TY  - JOUR
A1  - Siebert, Nikolai
A1  - Troschke-Meurer, Sascha
A1  - Marx, Madlen
A1  - Zumpe, Maxi
A1  - Ehlert, Karoline
A1  - Gray, Juliet
A1  - Garaventa, Alberto
A1  - Manzitti, Carla
A1  - Ash, Shifra
A1  - Klingebiel, Thomas
A1  - Beck, James F.
A1  - Castel, Victoria
A1  - Valteau-Couanet, Dominique
A1  - Loibner, Hans
A1  - Ladenstein, Ruth
A1  - Lode, Holger
T1  - 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
T2  - Cancers
N2  - 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.
KW  - neuroblastoma
KW  - anti-GD2 immunotherapy
KW  - ch14.18/CHO
KW  - pain
KW  - long-term infusion
KW  - HACA
KW  - complement dependent cytotoxicity
Y1  - 2018
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/47712
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-477127
SN  - 2072-6694
N1  - 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).
VL  - 10
IS  - 10, Art. 387
SP  - 1
EP  - 16
PB  - MDPI
CY  - Basel
ER  -