Tolerability, response and outcome of high-risk neuroblastoma patients treated with long-term infusion of anti-GD2 antibody ch14.18/CHO

Ina Mueller, Karoline Ehlert, Stefanie Endres, Lena Pill, Nikolai Siebert, Silke Kietz, Penelope Brock, Alberto Garaventa, Dominique Valteau-Couanet, Evelyne Janzek, Norbert Hosten, Andreas Zinke, Winfried Barthlen, Emine Varol, Hans Loibner, Ruth Ladenstein, Holger N Lode

Research output: Contribution to journalArticle

Abstract

Immunotherapy with short term infusion (STI) of monoclonal anti-GD2 antibody (mAb) ch14.18 (4 × 25 mg/m2/d; 8-20 h) in combination with cytokines and 13-cis retinoic acid (RA) prolonged survival in high-risk neuroblastoma (NB) patients. Here, we investigated long-term infusion (LTI) of ch14.18 produced in Chinese hamster ovary cells (ch14.18/CHO; 10 × 10 mg/m2; 24 h) in combination with subcutaneous (s.c.) interleukin-2 (IL-2) in a single center program and report clinical response, toxicity and survival. Fifty-three high-risk NB patients received up to 6 cycles of 100 mg/m2 ch14.18/CHO (d8-17) as LTI combined with 6 × 106 IU/m2 s.c. IL-2 (d1-5; 8-12) and 160 mg/m2 oral RA (d19-32). Pain toxicity was documented with validated pain scores and intravenous (i.v.) morphine usage. Response was assessed in 37/53 evaluable patients following International Neuroblastoma Risk Group criteria. Progression-free (PFS) and overall survival (OS) was analyzed by the Kaplan-Meier method and compared to a matched historical control group from the database of AIEOP, the "Italian Pediatric Ematology and Oncology Association". LTI of ch14.18/CHO showed acceptable toxicity profile indicated by low pain scores, reduced i.v. morphine usage and low frequency of Grade ≥3 adverse events that allowed outpatient treatment. We observed a best response rate of 40.5% (15/37; 5 CR, 10 PR), 4-year (4 y) PFS of 33.1% (observation 0.1- 4.9 y, mean: 2.2 y) and a 4 y OS of 47.7% (observation 0.27 - 5.20 y, mean: 3.6 y). Survival of the entire cohort (53/53) and the relapsed patients (29/53) was significantly improved compared to historical controls. LTI of ch14.18/CHO thus shows an acceptable toxicity profile, objective clinical responses and a strong signal of clinical efficacy in NB patients.

Original languageEnglish
Pages (from-to)55-61
Number of pages7
JournalmAbs
Volume10
Issue number1
DOIs
Publication statusPublished - Jan 2018

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Neuroblastoma
Anti-Idiotypic Antibodies
Survival
Pain
Morphine
Interleukin-2
Observation
Isotretinoin
CHO Cells
Cricetulus
Tretinoin
Immunotherapy
ch14.18 monoclonal antibody
Ovary
Outpatients
Monoclonal Antibodies
Databases
Pediatrics
Cytokines
Control Groups

Keywords

  • Adolescent
  • Adult
  • Antibodies, Monoclonal/administration & dosage
  • Antineoplastic Agents, Immunological/administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols/adverse effects
  • Child
  • Child, Preschool
  • Drug Administration Schedule
  • Female
  • Gangliosides/immunology
  • Humans
  • Immunotherapy/adverse effects
  • Infant
  • Infusions, Intravenous
  • Interleukin-2/administration & dosage
  • Isotretinoin/administration & dosage
  • Male
  • Neuroblastoma/immunology
  • Progression-Free Survival
  • Time Factors
  • Treatment Outcome
  • Young Adult

Cite this

Tolerability, response and outcome of high-risk neuroblastoma patients treated with long-term infusion of anti-GD2 antibody ch14.18/CHO. / Mueller, Ina; Ehlert, Karoline; Endres, Stefanie; Pill, Lena; Siebert, Nikolai; Kietz, Silke; Brock, Penelope; Garaventa, Alberto; Valteau-Couanet, Dominique; Janzek, Evelyne; Hosten, Norbert; Zinke, Andreas; Barthlen, Winfried; Varol, Emine; Loibner, Hans; Ladenstein, Ruth; Lode, Holger N.

In: mAbs, Vol. 10, No. 1, 01.2018, p. 55-61.

Research output: Contribution to journalArticle

Mueller, I, Ehlert, K, Endres, S, Pill, L, Siebert, N, Kietz, S, Brock, P, Garaventa, A, Valteau-Couanet, D, Janzek, E, Hosten, N, Zinke, A, Barthlen, W, Varol, E, Loibner, H, Ladenstein, R & Lode, HN 2018, 'Tolerability, response and outcome of high-risk neuroblastoma patients treated with long-term infusion of anti-GD2 antibody ch14.18/CHO', mAbs, vol. 10, no. 1, pp. 55-61. https://doi.org/10.1080/19420862.2017.1402997
Mueller, Ina ; Ehlert, Karoline ; Endres, Stefanie ; Pill, Lena ; Siebert, Nikolai ; Kietz, Silke ; Brock, Penelope ; Garaventa, Alberto ; Valteau-Couanet, Dominique ; Janzek, Evelyne ; Hosten, Norbert ; Zinke, Andreas ; Barthlen, Winfried ; Varol, Emine ; Loibner, Hans ; Ladenstein, Ruth ; Lode, Holger N. / Tolerability, response and outcome of high-risk neuroblastoma patients treated with long-term infusion of anti-GD2 antibody ch14.18/CHO. In: mAbs. 2018 ; Vol. 10, No. 1. pp. 55-61.
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T1 - Tolerability, response and outcome of high-risk neuroblastoma patients treated with long-term infusion of anti-GD2 antibody ch14.18/CHO

AU - Mueller, Ina

AU - Ehlert, Karoline

AU - Endres, Stefanie

AU - Pill, Lena

AU - Siebert, Nikolai

AU - Kietz, Silke

AU - Brock, Penelope

AU - Garaventa, Alberto

AU - Valteau-Couanet, Dominique

AU - Janzek, Evelyne

AU - Hosten, Norbert

AU - Zinke, Andreas

AU - Barthlen, Winfried

AU - Varol, Emine

AU - Loibner, Hans

AU - Ladenstein, Ruth

AU - Lode, Holger N

PY - 2018/1

Y1 - 2018/1

N2 - Immunotherapy with short term infusion (STI) of monoclonal anti-GD2 antibody (mAb) ch14.18 (4 × 25 mg/m2/d; 8-20 h) in combination with cytokines and 13-cis retinoic acid (RA) prolonged survival in high-risk neuroblastoma (NB) patients. Here, we investigated long-term infusion (LTI) of ch14.18 produced in Chinese hamster ovary cells (ch14.18/CHO; 10 × 10 mg/m2; 24 h) in combination with subcutaneous (s.c.) interleukin-2 (IL-2) in a single center program and report clinical response, toxicity and survival. Fifty-three high-risk NB patients received up to 6 cycles of 100 mg/m2 ch14.18/CHO (d8-17) as LTI combined with 6 × 106 IU/m2 s.c. IL-2 (d1-5; 8-12) and 160 mg/m2 oral RA (d19-32). Pain toxicity was documented with validated pain scores and intravenous (i.v.) morphine usage. Response was assessed in 37/53 evaluable patients following International Neuroblastoma Risk Group criteria. Progression-free (PFS) and overall survival (OS) was analyzed by the Kaplan-Meier method and compared to a matched historical control group from the database of AIEOP, the "Italian Pediatric Ematology and Oncology Association". LTI of ch14.18/CHO showed acceptable toxicity profile indicated by low pain scores, reduced i.v. morphine usage and low frequency of Grade ≥3 adverse events that allowed outpatient treatment. We observed a best response rate of 40.5% (15/37; 5 CR, 10 PR), 4-year (4 y) PFS of 33.1% (observation 0.1- 4.9 y, mean: 2.2 y) and a 4 y OS of 47.7% (observation 0.27 - 5.20 y, mean: 3.6 y). Survival of the entire cohort (53/53) and the relapsed patients (29/53) was significantly improved compared to historical controls. LTI of ch14.18/CHO thus shows an acceptable toxicity profile, objective clinical responses and a strong signal of clinical efficacy in NB patients.

AB - Immunotherapy with short term infusion (STI) of monoclonal anti-GD2 antibody (mAb) ch14.18 (4 × 25 mg/m2/d; 8-20 h) in combination with cytokines and 13-cis retinoic acid (RA) prolonged survival in high-risk neuroblastoma (NB) patients. Here, we investigated long-term infusion (LTI) of ch14.18 produced in Chinese hamster ovary cells (ch14.18/CHO; 10 × 10 mg/m2; 24 h) in combination with subcutaneous (s.c.) interleukin-2 (IL-2) in a single center program and report clinical response, toxicity and survival. Fifty-three high-risk NB patients received up to 6 cycles of 100 mg/m2 ch14.18/CHO (d8-17) as LTI combined with 6 × 106 IU/m2 s.c. IL-2 (d1-5; 8-12) and 160 mg/m2 oral RA (d19-32). Pain toxicity was documented with validated pain scores and intravenous (i.v.) morphine usage. Response was assessed in 37/53 evaluable patients following International Neuroblastoma Risk Group criteria. Progression-free (PFS) and overall survival (OS) was analyzed by the Kaplan-Meier method and compared to a matched historical control group from the database of AIEOP, the "Italian Pediatric Ematology and Oncology Association". LTI of ch14.18/CHO showed acceptable toxicity profile indicated by low pain scores, reduced i.v. morphine usage and low frequency of Grade ≥3 adverse events that allowed outpatient treatment. We observed a best response rate of 40.5% (15/37; 5 CR, 10 PR), 4-year (4 y) PFS of 33.1% (observation 0.1- 4.9 y, mean: 2.2 y) and a 4 y OS of 47.7% (observation 0.27 - 5.20 y, mean: 3.6 y). Survival of the entire cohort (53/53) and the relapsed patients (29/53) was significantly improved compared to historical controls. LTI of ch14.18/CHO thus shows an acceptable toxicity profile, objective clinical responses and a strong signal of clinical efficacy in NB patients.

KW - Adolescent

KW - Adult

KW - Antibodies, Monoclonal/administration & dosage

KW - Antineoplastic Agents, Immunological/administration & dosage

KW - Antineoplastic Combined Chemotherapy Protocols/adverse effects

KW - Child

KW - Child, Preschool

KW - Drug Administration Schedule

KW - Female

KW - Gangliosides/immunology

KW - Humans

KW - Immunotherapy/adverse effects

KW - Infant

KW - Infusions, Intravenous

KW - Interleukin-2/administration & dosage

KW - Isotretinoin/administration & dosage

KW - Male

KW - Neuroblastoma/immunology

KW - Progression-Free Survival

KW - Time Factors

KW - Treatment Outcome

KW - Young Adult

U2 - 10.1080/19420862.2017.1402997

DO - 10.1080/19420862.2017.1402997

M3 - Article

C2 - 29120699

VL - 10

SP - 55

EP - 61

JO - mAbs

JF - mAbs

SN - 1942-0870

IS - 1

ER -