1. 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
- Author
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Victoria Castel, Sascha Troschke-Meurer, Thomas Klingebiel, Carla Manzitti, James F. Beck, Juliet C. Gray, Holger N. Lode, Nikolai Siebert, Alberto Garaventa, Maxi Zumpe, Madlen Marx, Ruth Ladenstein, Dominique Valteau-Couanet, Karoline Ehlert, Shifra Ash, and Hans Loibner
- Subjects
Interleukin 2 ,Cancer Research ,education ,Pharmacology ,lcsh:RC254-282 ,Article ,03 medical and health sciences ,neuroblastoma ,0302 clinical medicine ,Pharmacokinetics ,HACA ,Neuroblastoma ,medicine ,anti-GD(2) immunotherapy ,pain ,ddc:610 ,anti-GD2 immunotherapy ,Antibody-dependent cell-mediated cytotoxicity ,Chemistry ,ch14.18/CHO ,ch1418/CHO ,long-term infusion ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Complement-dependent cytotoxicity ,complement dependent cytotoxicity ,Oncology ,030220 oncology & carcinogenesis ,Pharmacodynamics ,Toxicity ,Morphine ,030215 immunology ,medicine.drug - 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&ndash, 18) combined with s.c. IL-2 (6 ×, 106 IU/m2/d, d1&ndash, 5, d8&ndash, 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 µ, g/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.
- Published
- 2018