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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

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
Article number387
JournalCancers
Volume10
Issue number10
DOIs
StatePublished - 17 Oct 2018
Externally publishedYes

Funding

FundersFunder number
Hector StiftungM57
Cancer Research UK
Deutsche KinderkrebsstiftungDKS 2014.05 A/B

    Keywords

    • Anti-gd2 immunotherapy
    • Ch14.18/CHO
    • Complement dependent cytotoxicity
    • Haca
    • Long-term infusion
    • Neuroblastoma
    • Pain

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