Abstract
Neuroblastoma (NB) is the most common extracranial solid tumor in children and, in the high-risk group, has a 5-year mortality rate of ~50%. The high mortality rate and significant treatment-related morbidities associated with current standard of care therapies belie the critical need for more tolerable and effective treatments for this disease. While the monoclonal antibody dinutuximab has demonstrated the potential for immunotherapy to improve overall NB outcomes, the 5-year overall survival of high-risk patients has not yet substantially changed. The frequency and type of invariant natural killer T cells (iNKTs) and natural killer cells (NKs) has been associated with improved outcomes in several solid and liquid malignancies, including NB. Indeed, iNKTs and NKs inhibit tumor associated macrophages (TAMs) and myeloid derived suppressor cells (MDSCs), kill cancer stem cells (CSCs) and neuroblasts, and robustly secrete cytokines to recruit additional immune effectors. These capabilities, and promising pre-clinical and early clinical data suggest that iNKT- and NK-based therapies may hold promise as both stand-alone and combination treatments for NB. In this review we will summarize the biologic features of iNKTs and NKs that confer advantages for NB immunotherapy, discuss the barriers imposed by the NB tumor microenvironment, and examine the current state of such therapies in pre-clinical models and clinical trials.
Highlights
Neuroblastoma (NB) is the most common extracranial solid tumor in children and accounts for ∼15% of childhood cancer deaths [1]
NB is stratified into risk groups on the basis of clinical and molecular features using the International Neuroblastoma Risk Group (INRG) classification with the high-risk group being the most prevalent [2]
This study aims to identify the maximum tolerated dose of chimeric antigen receptor (CAR)-invariant natural killer T cells (iNKTs) and involves the use of expanded autologous iNKTs modified with a GD2-CAR containing the IL-15 gene
Summary
Neuroblastoma (NB) is the most common extracranial solid tumor in children and accounts for ∼15% of childhood cancer deaths [1]. The addition of dinutuximab to irinotecan and temozolomide in the relapsed or refractory NB setting demonstrated dramatic clinical activity. In those treated with the dinutuximab-containing regimen, 9 out of patients (53%) had a disease response vs 1 out of patients (6%) in a comparator arm that included the same chemotherapy but without dinutuximab [7]. These studies demonstrate that dinutuximab immunotherapy has significant clinical utility in both minimal and high disease burden contexts. Improving the long-term efficacy of these promising immunotherapies in HRNB remains an important unsolved challenge
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