarray data for use in connectivity mapping aimed at identifying new agents for immune modulation. The most promising strategies then will be tested with our in vivo NOD/SCID models, which include imaging, of minimal and established disseminated and local disease. These experiments will provide the basis for clinical trial development.

Public Health Relevance

The proposed laboratory research will define new strategies for increasing the ability of Natural Killer (NK) cells and antibodies to kill small and large numbers of neuroblastoma cells. Results will provide a blueprint for clinical investigators in the New Approaches to Neuroblastoma Therapy (NANT) consortium to develop NK and antibody treatments for children with resistant or recurrent neuroblastoma. If the treatments are successful, they will improve the survival of children with neuroblastoma.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA081403-15
Application #
8677719
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
15
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Children's Hospital of Los Angeles
Department
Type
DUNS #
City
Los Angeles
State
CA
Country
United States
Zip Code
90027
DuBois, Steven G; Marachelian, Araz; Fox, Elizabeth et al. (2016) Phase I Study of the Aurora A Kinase Inhibitor Alisertib in Combination With Irinotecan and Temozolomide for Patients With Relapsed or Refractory Neuroblastoma: A NANT (New Approaches to Neuroblastoma Therapy) Trial. J Clin Oncol 34:1368-75
Trieu, Megan; DuBois, Steven G; Pon, Elizabeth et al. (2016) Impact of Whole-Body Radiation Dose on Response and Toxicity in Patients With Neuroblastoma After Therapy With 131 I-Metaiodobenzylguanidine (MIBG). Pediatr Blood Cancer 63:436-42
DuBois, Steven G; Groshen, Susan; Park, Julie R et al. (2015) Phase I Study of Vorinostat as a Radiation Sensitizer with 131I-Metaiodobenzylguanidine (131I-MIBG) for Patients with Relapsed or Refractory Neuroblastoma. Clin Cancer Res 21:2715-21
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DuBois, S G; Allen, S; Bent, M et al. (2015) Phase I/II study of (131)I-MIBG with vincristine and 5 days of irinotecan for advanced neuroblastoma. Br J Cancer 112:644-9
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Huang, Shih-ying; Bolch, Wesley E; Lee, Choonsik et al. (2015) Patient-specific dosimetry using pretherapy [¹²⁴I]m-iodobenzylguanidine ([¹²⁴I]mIBG) dynamic PET/CT imaging before [¹³¹I]mIBG targeted radionuclide therapy for neuroblastoma. Mol Imaging Biol 17:284-94

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