Pharmacokinetics and pharmacodynamics of ch14.18/CHO in relapsed/refractory high-risk neuroblastoma patients treated by long-term infusion in combination with IL-2

Abstract

(2016) Pharmacokinetics and pharmacodynamics of ch14.18/CHO in relapsed/refractory high-risk neuroblastoma patients treated by long-term infusion in combination with IL-2, mAbs, 8:3, 604-616, DOI: 10.1080/19420862.2015 To link to this article: https://doi.org/10. 1080/19420862.2015 .8 mg£d/ml, respectively, were not significantly different. Importantly, we detected ch14.18/CHO trough concentration of 1 mg/ml at time points preceding subsequent antibody infusions after cycle 1, allowing a persistent activation of antibody effector mechanisms over the entire treatment period of 6 months. HACA responses were observed in 10/ 53 (19%) patients, similar to STI (21%), indicating LTI had no effect on the immunogenicity of ch14.18/ CHO. In conclusion, LTI of ch14.18/CHO induced effector mechanisms over the entire treatment period, and may therefore emerge as the preferred delivery method of anti-GD2 immunotherapy to NB patients.

Neuroblastoma patients with high-affinity FCGR2A, -3A and stimulatory KIR 2DS2 treated by long-term infusion of anti-GD2 antibody ch14.18/CHO show higher ADCC levels and improved event-free survival

“…Ab concentrations were determined as previously described. 6 We found no difference in ch14.18/CHO levels between patient cohorts (data not shown, p D 0.782 and p D 0.642 for FCGR2A high vs. low and FCGR3A high vs. low cohorts, respectively). These data show that differences in ADCC levels observed are not related to varying ch14.18/CHO concentrations.…”

“…5 We further showed that this novel delivery method of ch14.18/ CHO induced Ab effector mechanisms (ADCC and CDC) over the entire treatment period of 6 mo and may therefore emerge as the preferred delivery method of anti-GD 2 Ab in NB patients. 6 We reported ch14.18/CHO C max concentrations of 12.56 § 0.68 mg/mL and a CDC activity of 88 § 2%, showing a low degree of variability in contrast to patient-specific ADCC levels of 21 § 3% at this time point. 6 This variation in ADCC may be associated with many factors including the cytotoxic activity of effector cells such as natural killer (NK) cells, monocytes, neutrophils and macrophages that play a crucial role in Ab-mediated antitumor effects.…”

“…6 We reported ch14.18/CHO C max concentrations of 12.56 § 0.68 mg/mL and a CDC activity of 88 § 2%, showing a low degree of variability in contrast to patient-specific ADCC levels of 21 § 3% at this time point. 6 This variation in ADCC may be associated with many factors including the cytotoxic activity of effector cells such as natural killer (NK) cells, monocytes, neutrophils and macrophages that play a crucial role in Ab-mediated antitumor effects. 7,8 Therefore, the investigation of genes contributing to the cytotoxic activity of effector cells is of particular interest.…”

Neuroblastoma Patients' KIR and KIR-Ligand Genotypes Influence Clinical Outcome for Dinutuximab-based Immunotherapy: A Report from the Children's Oncology Group

“…Human anti-mouse antibody (HAMA) responses against murine mAbs can reduce the efficacy of the antibody immunotherapy by neutralizing the antibody, not allowing for effective recruitment of immune cells to the tumor site. It is possible that the frequent induction of a neutralizing (HAMA) response to 3F8 vs. the infrequent induction of a human anti-chimeric antibody (HACA) response to ch14.18 (23,24), or the use of IL2, may somehow account for the differential association of KIR-ligand missing status with better outcome for anti-GD2 treated patients in the MSKCC regimen but not the COG regimen.…”

Individualized therapy in neuroblastoma

“…2. Ганглиозид GD2 является целью для GD2-направленной иммунотерапии [55][56][57][58]. Он в большей степени экспрессируется на клетках первич-ной НБ.…”