Abstract
ABSTRACTImmunotherapy with the anti-GD2 antibody (Ab) ch14.18/CHO in combination with interleukin 2 (IL-2) has improved survival of high-risk neuroblastoma (NB) patients. Here, we report immunotherapy-related effects on circulating NK cells, regulatory T cells (Tregs), granulocytes as well as on Ab-dependent cell-mediated cytotoxicity (ADCC) and cytokines IFN-γ, IL-6, IL-10, IL-18 and CCL2 and their association with progression-free survival (PFS).In a closed single-center program, 53 patients received five cycles of 6 × 106 IU/m2 subcutaneous IL-2 (d1-5; 8–12) combined with long-term infusion (LTI) of 100 mg/m2 ch14.18/CHO (d8-18). Immune cells and cytokines were analyzed by flow cytometry and ADCC by calcein-AM-based cytotoxicity assay.IL-2 administration increased cytotoxic NK cell-, eosinophil- and Treg counts in cycle 1 (2.9-, 3.1- and 20.7-fold, respectively) followed by further increase in subsequent cycles, whereas neutrophil levels were elevated only after the ch14.18/CHO infusion (2.4-fold change). Serum concentrations of IFN-γ, IL-6, IL-10, IL-18 and CCL2 in cycle 1 were increased during the combinatorial therapy (peak levels of 3,656 ± 655 pg/ml, 162 ± 38 pg/ml, 20.91 ± 4.74 pg/ml, 1,584 ± 196 pg/ml and 2,159 ± 252 pg/ml, respectively). Surprisingly, we did not observe any correlation between NK-, eosinophil- or neutrophil levels and PFS. In contrast, patients with low Tregs showed significantly improved PFS compared to those who had high levels. Treg counts negatively correlated with INF-γ serum concentrations and patients with high INF-γ and IL-18 had significantly improved survival compared to those with low levels.In conclusion, LTI of ch14.18/CHO in combination with IL-2 resulted in Treg induction that inversely correlated with IFN-γ levels and PFS.
Highlights
Survival of patients with high-risk neuroblastoma (NB) is still poor despite multimodal therapy.[1]
High-risk NB patients with high-affinity polymorphisms of FCGR 2A and −3A that are expressed on neutrophils and cytotoxic natural killer (NK) cells, showed an increased Ab-dependent cellular cytotoxicity (ADCC) and an improved event-free survival (EFS) when treated with ch14.18/CHO in combination with interleukin 2 (IL-2) compared to those with low-affinity polymorphisms.[11]
Since NK cells, neutrophils and eosinophils mediate ADCC, we evaluated in cycle 1, whether their cell counts correlate with ADCC levels determined on d15 using a validated calcein-AMbased cytotoxicity assay.[29]
Summary
Survival of patients with high-risk neuroblastoma (NB) is still poor despite multimodal therapy.[1]. Anti-GD2 mAbs act through binding to the tumorassociated antigen GD2 expressed by NB cells. This results in the attraction of immune cells such as cytotoxic natural killer (NK) cells and granulocytes (neutrophils, eosinophils), that can directly eradicate tumor cells via Ab-dependent cellular cytotoxicity (ADCC) known to be one of the main antitumor mechanisms of mAbs.[3,4,5,6,7,8,9,10] The level of ADCC depends on genetic and/or immune-modulating factors, such as polymorphisms in Fc-γ receptors (FCGR), and immunestimulating cytokines. High-risk NB patients with high-affinity polymorphisms of FCGR 2A and −3A that are expressed on neutrophils and cytotoxic NK cells, showed an increased ADCC and an improved EFS when treated with ch14.18/CHO in combination with IL-2 compared to those with low-affinity polymorphisms.[11]
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