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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.

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.
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.
2072-6694
Siebert, Nikolai
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Troschke-Meurer, Sascha
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Marx, Madlen
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Zumpe, Maxi
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Ehlert, Karoline
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Gray, Juliet
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Garaventa, Alberto
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Manzitti, Carla
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Ash, Shifra
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Klingebiel, Thomas
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Beck, James
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Castel, Victoria
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Valteau-Couanet, Dominique
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Loibner, Hans
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Ladenstein, Ruth
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Lode, Holger N.
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Siebert, Nikolai
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Troschke-Meurer, Sascha
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Marx, Madlen
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Zumpe, Maxi
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Ehlert, Karoline
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Gray, Juliet
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Garaventa, Alberto
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Manzitti, Carla
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Ash, Shifra
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Klingebiel, Thomas
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Beck, James
7f20d13d-5bf8-4164-aea6-1abd4807f393
Castel, Victoria
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Valteau-Couanet, Dominique
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Loibner, Hans
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Ladenstein, Ruth
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Lode, Holger N.
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Siebert, Nikolai, Troschke-Meurer, Sascha, Marx, Madlen, Zumpe, Maxi, Ehlert, Karoline, Gray, Juliet, Garaventa, Alberto, Manzitti, Carla, Ash, Shifra, Klingebiel, Thomas, Beck, James, Castel, Victoria, Valteau-Couanet, Dominique, Loibner, Hans, Ladenstein, Ruth and Lode, Holger 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), [387]. (doi:10.3390/cancers10100387).

Record type: Article

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.

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Accepted/In Press date: 11 October 2018
e-pub ahead of print date: 17 October 2018
Published date: 17 October 2018

Identifiers

Local EPrints ID: 428349
URI: http://eprints.soton.ac.uk/id/eprint/428349
ISSN: 2072-6694
PURE UUID: 34c737b3-f3e4-48f7-8417-29fdfabecd9a
ORCID for Juliet Gray: ORCID iD orcid.org/0000-0002-5652-4722

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Date deposited: 21 Feb 2019 17:30
Last modified: 16 Mar 2024 03:33

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Contributors

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

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