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

Hans Loibner¹  Juliet Gray²  Sascha Troschke-Meurer³  Karoline Ehlert³  Maxi Zumpe³  Nikolai Siebert³  HolgerN. Lode³  Madlen Marx³  Alberto Garaventa⁴  Carla Manzitti⁴  Shifra Ash⁵  Victoria Castel⁶  Dominique Valteau-Couanet⁷  Ruth Ladenstein⁸  James Beck⁹  Thomas Klingebiel^1,10 

[1] Advisor to Apeiron Biologics AG, 1030 Vienna, Austria;Department of Paediatric Oncology, University Hospital Southampton, Southampton SO14 0YG, UK;Department of Pediatric Oncology and Hematology, University Medicine Greifswald, 17475 Greifswald, Germany;Oncology Unit, Istituto Giannina Gaslini, 16147 Genova, Italy;Pediatric Hemato-Oncology Division, Schneider Children Medical Center, Kaplan 14, Petach Tikva 4920235, Israel;Pediatric Hemato-Oncology Unit, University Hospital La Fe, 46026 Valencia, Spain;Pediatric and Adolescent Oncology, Gustave Roussy Université Paris-Sud, 94800 Villejuif, France;St. Anna Children’s Hospital and Children’s Cancer Research Institute (CCRI), Department of Paediatrics, Medical University, Kinderspitalgasse 6, 1090 Vienna, Austria;University Children’s Hospital, Friedrich Schiller University Jena, 07747 Jena, Germany;University Children’s Hospital, Goethe University Frankfurt, 60596 Frankfurt, Germany;

关键词: neuroblastoma;    anti-GD2 immunotherapy;    ch14.18/CHO;    pain;    long-term infusion;    HACA;    complement dependent cytotoxicity;   

DOI  :  10.3390/cancers10100387

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown