Validated detection of human anti-chimeric immune responses in serum of neuroblastoma patients treated with ch14.18/CHO

Siebert, Nikolai; Eger, Christin; Seidel, Daniel; Jüttner, Madlen; Lode, Holger N.

doi:10.1016/j.jim.2014.04.001

Cited by 15 publications

(21 citation statements)

References 8 publications

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“…18 Therefore, we analyzed patients treated with the LTI regimen for HACA development using the previously described ELISA method. 12 We observed the induction of HACA in 10/53 (19%) of patients. These data are in line with our previous report showing HACA in 21% patients treated with STI of ch14.18/CHO 6 and in (3/14) 21% of patients treated with STI of ch14.18/SP2/0, 15 indicating similar immunogenicity of ch14.18/SP2/0 and ch14.18/CHO irrespective of the treatment regimen.…”

Section: Discussionmentioning

confidence: 70%

“…12 Samples were analyzed on d 8 (prior to the start of the subsequent Ab treatment cycle) in cycles 2, 3, 4 and 5 and compared to baseline (prior to first Ab administration; d 1, cycle 1; Table 3). If HACA was detectable in any serum sample (LOD of HACA-ELISA 1.1 mg/ml), patients were defined as HACA-positive.…”

Section: Analysis Of Haca and Impact On Pkmentioning

confidence: 99%

“…12 Briefly, based on the one arm binding principle, ch14.18/CHO was used as a capture Ab and biotinylated ch14.18/CHO as a detection Ab. 1% (w/v) BSA/PBS (pH 7.4) buffer served as a blocking reagent.…”

Section: Human Anti-chimeric Ab Responsementioning

confidence: 99%

“…Instead of STI over five days (5 £ 20 mg/m2/d, 8h infusion), 53 high-risk NB patients received the same cumulative dose of 100 mg/m2 ch14.18/CHO given as a continuous long-term infusion (LTI) over 10 days (10£ 10 mg/m2/d). Similar to the reported randomized, open label Phase 3 clinical trial, 4 patients received ch14.18/CHO in combination with a cytokine (6£ 106/d IU/m2 subcutaneous (s.c.) interleukin (IL)-2, d 1-5, followed by a combined application of IL-2 (d [8][9][10][11][12] with LTI of ch14.18/CHO (d 8-18)). A reduced toxicity profile of the new treatment protocol was indicated by significantly decreased morphine usage and low pain scores.…”

Section: Introductionmentioning

confidence: 99%

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

Siebert

Eger

Seidel

et al. 2016

mAbs

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(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.

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Section: Discussionmentioning

confidence: 70%

Section: Analysis Of Haca and Impact On Pkmentioning

confidence: 99%

Section: Human Anti-chimeric Ab Responsementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Siebert

Eger

Seidel

et al. 2016

mAbs

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“…To reduce side effects including neuropathic pain, a Phase I/II clinical trial was initiated based on the same cumulative dose of ch14.18/CHO (100 mg/m 2 /cycle) infused over a longer time period (ten days) (Eudra CT: 2009-018077-3). Within these trial protocols, a set of immune monitoring assays including the detection of ch14.18/CHO serum levels [11] and human anti-ch14.18/CHO immune responses [12], are implemented with the aim to identify immune biomarkers correlating with clinical response to ch14.18/CHO therapy. For a comprehensive assessment, validated bioassays to determine effector functions of ch14.18/CHO namely patient specific ADCC and CDC are of critical importance.…”

Section: Introductionmentioning

confidence: 99%

Functional Bioassays for Immune Monitoring of High-Risk Neuroblastoma Patients Treated with ch14.18/CHO Anti-GD2 Antibody

et al. 2014

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Effective treatment of high-risk neuroblastoma (NB) remains a major challenge in pediatric oncology. Human/mouse chimeric monoclonal anti-GD2 antibody (mAb) ch14.18 is emerging as a treatment option to improve outcome. After establishing a production process in Chinese hamster ovary (CHO) cells, ch14.18/CHO was made available in Europe for clinical trials. Here, we describe validated functional bioassays for the purpose of immune monitoring of these trials and demonstrate GD2-specific immune effector functions of ch14.18/CHO in treated patients. Two calcein-based bioassays for complement-dependent- (CDC) and antibody-dependent cellular cytotoxicity (ADCC) were set up based on patient serum and immune cells tested against NB cells. For this purpose, we identified LA-N-1 NB cells as best suited within a panel of cell lines. Assay conditions were first established using serum and cells of healthy donors. We found an effector-to-target (E:T) cell ratio of 20∶1 for PBMC preparations as best suited for GD2-specific ADCC analysis. A simplified method of effector cell preparation by lysis of erythrocytes was evaluated revealing equivalent results at an E:T ratio of 40∶1. Optimal results for CDC were found with a serum dilution at 1∶8. For validation, both within-assay and inter-assay precision were determined and coefficients of variation (CV) were below 20%. Sample quality following storage at room temperature (RT) showed that sodium-heparin-anticoagulated blood and serum are stable for 48 h and 96 h, respectively. Application of these bioassays to blood samples of three selected high-risk NB patients treated with ch14.18/CHO (100 mg/m2) revealed GD2-specific increases in CDC (4.5–9.4 fold) and ADCC (4.6–6.0 fold) on day 8 compared to baseline, indicating assay applicability for the monitoring of multicenter clinical trials requiring sample shipment at RT for central lab analysis.

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Long-term, continuous infusion of single-agent dinutuximab beta for relapsed/refractory neuroblastoma: an open-label, single-arm, Phase 2 study

Lode,

Ehlert,

Huber

et al. 2023

Br J Cancer

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Background Short-term infusions of dinutuximab beta plus isotretinoin and cytokines administered in previous immunotherapy studies in neuroblastoma were associated with severe pain. Here, long-term, continuous infusion of single-agent dinutuximab beta was evaluated in patients with relapsed/refractory neuroblastoma. Methods In this open-label, single-arm, Phase 2 study, patients with either refractory or relapsed high-risk neuroblastoma received dinutuximab beta by continuous infusion over 10 days of each cycle, for up to five cycles. The primary endpoint was objective response rate 24 weeks after the end of cycle 5. Secondary endpoints included adverse events, intravenous morphine use, best response, duration of response, and three-year progression-free and overall survival. Results Of the 40 patients included, 38 had evaluable response. Objective response rate was 26% and best response rate 37%. Median duration of response was 238 days (IQR 108–290). Three-year progression-free and overall survival rates were 31% (95% CI 17–47) and 66% (95% CI 47–79), respectively. Prophylactic intravenous morphine use and duration of use decreased with increasing cycles. The most common grade 3 treatment-related adverse events were pain, diarrhea, and hypokalemia. Conclusion Long-term continuous infusion of single-agent dinutuximab beta is tolerable and associated with clinically meaningful responses in patients with relapsed/refractory high-risk neuroblastoma. Clinical trial registration The study is registered with ClinicalTrials.gov (NCT02743429) and EudraCT (2014-000588-42).

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Validated detection of human anti-chimeric immune responses in serum of neuroblastoma patients treated with ch14.18/CHO

Cited by 15 publications

References 8 publications

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

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

Functional Bioassays for Immune Monitoring of High-Risk Neuroblastoma Patients Treated with ch14.18/CHO Anti-GD2 Antibody

Long-term, continuous infusion of single-agent dinutuximab beta for relapsed/refractory neuroblastoma: an open-label, single-arm, Phase 2 study

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