Immunotherapy of Relapsed Refractory Neuroblastoma With Expanded NK Cells

Summary

Objectives

This NANT trial will determine the maximum tolerated dose (MTD) of autologous expanded
natural killer (NK) cells when combined with standard dosing of dinutuximab and will assess
the feasibility of adding lenalidomide at the recommended Phase II dose of the expanded NK
cells with dinutuximab, for treatment of children with refractory or recurrent neuroblastoma.

Dinutuximab is a chimeric antibody against GD2, which is expressed on a majority of
neuroblastoma cells. It has been shown to increase EFS and OS in patients with high-risk
neuroblastoma when given after autologous stem cell transplant in combination with
subcutaneous GM-CSF and intravenous IL-2, followed by isotretinoin. Lenalidomide has been
studied in children with solid tumors and can safely be given to patients based on 2 prior
trials in children. It was also shown to have immunomodulatory effects and is synergistic
with dinutuximab. Lenalidomide is also an oral agent that can be given in the outpatient
setting. Natural killer cells are lymphocytes of the innate immune system that have the
ability to recognize and kill malignant cells, including neuroblastoma. Dinutuximab and
lenalidomide both exert part of their anti-cancer effect through the activation of natural
killer cells. Patients were given these in combination in the NANT 2011-04 study where the
safety and immunomodulatory effect were established. The dose level proposed in this study is
based off of these data. Natural killer cells are dysfunctional and low in number in many
cancer patients, and number and function are further suppressed by chemotherapy and
radiation. Investigators hypothesize that autologous NK cells can be expanded and activated
ex vivo and readministered to restore number and function, and in combination with
lenalidomide and dinutuximab will provide an anti-tumor effect in patients with relapsed or
refractory neuroblastoma.

Investigators will determine the feasibility of centralized expansion, cryopreservation, and
distribution of autologous NK cells. Investigators will then determine the maximum tolerated
dose by assessing the toxicities of autologous expanded NK cells given with dinutuximab; by
assessing the toxicities, cytokinetics and immunomodulatory effects, Investigators will
select the recommended Phase II dose of the two-agent combination after dose escalation of
the NK cells and then adding lenalidomide to the combination to establish the three-agent
combination.

Cytokinetics (persistence of infused NK cells) and immune function studies will be required
for all patients entered on this study. In addition to routine assessment of response,
quantification of rare tumor cell detection in blood and bone marrow using TLDA will also
provide another measure of possible anti-tumor efficacy to support the rationale for the
final schedule chosen.