Neuroblastoma (NB) is the most common extracranial solid tumor of childhood. While intensive induction chemotherapy and aggressive surgery have improved remission rates in young patients, results have been less impressive in older patients and in the 40% of patients with chemo resistant NB. Metastatic NB in children >18 months of age at diagnosis carries a long-term relapse-free survival of only ~20%. These disappointing results are compelling reasons for pursuing novel therapeutic approaches. One successful alternative approach has been immunotherapy with 3F8, a murine IgG3 monoclonal antibody to the GD2 glycolipid antigen ubiquitously present on NB cells. While 3F8 administration confers a clear survival benefit to NB patients in remission, it is not effective for patients with resistantsoft tissue NB or patients with progressive disease. This may be due in part to its dependence on antibody- dependent cell-mediated cytotoxicity (ADCC), the latter mediated largely by natural killer (NK) cells, which are depleted in heavily pre-treated patients. Adoptive transfer of NK cell from a healthy allogeneic source may restore and enhance 3F8 effects in these poor-risk patients. Natural killer (NK) cells are lymphocytes that have the capacity for antitumor activity via multiple pathways, including ADCC through engagement of the CD16 Fc receptor. The capacity of an NK cell for cytotoxic response, however, is dictated by its cell surface receptors, specifically the inhibitory and activating killer-Ig like receptors (KIR) that are specific for sel-MHC class I molecules. To maximize the effects of adoptively transferred NK cells, one should select donors from whom there is the greatest likelihood of engendering NK alloreactivity and of achieving highest functional NK response. This can be accomplished by selecting donors based on the HLA and KIR genotypes of the donor and the patient and by evaluating NK function using an in vitro system that may reflect the tumor MHC environment in vivo. In the first aim of the proposal, we propose that up regulation of MHC class I molecules on the tumor selectively inhibits normally responsive NK populations, leaving the normally hypofunctional, """"""""unlicensed"""""""" NK population to mediate ADCC in patients. Inflammatory cytokines elaborated during antibody therapy may also enhance unlicensed NK activity. The activity of the unlicensed NK population can be significant and should be considered when selecting an NK donor for adoptive transfer. This proposal presents a novel immunotherapeutic approach for the treatment of high-risk neuroblastoma. Combination of 3F8 monoclonal antibody with adoptively transferred NK cells from appropriately selected donors should increase ADCC, antibody efficacy, and tumor eradication. Because these immunologic approaches have never been studied in combination for a solid tumor or in the pediatric population, a phase I study to examine the safety of 3F8 combined with escalating doses of NK cells is necessary and represents the second aim of the proposal. Potential toxicities of NK and 3F8 therapies, a toxicity monitoring plan, dose escalation plan, the expected outcome and stopping rules are presented. Donor-recipient KIR/HLA immunogenetics and donor FcR polymorphism will be correlated with NK activation and cytotoxic function against NB target cells in vitro. Demonstration of safety and feasibility of combining adoptively transferred NK cells with monoclonal antibody will not only result in a more potent therapeutic approach for poor-prognosis NB patients, but will be broadly applicable to other cancer populations such as lymphoma and breast carcinoma currently treated with monoclonal antibodies. Correlating donor-recipient KIR/HLA effects with outcome will clarify donor prioritization algorithms and provide prognostic value for future NK immunotherapy studies.

Public Health Relevance

Natural killer (NK) cells are a vital component of the body's immune system, protecting the individual from developing cancer. This proposal is designed to help physicians use NK cells and the immune system as treatment for children with neuroblastoma, a childhood cancer. Findings from this study will be informative for other cancers that may also be killed by NK cells.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Clinical Oncology Study Section (CONC)
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Timmer, William C
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New York
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Forlenza, Christopher J; Boudreau, Jeanette E; Zheng, Junting et al. (2016) KIR3DL1 Allelic Polymorphism and HLA-B Epitopes Modulate Response to Anti-GD2 Monoclonal Antibody in Patients With Neuroblastoma. J Clin Oncol 34:2443-51
Tarek, Nidale; Le Luduec, Jean-Benoit; Gallagher, Meighan M et al. (2012) Unlicensed NK cells target neuroblastoma following anti-GD2 antibody treatment. J Clin Invest 122:3260-70