Nikolai Siebert, Sascha Troschke-Meurer, Madlen Marx, Maxi Zumpe, Karoline Ehlert, Juliet Gray, Alberto Garaventa, Carla Manzitti, Shifra Ash, Thomas Klingebiel, James F. Beck, Victoria Castel, Dominique Valteau-Couanet, Hans Loibner, Ruth Ladenstein, Holger Lode
- 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.
MetadatenAuthor: | Nikolai SiebertORCiDGND, Sascha Troschke-MeurerORCiDGND, Madlen MarxGND, Maxi Zumpe, Karoline Ehlert, Juliet Gray, Alberto Garaventa, Carla Manzitti, Shifra Ash, Thomas KlingebielORCiDGND, James F. Beck, Victoria Castel, Dominique Valteau-Couanet, Hans Loibner, Ruth LadensteinORCiD, Holger LodeORCiDGND |
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URN: | urn:nbn:de:hebis:30:3-477127 |
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DOI: | https://doi.org/10.3390/cancers10100387 |
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ISSN: | 2072-6694 |
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Pubmed Id: | https://pubmed.ncbi.nlm.nih.gov/30336605 |
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Parent Title (English): | Cancers |
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Publisher: | MDPI |
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Place of publication: | Basel |
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Document Type: | Article |
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Language: | English |
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Year of Completion: | 2018 |
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Date of first Publication: | 2018/10/17 |
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Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
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Release Date: | 2018/10/23 |
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Tag: | HACA; anti-GD2 immunotherapy; ch14.18/CHO; complement dependent cytotoxicity; long-term infusion; neuroblastoma; pain |
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Volume: | 10 |
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Issue: | 10, Art. 387 |
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Page Number: | 16 |
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First Page: | 1 |
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Last Page: | 16 |
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Note: | This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0). |
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HeBIS-PPN: | 439187605 |
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Institutes: | Medizin / Medizin |
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Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
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Sammlungen: | Universitätspublikationen |
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Licence (German): | Creative Commons - Namensnennung 4.0 |
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