Abstract
ABSTRACTImmunotherapy with anti-GD2 antibody (Ab) ch14.18/CHO is effective for treatment of high-risk neuroblastoma (NB) patients and is mainly based on GD2-specific Ab-dependent cellular cytotoxicity (ADCC). Strategies to further enhance the efficacy are important and currently explored in prospective clinical trials randomizing ch14.18/CHO ± IL-2. Recently, expression of programmed death 1 (PD-1) inhibitory receptor by effector cells and its ligand (PD-L1) by tumor cells has been shown. Here, we report for the first time effects of PD-1 blockade on ch14.18/CHO-based immunotherapy and mechanisms involved.Expression of PD-1 and PD-L1 on NB and effector cells was analyzed by RT-PCR and flow cytometry in the presence of ch14.18/CHO and/or IL-2. The effect of PD-1 blockade on ch14.18/CHO-mediated anti-NB immune response was evaluated using anti-PD-1 Ab both in vitro (Nivolumab) and in a syngeneic PD-L1+/GD2+ NB mouse model (anti-mouse PD-1).Culture of NB cells LA-N-1 (low PD-L1 baseline expression) with leukocytes and subtherapeutic ch14.18/CHO concentrations for 24 h induced strong upregulation of PD-L1, which was further increased by IL-2 resulting in complete inhibition of ch14.18/CHO-mediated ADCC. Importantly, blockade with Nivolumab reversed the PD-L1-dependent inhibition of ADCC. Similarly, co-incubation with anti-CD11b Ab abrogated the PD-L1 upregulation and restored ADCC. Mice treated with ch14.18/CHO in combination with PD-1 blockade showed a strong reduction of tumor growth, prolonged survival and the highest cytotoxicity against NB cells.In conclusion, ch14.18/CHO-mediated effects upregulate the inhibitory immune checkpoint PD-1/PD-L1, and combination of ch14.18/CHO with PD-1 blockade results in synergistic treatment effects in mice representing a new effective treatment strategy against GD2-positive cancers.
Highlights
One of the major challenges in pediatric oncology is the effective treatment of high-risk neuroblastoma (NB) patients
In Europe, ch14.18/CHO was remanufactured in Chinese Hamster Ovary (CHO) cells and applied with and without IL-2 for the treatment of NB showing similar clinical activity and pharmacokinetics compared with the ch14.18 produced in SP2/0 cells,[3] and ch14.18/CHO was approved by the European Medicines Agency for the treatment of NB
We evaluated the percentage of mice that were killed ahead of schedule due to tumor burden as described in “Material and Methods.” 60% of mice (6/10) of the control group receiving 0.9% NaCl were removed from the experiment ahead of schedule compared with 20% (2/10) and 40% (4/10) of mice treated with ch14.18/CHO and anti-programmed death 1 (PD-1) monotherapy, respectively
Summary
One of the major challenges in pediatric oncology is the effective treatment of high-risk neuroblastoma (NB) patients. The 5-year event-free survival (EFS) rate following standard therapy still remains less than 50%.1. The Children’s Oncology Group (COG) reported that treatment of high-risk NB patients with the human/mouse chimeric Ab ch14.18 produced in SP2/0 cells in combination with cytokines (GM-CSF and IL-2) improved 2-year event-free survival (EFS) and overall survival (OS) by 20% and 11%, respectively.[2] This Ab/cytokine combination therapy was approved by the American Food and Drug Administration for the treatment of NB. In Europe, ch14.18/CHO was remanufactured in Chinese Hamster Ovary (CHO) cells and applied with and without IL-2 for the treatment of NB showing similar clinical activity and pharmacokinetics compared with the ch14.18 produced in SP2/0 cells,[3] and ch14.18/CHO was approved by the European Medicines Agency for the treatment of NB.
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