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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
- Source :
- Cancers, Vol 10, Iss 10, p 387 (2018), Cancers, r-IIS La Fe. Repositorio Institucional de Producción Científica del Instituto de Investigación Sanitaria La Fe, instname, Volume 10, Issue 10
- Publication Year :
- 2018
- Publisher :
- MDPI AG, 2018.
-
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<br />d8&ndash<br />18) combined with s.c. IL-2 (6 &times<br />106 IU/m2/d<br />d1&ndash<br />5, d8&ndash<br />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 &plusmn<br />0.50 &micro<br />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.
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 20726694
- Volume :
- 10
- Issue :
- 10
- Database :
- OpenAIRE
- Journal :
- Cancers
- Accession number :
- edsair.doi.dedup.....2edea7f41a809616a3808c7535f6801a