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Expert Review of Clinical Pharmacology 2016Neuroblastoma (NB) is the most common extra cranial solid tumor of childhood, with 60% of patients presenting with high risk (HR) NB by means of clinical, pathological... (Review)
Review
Neuroblastoma (NB) is the most common extra cranial solid tumor of childhood, with 60% of patients presenting with high risk (HR) NB by means of clinical, pathological and biological features. The 5-year survival rate for HR-NB remains below 40%, with the majority of patients suffering relapse from chemorefractory tumor. Immunotherapy is the main strategy against minimal residual disease and clinical experience has mostly focused on monoclonal antibodies (MoAb) against the glycolipid disialoganglioside GD2. Three anti-GD2 antibodies have been tested in the clinic including murine 14G2a, human-mouse chimeric ch14.18 and 3F8. Anti-GD2 MoAb induces cellular cytoxicity against NB and is most effective when effector cells like natural killer cells, granulocytes and macrophages are amplified by cytokines. The combination of cytokines IL-2 and GM-CSF with the anti-GD2 MoAb ch14.18 (Dinutuximab) has shown a significant improvement in outcome for HR-NB. The FDA and EMA approved dinutuximab (Unituxin(R)) in 2015 for the treatment of patients with HR-NB who achieved at least a partial response after multimodality therapy.
Topics: Antibodies, Monoclonal; Antineoplastic Agents; Child; Drug Resistance, Neoplasm; Humans; Immunotherapy; Neuroblastoma
PubMed: 26934530
DOI: 10.1586/17512433.2016.1160775 -
Journal For Immunotherapy of Cancer Jul 2023Immunotherapy targeting GD2 is very effective against high-risk neuroblastoma, though administration of anti-GD2 antibodies induces severe and dose-limiting neuropathic...
BACKGROUND
Immunotherapy targeting GD2 is very effective against high-risk neuroblastoma, though administration of anti-GD2 antibodies induces severe and dose-limiting neuropathic pain by binding GD2-expressing sensory neurons. Previously, the IgG1 ch14.18 (dinutuximab) antibody was reformatted into the IgA1 isotype, which abolishes neuropathic pain and induces efficient neutrophil-mediated antibody-dependent cellular cytotoxicity (ADCC) via activation of the Fc alpha receptor (FcαRI/CD89).
METHODS
To generate an antibody suitable for clinical application, we engineered an IgA molecule (named IgA3.0 ch14.18) with increased stability, mutated glycosylation sites and substituted free (reactive) cysteines. The following mutations were introduced: N45.2G and P124R (CH1 domain), C92S, N120T, I121L and T122S (CH2 domain) and a deletion of the tail piece P131-Y148 (CH3 domain). IgA3.0 ch14.18 was evaluated in binding assays and in ADCC and antibody-dependent cellular phagocytosis (ADCP) assays with human, neuroblastoma patient and non-human primate effector cells. We performed mass spectrometry analysis of -glycans and evaluated the impact of altered glycosylation in IgA3.0 ch14.18 on antibody half-life by performing pharmacokinetic (PK) studies in mice injected intravenously with 5 mg/kg antibody solution. A dose escalation study was performed to determine in vivo efficacy of IgA3.0 ch14.18 in an intraperitoneal mouse model using 9464D-GD2 neuroblastoma cells as well as in a subcutaneous human xenograft model using IMR32 neuroblastoma cells. Binding assays and PK studies were compared with one-way analysis of variance (ANOVA), ADCC and ADCP assays and in vivo tumor outgrowth with two-way ANOVA followed by Tukey's post-hoc test.
RESULTS
ADCC and ADCP assays showed that particularly neutrophils and macrophages from healthy donors, non-human primates and patients with neuroblastoma are able to kill neuroblastoma tumor cells efficiently with IgA3.0 ch14.18. IgA3.0 ch14.18 contains a more favorable glycosylation pattern, corresponding to an increased antibody half-life in mice compared with IgA1 and IgA2. Furthermore, IgA3.0 ch14.18 penetrates neuroblastoma tumors in vivo and halts tumor outgrowth in both 9464D-GD2 and IMR32 long-term tumor models.
CONCLUSIONS
IgA3.0 ch14.18 is a promising new therapy for neuroblastoma, showing (1) increased half-life compared to natural IgA antibodies, (2) increased protein stability enabling effortless production and purification, (3) potent CD89-mediated tumor killing in vitro by healthy subjects and patients with neuroblastoma and (4) antitumor efficacy in long-term mouse neuroblastoma models.
Topics: Humans; Animals; Mice; Immunoglobulin A; Neuroblastoma; Immunotherapy; Immunoglobulin G; Antibody-Dependent Cell Cytotoxicity; Disease Models, Animal
PubMed: 37479484
DOI: 10.1136/jitc-2023-006948 -
The Journal of Pharmacology and... Sep 2019Neuroblastoma (NB) is the most common extracranial solid tumor preferentially occurring in preschoolers. Its characteristic aggressiveness and heterogeneous clinical... (Review)
Review
Neuroblastoma (NB) is the most common extracranial solid tumor preferentially occurring in preschoolers. Its characteristic aggressiveness and heterogeneous clinical behavior are especially visible in relapsed or refractory cases and hamper therapeutic success. Although the introduction of novel antitumor agents, such as dinutuximab, isotretinoin, irinotecan, or I-131- metaiodobenzylguanidine, has increased survival rates, the situation in high-risk NB remains dismal. Moreover, treatment is particularly aggressive in these patients, leading to short- and long-term toxicities. The extensive research performed using nanotechnology in recent decades has prompted its application as a therapeutic alternative to overcome some of the common limitations of conventional chemotherapy. Nevertheless, the therapeutic role of nanomedicine in pediatric tumors like NB is not fully elucidated, and to date, only albumin-bound paclitaxel nanoparticles have reached clinic stages. In this review, we summarize the current therapeutic strategies for NB with special attention to the use of nanomedicine. We also highlight the preclinical studies on passive and active targeting nanodelivery of therapeutics in experimental NB models.
Topics: Animals; Antineoplastic Agents; Brain Neoplasms; Drug Delivery Systems; Humans; Nanotechnology; Neuroblastoma
PubMed: 30635473
DOI: 10.1124/jpet.118.255067 -
Targeted Oncology Apr 2016Dinutuximab (ch14.18; Unituxin™) is a chimeric human-mouse monoclonal antibody that binds to the glycolipid antigen disialoganglioside, which is highly expressed on... (Review)
Review
Dinutuximab (ch14.18; Unituxin™) is a chimeric human-mouse monoclonal antibody that binds to the glycolipid antigen disialoganglioside, which is highly expressed on the surface of neuroblastoma cells. This intravenous drug is approved in the EU and USA as combination therapy with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-2 and isotretinoin for the postconsolidation treatment of patients with high-risk neuroblastoma. In a multinational, phase III study in this patient population, event-free survival (EFS) benefits with the dinutuximab-containing regimen versus isotretinoin alone were observed at the time of the primary (p = 0.0115) and confirmatory (p = 0.0330) efficacy analyses, although the observed p-value for the between-group difference in EFS for the primary efficacy analysis did not cross the prespecified boundary for statistical significance (p < 0.0108). Significant and sustained (5 years) overall survival benefits were seen with the dinutuximab-containing regimen versus isotretinoin alone. Despite pretreatment with analgesics, antihistamines and antipyretics, serious adverse reactions have been reported with the dinutuximab-containing regimen, with infusion reactions and neuropathy prompting the US FDA to issue boxed warnings. Dinutuximab administered in combination with GM-CSF, IL-2 and isotretinoin represents an important advance in the postconsolidation treatment of patients with high-risk neuroblastoma, with its benefits outweighing its risks in a patient population with a poor prognosis and limited therapeutic options.
Topics: Animals; Antibodies, Monoclonal; Clinical Trials, Phase III as Topic; Humans; Neuroblastoma; Randomized Controlled Trials as Topic
PubMed: 26891967
DOI: 10.1007/s11523-016-0420-2 -
Targeted Oncology Jan 2023The anti-GD2 antibody dinutuximab beta (Qarziba) has been added to the present standard of care for patients with high-risk neuroblastoma in Europe based on the positive... (Review)
Review
The anti-GD2 antibody dinutuximab beta (Qarziba) has been added to the present standard of care for patients with high-risk neuroblastoma in Europe based on the positive results obtained in different studies. In both the first-line and relapsed/refractory settings, treatment with dinutuximab beta attains objective clinical responses in children with high-risk neuroblastoma. Its incorporation has changed the outcome for these patients and optimized management should be guaranteed to minimize possible adverse effects. Most prevalent adverse events include pain, allergic reactions, fever and capillary leak syndrome. There are still no evidence-based clinical guidelines that include the latest published evidence to optimize its use, as it depends on the experience gained in each referral center. Topics such as the mode of preparation and administration, the concomitant use of interleukin-2, the recommended pediatric age and dose for its use, or the adequate management of possible toxicities are important aspects to review. The objective of this article was to update the clinical guide to management with dinutuximab beta of children with neuroblastoma based on the most recent published evidence and our own experience in clinical practice.
Topics: Child; Humans; Neuroblastoma; Antibodies, Monoclonal; Europe
PubMed: 36504394
DOI: 10.1007/s11523-022-00930-w -
PharmacoEconomics Aug 2019As part of its Single Technology Appraisal (STA) process, the UK National Institute for Health and Care Excellence (NICE) invited the manufacturer (EUSA Pharma) of... (Review)
Review
As part of its Single Technology Appraisal (STA) process, the UK National Institute for Health and Care Excellence (NICE) invited the manufacturer (EUSA Pharma) of dinutuximab beta (Qarziba) to submit evidence of its clinical and cost effectiveness for treating neuroblastoma. The BMJ Technology Assessment Group (BMJ-TAG) was commissioned to act as the Evidence Review Group (ERG), reviewing the submission from the company. The Decision Support Unit (DSU) was commissioned to review additional evidence submitted by the company and to undertake further analyses. This article presents the critical review of the company's submissions by the ERG and DSU, further analyses undertaken by the DSU, and the outcome of the NICE guidance. The clinical effectiveness for dinutuximab beta was derived from a phase III randomised controlled trial (RCT) that assessed the safety and efficacy of the addition of interleukin (IL)-2 to dinutuximab beta plus isotretinoin. This trial did not inform the relative effectiveness of dinutuximab beta versus isotretinoin alone, which was established practice in the UK for maintenance treatment. In the absence of direct evidence, the company initially conducted a naïve indirect treatment comparison against a historical control, and later performed a matching-adjusted indirect comparison (MAIC) against the isotretinoin arm of an RCT comparing dinutuximab alpha and isotretinoin. The company submitted a partitioned survival analysis model that calculated the incremental cost effectiveness of dinutuximab beta versus isotretinoin. The company's original incremental cost-effectiveness ratio (ICER) was £22,338 per quality-adjusted life-year (QALY) gained. However, the ERG were concerned that the company's ICER was not suitable for decision making, and thus carried out initial exploratory analysis as a first step to overcome the naïve estimation of treatment effectiveness in the model. The ERG's analysis estimated an ICER of £111,858 per QALY gained. In their revised analysis incorporating the MAIC and other changes as requested by the appraisal committee, the company's ICER was £24,661 per QALY gained. When the DSU incorporated longer-term isotretinoin data and made corrections to the model, the ICER increased to between £62,886 and £87,164 per QALY gained depending on the choice of survival model. A confidential Patient Access Scheme (PAS) decreased the ICERs. The ICERs with the PAS were over £40,000 per QALY gained, but the NICE committee additionally considered the patient population and its size, the disease severity, the potential for significant survival benefit and uncaptured health benefits, and recommended dinutuximab beta as a treatment option, subject to the company providing the agreed discount in the PAS.
Topics: Antibodies, Monoclonal; Antineoplastic Agents; Cost-Benefit Analysis; Humans; Isotretinoin; Neuroblastoma; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Survival Analysis; Technology Assessment, Biomedical
PubMed: 30465228
DOI: 10.1007/s40273-018-0744-0 -
Children (Basel, Switzerland) Jun 2022To determine the potential benefits and feasibility of administering maintenance therapy with dinutuximab beta for high-risk neuroblastoma (HRNB) in clinical practice, a...
To determine the potential benefits and feasibility of administering maintenance therapy with dinutuximab beta for high-risk neuroblastoma (HRNB) in clinical practice, a retrospective review of charts of patients with HRNB treated at a single center in Croatia (2012-2021) was undertaken. Of 23 patients with HRNB, 11 received up to five cycles of dinutuximab beta as part of multimodal therapy; 12 patients did not (i.e., no immunotherapy). In the no immunotherapy group, one patient had complete remission (8%), and 11 patients died of tumor progression (92%). In the dinutuximab beta group, eight patients had complete remission (73%; median duration of response 5 years and 2 months), one had stable disease (9%), and two died of disease (18%). Patients who received dinutuximab beta had a higher median event-free survival (40.0 months [range: 12.5-83.0]) and median overall survival (56.0 months [range: 16.2-101.0]) than those who did not (12.9 months [range: 3.3-126.0] and 20.7 months [3.3-126.0], respectively). Dinutuximab beta was generally well tolerated; adverse events were manageable and as reported in clinical studies. These results confirm the benefits and feasibility of maintenance therapy with dinutuximab beta as part of multimodal therapy for patients with HRNB in real-world clinical practice.
PubMed: 35883927
DOI: 10.3390/children9070943 -
Cancers Jun 2023The anti-disialoganglioside (GD2) monoclonal antibody dinutuximab beta is approved for the maintenance treatment of high-risk neuroblastoma. Dinutuximab beta combined...
Effect and Tolerance of N5 and N6 Chemotherapy Cycles in Combination with Dinutuximab Beta in Relapsed High-Risk Neuroblastoma Patients Who Failed at Least One Second-Line Therapy.
The anti-disialoganglioside (GD2) monoclonal antibody dinutuximab beta is approved for the maintenance treatment of high-risk neuroblastoma. Dinutuximab beta combined with different chemotherapy regimens is being investigated in various clinical settings. We conducted a retrospective clinical chart review of 25 patients with relapsed/refractory neuroblastoma who had failed ≥1 second-line therapy and received compassionate use treatment with dinutuximab beta long-term infusion combined with the induction chemotherapy regimens N5 (cisplatin, etoposide, vindesine) and N6 (vincristine, dacarbazine, ifosfamide, doxorubicin) recommended by the German Pediatric Oncology and Hematology Group [GPOH] guidelines. The treatment did not result in any unexpected severe toxicities or in any major treatment delays. Grade 3/4 pain was reported by 4/25 patients in cycle 1, decreasing to 0/9 patients in cycles 3 and 4. The median follow-up was 0.6 years. The best response in this group was 48% (12/25 patients), which included three patients with minor responses. At 1 year, the estimated event-free survival was 27% (95% confidence interval [CI] 8-47) and overall survival was 44% (95% CI 24-65). Combining long-term infusion of dinutuximab beta with N5 and N6 chemotherapy demonstrated an acceptable safety profile and encouraging objective response rates in heavily pretreated patients with high-risk neuroblastoma, warranting further evaluation in clinical trials.
PubMed: 37444475
DOI: 10.3390/cancers15133364 -
British Journal of Cancer Nov 2023Short-term infusions of dinutuximab beta plus isotretinoin and cytokines administered in previous immunotherapy studies in neuroblastoma were associated with severe...
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).
Topics: Humans; Morphine Derivatives; Neoplasm Recurrence, Local; Neuroblastoma; Pain
PubMed: 37813959
DOI: 10.1038/s41416-023-02457-x -
Journal of Clinical Medicine Sep 2023Despite highly intensive multimodality treatment regimens, the prognosis of patients with high-risk neuroblastoma (HRNB) and central nervous system (CNS) relapse remains...
Multimodal Therapy with Consolidating Haploidentical Stem Cell Transplantation and Dinutuximab Beta for Patients with High-Risk Neuroblastoma and Central Nervous System Relapse.
Despite highly intensive multimodality treatment regimens, the prognosis of patients with high-risk neuroblastoma (HRNB) and central nervous system (CNS) relapse remains poor. We retrospectively reviewed data from 13 patients with HRNB and CNS relapse who received multimodal therapy with consolidating haploidentical stem cell transplantation (haplo-SCT) followed by dinutuximab beta ± subcutaneous interleukin-2 (scIL-2). Following individual relapse treatment, patients aged 1-21 years underwent haplo-SCT with T/B-cell-depleted grafts followed by dinutuximab beta 20 mg/m/day × 5 days for 5-6 cycles. If a response was demonstrated after cycle 5 or 6, patients received up to nine treatment cycles. After haplo-SCT, eight patients had a complete response, four had a partial response, and one had a stable disease. All 13 patients received ≥3 cycles of immunotherapy. At the end of the follow-up, 9/13 patients (66.7%) demonstrated complete response. As of July 2023, all nine patients remain disease-free, with a median follow-up time of 5.1 years since relapse. Estimated 5-year event-free and overall survival rates were 55.5% and 65.27%, respectively. Dinutuximab beta ± scIL-2 following haplo-SCT is a promising treatment option with a generally well-tolerated safety profile for patients with HRNB and CNS relapse.
PubMed: 37834840
DOI: 10.3390/jcm12196196