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.