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

  • 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.

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Author:Nikolai SiebertORCiDGND, Sascha Troschke-MeurerORCiDGND, Madlen Marx, Maxi Zumpe, Karoline Ehlert, Juliet Gray, Alberto Garaventa, Carla Manzitti, Shifra Ash, Thomas KlingebielORCiDGND, James F. Beck, Victoria Castel, Dominique Valteau-Couanet, Hans Loibner, Ruth Ladenstein, Holger Nikolaus Lode
URN:urn:nbn:de:hebis:30:3-477127
DOI:https://doi.org/10.3390/cancers10100387
ISSN:2072-6694
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/30336605
Parent Title (English):Cancers
Publisher:MDPI
Place of publication:Basel
Document Type:Article
Language:English
Year of Completion:2018
Date of first Publication:2018/10/17
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2018/10/23
Tag:HACA; anti-GD2 immunotherapy; ch14.18/CHO; complement dependent cytotoxicity; long-term infusion; neuroblastoma; pain
Volume:10
Issue:10, Art. 387
Page Number:16
First Page:1
Last Page:16
Note:
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).
HeBIS-PPN:439187605
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 4.0