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

Nikolai Siebert, Sascha Troschke-Meurer, Madlen Marx, Maxi Zumpe, Karoline Ehlert, Juliet Gray, Alberto Garaventa, Carla Manzitti, Shifra Ash, Thomas Klingebiel, James Beck, Victoria Castel, Dominique Valteau-Couanet, Hans Loibner, Ruth Ladenstein, Holger N Lode

Research output: Contribution to journalArticle

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.

Original languageEnglish
JournalCancers
Volume10
Issue number10
DOIs
Publication statusPublished - Oct 17 2018

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