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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Immunomodulation
Interleukin-2
Antibody-Dependent Cell Cytotoxicity
Pain
Human Development
Therapeutics
Anti-Idiotypic Antibodies
ch14.18 monoclonal antibody
Antibodies
Neuroblastoma
Immunotherapy
Morphine
Interleukin-6
Pharmacokinetics
Survival

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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. / 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; Lode, Holger N.

In: Cancers, Vol. 10, No. 10, 17.10.2018.

Research output: Contribution to journalArticle

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, HN 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, vol. 10, no. 10. https://doi.org/10.3390/cancers10100387
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 ; Lode, Holger N. / 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. In: Cancers. 2018 ; Vol. 10, No. 10.
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title = "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",
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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T1 - Impact of HACA on Immunomodulation and Treatment Toxicity Following ch14.18/CHO Long-Term Infusion with Interleukin-2

T2 - Results from a SIOPEN Phase 2 Trial

AU - Siebert, Nikolai

AU - Troschke-Meurer, Sascha

AU - Marx, Madlen

AU - Zumpe, Maxi

AU - Ehlert, Karoline

AU - Gray, Juliet

AU - Garaventa, Alberto

AU - Manzitti, Carla

AU - Ash, Shifra

AU - Klingebiel, Thomas

AU - Beck, James

AU - Castel, Victoria

AU - Valteau-Couanet, Dominique

AU - Loibner, Hans

AU - Ladenstein, Ruth

AU - Lode, Holger N

PY - 2018/10/17

Y1 - 2018/10/17

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.

AB - 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.

U2 - 10.3390/cancers10100387

DO - 10.3390/cancers10100387

M3 - Article

C2 - 30336605

VL - 10

JO - Cancers

JF - Cancers

SN - 2072-6694

IS - 10

ER -