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Cancers 2018, 10(10), 387; https://doi.org/10.3390/cancers10100387

Impact of HACA on Immunomodulation and Treatment Toxicity Following ch14.18/CHO Long-Term Infusion with Interleukin-2: Results from a SIOPEN Phase 2 Trial

1
Department of Pediatric Oncology and Hematology, University Medicine Greifswald, 17475 Greifswald, Germany
2
Department of Paediatric Oncology, University Hospital Southampton, Southampton SO14 0YG, UK
3
Oncology Unit, Istituto Giannina Gaslini, 16147 Genova, Italy
4
Pediatric Hemato-Oncology Division, Schneider Children Medical Center, Kaplan 14, Petach Tikva 4920235, Israel
5
University Children’s Hospital, Goethe University Frankfurt, 60596 Frankfurt, Germany
6
University Children’s Hospital, Friedrich Schiller University Jena, 07747 Jena, Germany
7
Pediatric Hemato-Oncology Unit, University Hospital La Fe, 46026 Valencia, Spain
8
Pediatric and Adolescent Oncology, Gustave Roussy Université Paris-Sud, 94800 Villejuif, France
9
Advisor to Apeiron Biologics AG, 1030 Vienna, Austria
10
St. Anna Children’s Hospital and Children’s Cancer Research Institute (CCRI), Department of Paediatrics, Medical University, Kinderspitalgasse 6, 1090 Vienna, Austria
*
Author to whom correspondence should be addressed.
Received: 14 August 2018 / Revised: 17 September 2018 / Accepted: 11 October 2018 / Published: 17 October 2018
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Abstract

GD2-directed immunotherapies improve survival of high-risk neuroblastoma (NB) patients (pts). Treatment with chimeric anti-GD2 antibodies (Ab), such as ch14.18, can induce development of human anti-chimeric Ab (HACA). Here, we report HACA effects on ch14.18/CHO pharmacokinetics, pharmacodynamics and pain intensity in pts treated by long-term infusion (LTI) of ch14.18/CHO combined with IL-2. 124 pts received up to 5 cycles of ch14.18/CHO 10 days (d) infusion (10 mg/m2/d; d8–18) combined with s.c. IL-2 (6 × 106 IU/m2/d; d1–5, d8–12). HACA, treatment toxicity, ch14.18/CHO levels, Ab-dependent cellular- (ADCC) and complement-dependent cytotoxicity (CDC) were assessed using respective validated assays. HACA-negative pts showed a steadily decreased pain in cycle 1 (74% pts without morphine by d5 of LTI) with further decrease in subsequent cycles. Ch14.18/CHO peak concentrations of 11.26 ± 0.50 µg/mL found in cycle 1 were further elevated in subsequent cycles and resulted in robust GD2-specific CDC and ADCC. Development of HACA (21% of pts) resulted in strong reduction of ch14.18/CHO levels, abrogated CDC and ADCC. Surprisingly, no difference in pain toxicity between HACA-positive and -negative pts was found. In conclusion, ch14.18/CHO LTI combined with IL-2 results in strong activation of Ab effector functions. Importantly, HACA response abrogated CDC but did not affect pain intensity indicating CDC-independent pain induction. View Full-Text
Keywords: neuroblastoma; anti-GD2 immunotherapy; ch14.18/CHO; pain; long-term infusion; HACA; complement dependent cytotoxicity neuroblastoma; anti-GD2 immunotherapy; ch14.18/CHO; pain; long-term infusion; HACA; complement dependent cytotoxicity
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Siebert, N.; Troschke-Meurer, S.; Marx, M.; Zumpe, M.; Ehlert, K.; Gray, J.; Garaventa, A.; Manzitti, C.; Ash, S.; Klingebiel, T.; Beck, J.; Castel, V.; Valteau-Couanet, D.; Loibner, H.; Ladenstein, R.; Lode, H.N. Impact of HACA on Immunomodulation and Treatment Toxicity Following ch14.18/CHO Long-Term Infusion with Interleukin-2: Results from a SIOPEN Phase 2 Trial. Cancers 2018, 10, 387.

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