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Biologics : Targets & Therapy 2019Neuroblastoma (NB) is a pediatric cancer of the sympathetic nervous system which accounts for 8% of childhood cancers. Most NBs express high levels of the... (Review)
Review
Neuroblastoma (NB) is a pediatric cancer of the sympathetic nervous system which accounts for 8% of childhood cancers. Most NBs express high levels of the disialoganglioside GD2. Several antibodies have been developed to target GD2 on NB, including the human/mouse chimeric antibody ch14.18, known as dinutuximab. Dinutuximab used in combination with granulocyte-macrophage colony-stimulating factor, interleukin-2, and isotretinoin (13-retinoic acid) has a US Food and Drug Administration (FDA)-registered indication for treating high-risk NB patients who achieved at least a partial response to prior first-line multi-agent, multimodality therapy. The FDA registration resulted from a prospective randomized trial assessing the benefit of adding dinutuximab + cytokines to post-myeloablative maintenance therapy for high-risk NB. Dinutuximab has also shown promising antitumor activity when combined with temozolomide and irinotecan in treating NB progressive disease. Clinical activity of dinutuximab and other GD2-targeted therapies relies on the presence of the GD2 antigen on NB cells. Some NBs have been reported as GD2 low or negative, and such tumor cells could be nonresponsive to anti-GD2 therapy. As dinutuximab relies on complement and effector cells to mediate NB killing, factors affecting those components of patient response may also decrease dinutuximab effectiveness. This review summarizes the development of GD2 antibody-targeted therapy, the use of dinutuximab in both up-front and salvage therapy for high-risk NB, and the potential mechanisms of resistance to dinutuximab.
PubMed: 30613134
DOI: 10.2147/BTT.S114530 -
Neoplasia (New York, N.Y.) Aug 2023While immunotherapy for pediatric cancer has made great strides in recent decades, including the FDA approval of agents such as dinutuximab and tisgenlecleucel, these...
While immunotherapy for pediatric cancer has made great strides in recent decades, including the FDA approval of agents such as dinutuximab and tisgenlecleucel, these successes have rarely impacted children with pediatric central nervous system (CNS) tumors. As our understanding of the biological underpinnings of these tumors evolves, new immunotherapeutics are undergoing rapid clinical translation specifically designed for children with CNS tumors. Most recently, there have been notable clinical successes with oncolytic viruses, vaccines, adoptive cellular therapy, and immune checkpoint inhibition. In this article, the immunotherapy working group of the Pacific Pediatric Neuro-Oncology Consortium (PNOC) reviews the current and future state of immunotherapeutic CNS clinical trials with a focus on clinical trial development. Based on recent therapeutic trials, we discuss unique immunotherapy clinical trial challenges, including toxicity considerations, disease assessment, and correlative studies. Combinatorial strategies and future directions will be addressed. Through internationally collaborative efforts and consortia, we aim to direct this promising field of immuno-oncology to the next frontier of successful application against pediatric CNS tumors.
Topics: Child; Humans; Central Nervous System Neoplasms; Oncolytic Viruses; Immunotherapy
PubMed: 37244226
DOI: 10.1016/j.neo.2023.100909 -
Journal of Clinical Oncology : Official... Jan 2024Long-term survival in high-risk neuroblastoma (HRNB) is approximately 50%, with mortality primarily driven by relapse. Eflornithine (DFMO) to reduce risk of relapse...
PURPOSE
Long-term survival in high-risk neuroblastoma (HRNB) is approximately 50%, with mortality primarily driven by relapse. Eflornithine (DFMO) to reduce risk of relapse after completion of immunotherapy was investigated previously in a single-arm, phase II study (NMTRC003B; ClinicalTrials.gov identifier: NCT02395666) that suggested improved event-free survival (EFS) and overall survival (OS) compared with historical rates in a phase III trial (Children Oncology Group ANBL0032; ClinicalTrials.gov identifier: NCT00026312). Using patient-level data from ANBL0032 as an external control, we present new analyses to further evaluate DFMO as HRNB postimmunotherapy maintenance.
PATIENTS AND METHODS
NMTRC003B (2012-2016) enrolled patients with HRNB (N = 141) after standard up-front or refractory/relapse treatment who received up to 2 years of continuous treatment with oral DFMO (750 ± 250 mg/m twice a day). ANBL0032 (2001-2015) enrolled patients with HRNB postconsolidation, 1,328 of whom were assigned to dinutuximab (ch.14.18) treatment. Selection rules identified 92 NMTRC003B patients who participated in (n = 87) or received up-front treatment consistent with (n = 5) ANBL0032 (the DFMO/treated group) and 852 patients from ANBL0032 who could have been eligible for NMTRC003B after immunotherapy, but did not enroll (the NO-DFMO/control group). The median follow-up time for DFMO/treated patients was 6.1 years (IQR, 5.2-7.2) versus 5.0 years (IQR, 3.5-7.0) for NO-DFMO/control patients. Kaplan-Meier and Cox regression compared EFS and OS for overall groups, 3:1 (NO-DFMO:DFMO) propensity score-matched cohorts balanced on 11 baseline demographic and disease characteristics with exact matching on , and additional sensitivity analyses.
RESULTS
DFMO after completion of immunotherapy was associated with improved EFS (hazard ratio [HR], 0.50 [95% CI, 0.29 to 0.84]; = .008) and OS (HR, 0.38 [95% CI, 0.19 to 0.76]; = .007). The results were confirmed with propensity score-matched cohorts and sensitivity analyses.
CONCLUSION
The externally controlled analyses presented show a relapse risk reduction in patients with HRNB treated with postimmunotherapy DFMO.
Topics: Child; Humans; Eflornithine; Propensity Score; Neoplasm Recurrence, Local; Neuroblastoma; Recurrence; Disease-Free Survival
PubMed: 37883734
DOI: 10.1200/JCO.22.02875 -
Drugs May 2015United Therapeutics Corporation and the National Cancer Institute are developing dinutuximab (Unituxin™; ch14.18), a monoclonal antibody targeting GD2, for the... (Review)
Review
United Therapeutics Corporation and the National Cancer Institute are developing dinutuximab (Unituxin™; ch14.18), a monoclonal antibody targeting GD2, for the treatment of neuroblastoma. GD2 is a glycolipid found on the surface of tumour cells, which is overexpressed in neuroblastoma. Dinutuximab, an IgG1 human/mouse chimeric switch variant of murine monoclonal antibody 14G2a, binds to GD2 and induces antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity. The US FDA has recently approved the use of dinutuximab combination therapy for the treatment of high-risk neuroblastoma in paediatric patients. The marketing authorization application for dinutuximab is under regulatory review in the EU, and phase I-III development is underway in several other countries. This article summarizes the milestones in the development of dinutuximab leading to this first approval for use (in combination with granulocyte macrophage colony-stimulating factor, interleukin-2 and 13-cis retinoic acid) in the treatment of paediatric patients with high-risk neuroblastoma who achieve at least partial response to prior first-line multiagent, multimodality therapy.
Topics: Animals; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Child; Drug Approval; Gangliosides; Humans; Neuroblastoma; United States; United States Food and Drug Administration
PubMed: 25940913
DOI: 10.1007/s40265-015-0399-5 -
Frontiers in Oncology 2023Prognosis in children with refractory and relapsed high-risk neuroblastoma is poor. Only a minority of patients obtain remission when treated with second-line...
Prognosis in children with refractory and relapsed high-risk neuroblastoma is poor. Only a minority of patients obtain remission when treated with second-line chemotherapy regimens. Chemotherapy combined with anti-GD2 antibodies has previously been shown to increase response and survival rates. We retrospectively analyzed a cohort of 25 patients with relapsed or refractory high-risk neuroblastoma who were treated with irinotecan/temozolomide chemotherapy in combination with the anti-GD2 antibody dinutuximab beta. The therapy resulted in an objective response rate of 64%, with 32% of patients achieving a complete response. Response to treatment was observed in patients with refractory disease (n=5) and those with first (n=12) or consecutive (n=8) relapses, including patients with progressing disease. In four patients, best response was achieved after more than 5 cycles, suggesting that some patients may benefit from prolonged chemotherapy and dinutuximab beta treatment. Fourteen of our 25 patients had previously received dinutuximab beta, four of whom achieved complete response and six partial response (objective response rate 71%). The therapy was well tolerated, even in heavily pre-treated patients and those who had previously received dinutuximab beta treatment. Toxicities were comparable to those previously reported for the individual therapies, and no discontinuations due to toxicities occurred. Combination of chemotherapy with dinutuximab beta is a promising treatment option for patients with relapsed or refractory high-risk neuroblastoma and should be further explored in clinical studies.
PubMed: 36816982
DOI: 10.3389/fonc.2023.1082771 -
Australian Prescriber Dec 2020
Review
PubMed: 33363307
DOI: 10.18773/austprescr.2020.068 -
Pediatric Blood & Cancer Sep 2022Dinutuximab, an immune-mediated therapy indicated for high-risk neuroblastoma, targets the protein disialoganglioside (GD2) on neuroblastoma cells, neurons, and... (Observational Study)
Observational Study
BACKGROUND
Dinutuximab, an immune-mediated therapy indicated for high-risk neuroblastoma, targets the protein disialoganglioside (GD2) on neuroblastoma cells, neurons, and peripheral nerve fibers. Off-target effects lead to severe nerve pain. Pain regimens including continuous infusion opioids are required during treatment courses. Our institution utilizes a combination of intravenous (i.v.) lidocaine infusions and morphine for the treatment of dinutuximab-associated neuropathic pain.
OBJECTIVE
The primary outcome of this study was to compare morphine equivalents for cycle 1 of dinutuximab at an institution that uses i.v. lidocaine (primary) versus those that do not (comparison). Secondary outcomes included both dinutuximab infusion time and safety of i.v. lidocaine.
METHODS
A retrospective, multicentered, electronic chart review was performed at three tertiary academic medical centers. Patients between 0 and 18 years of age during their first course of dinutuximab were included to evaluate the primary outcome of adjuvant morphine equivalents needed.
RESULTS
Twenty-one patients were identified for inclusion. Total morphine equivalents at the primary institution were 1.87 mg/kg versus 1.79 mg/kg at the comparison institutions (P = 0.413). Dinutuximab infusion time was statistically significantly less at the primary institution: 610.5 minutes versus 676.23 minutes (P = 0.046). Only one patient at the primary institution experienced nausea, vomiting, and paresthesias.
CONCLUSIONS
This study did not find a statistically significant difference in morphine equivalents between patients receiving i.v. lidocaine and those who did not. Lidocaine use resulted in a statistically significant lower dinutuximab infusion time. Our data suggest it is a safe adjuvant medication, for use outside of the pediatric intensive care unit, in the treatment of dinutuximab-associated neuropathic pain.
Topics: Antibodies, Monoclonal; Child; Humans; Lidocaine; Morphine Derivatives; Neuralgia; Neuroblastoma; Retrospective Studies
PubMed: 35441791
DOI: 10.1002/pbc.29653 -
European Journal of Cancer (Oxford,... Sep 2022Novel effective therapies are urgently needed in recurrent osteosarcoma. GD2 is expressed in human osteosarcoma tumours and cell lines. This study evaluated the disease...
Phase 2 study of anti-disialoganglioside antibody, dinutuximab, in combination with GM-CSF in patients with recurrent osteosarcoma: A report from the Children's Oncology Group.
PURPOSE
Novel effective therapies are urgently needed in recurrent osteosarcoma. GD2 is expressed in human osteosarcoma tumours and cell lines. This study evaluated the disease control rate (DCR) in patients with recurrent osteosarcoma treated with the anti-GD2 antibody dinutuximab plus cytokine therapy as compared to historical outcomes.
METHODS
AOST1421 was a single-arm Phase 2 study for patients with recurrent pulmonary osteosarcoma in complete surgical remission. Patients received up to five cycles of dinutuximab (70 mg/m/cycle) with granulocyte-macrophage colony-stimulating factor (GM-CSF). Two different dinutuximab infusion schedules were studied: 35 mg/m/day over 20 h (2 days) and 17.5 mg/m/day over 10 h (4 days). Primary end point was DCR, defined as a proportion of patients event free at 12 months from enrolment. The historical benchmark was 12-month DCR of 20% (95% CI 10-34%). Dinutuximab would be considered effective if ≥ 16/39 patients remained event free. Secondary objectives included toxicity evaluation and pharmacokinetics.
RESULTS
Thirty-nine eligible patients were included in the outcome analysis. Dinutuximab did not demonstrate evidence of efficacy as 11/39 patients remained event free for a DCR of 28.2% (95% CI 15-44.9%). One of 136 administered therapy cycles met criteria for unacceptable toxicity when a patient experienced sudden death of unknown cause. Other ≥ Grade 3 toxicities included pain, diarrhoea, hypoxia, and hypotension. Pharmacokinetic parameters were similar in the two schedules.
CONCLUSIONS
The combination of dinutuximab with GM-CSF did not significantly improve DCR in recurrent osteosarcoma. Dinutuximab toxicity and pharmacokinetics in adolescent and young adult osteosarcoma patients were similar to younger patients. Other strategies for targeting GD2 in osteosarcoma are being developed.
Topics: Adolescent; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Child; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Neoplasm Recurrence, Local; Osteosarcoma; Young Adult
PubMed: 35809374
DOI: 10.1016/j.ejca.2022.05.035 -
Cancers Sep 2023Administration of chemoimmunotherapy using concurrent chemotherapy and an anti-GD2 monoclonal antibody (mAb), dinutuximab (DIN), demonstrated efficacy for the treatment...
Administration of chemoimmunotherapy using concurrent chemotherapy and an anti-GD2 monoclonal antibody (mAb), dinutuximab (DIN), demonstrated efficacy for the treatment of relapsed and refractory neuroblastoma. Chemoimmunotherapy, using a humanized anti-GD2 mAb, demonstrated a signal of activity in a phase 2 study for the treatment of patients with newly diagnosed high-risk neuroblastoma (HRNBL). In this single-institution retrospective study, patients with HRNBL received an Induction chemotherapy regimen plus DIN in all Induction cycles. Toxicity and response data were abstracted from the electronic medical record. Toxicities were graded by CTCAE v.5.0. The end of Induction (EOI) objective response rate was determined using the Revised International Neuroblastoma Response Criteria. Twenty-seven patients with HRNBL (23 newly diagnosed, 16 females, median age 3.9 years) started Induction chemoimmunotherapy from 27 January 2017 to 28 December 2022. All patients received DIN with all cycles of Induction therapy, and all but one patient completed Induction therapy. The most common non-hematologic grade ≥ 3 toxicities included fever (44%), hypoxemia (20%), and hypoalbuminemia (11%). End of Induction responses included eighteen with a complete response (CR), seven with a partial response (PR), one with progressive disease (PD), and zero with a minor response or stable disease. Twenty-six of twenty-seven patients (96%) completed all Induction cycles and were evaluable for a response. The EOI response of PR or better in the evaluable cohort was 96%. Dinutuximab was well tolerated with all Induction cycles, demonstrated an encouraging EOI response rate, and should be evaluated in a randomized study.
PubMed: 37760578
DOI: 10.3390/cancers15184609 -
Lung Cancer (Amsterdam, Netherlands) Apr 2022Topotecan is approved as second-line treatment for small cell lung cancer (SCLC). Irinotecan is also frequently used given its more convenient schedule and superior... (Randomized Controlled Trial)
Randomized Controlled Trial
Randomized phase 3 study of the anti-disialoganglioside antibody dinutuximab and irinotecan vs irinotecan or topotecan for second-line treatment of small cell lung cancer.
INTRODUCTION
Topotecan is approved as second-line treatment for small cell lung cancer (SCLC). Irinotecan is also frequently used given its more convenient schedule and superior tolerability. Preclinical studies support disialoganglioside (GD2) as an SCLC target and the combination of dinutuximab, an anti-GD2 antibody, plus irinotecan in this setting. We tested dinutuximab/irinotecan versus irinotecan or topotecan as second-line therapy in relapsed/refractory (RR) SCLC.
MATERIALS AND METHODS
Patients with RR SCLC and Eastern Cooperative Oncology Group performance status 0-1 were randomized 2:2:1 to receive dinutuximab 16-17.5 mg/m intravenous (IV)/irinotecan 350 mg/m IV (day 1), irinotecan 350 mg/m IV (day 1), or topotecan 1.5 mg/m IV (days 1-5) in 21-day cycles. The primary endpoint was overall survival (OS); secondary endpoints were progression-free survival (PFS), objective response rate (ORR; complete response [CR] + partial response [PR]), and clinical benefit rate (CBR; CR + PR + stable disease). Safety/tolerability were also assessed.
RESULTS
A total of 471 patients were randomized to dinutuximab/irinotecan (n = 187), irinotecan (n = 190), or topotecan (n = 94). Age, sex, performance status, prior therapies, and metastatic disease sites were similar between groups. Survival and response rates were not improved for patients receiving dinutuximab/irinotecan versus those receiving irinotecan or topotecan (median OS 6.9 vs 7.0 vs 7.4 months [p = 0.3132]; median PFS 3.5 vs 3.0 vs 3.4 months [p = 0.3482]; ORR confirmed 17.1% vs 18.9% vs 20.2% [p = 0.8043]; and CBR 67.4% vs 58.9% vs 68.1% [p = 0.0989]), respectively. Grade 3/4 adverse events (≥5% receiving dinutuximab/irinotecan) included neutropenia, anemia, diarrhea, and asthenia.
CONCLUSIONS
Dinutuximab/irinotecan treatment did not result in improved OS in RR SCLC versus irinotecan alone. Irinotecan administered every 21 days demonstrated comparable activity to topotecan administered daily × 5 every 21 days.
CLINICALTRIALS
gov Identifier. NCT03098030.
Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Humans; Irinotecan; Lung Neoplasms; Neoplasm Recurrence, Local; Small Cell Lung Carcinoma; Topotecan
PubMed: 35278766
DOI: 10.1016/j.lungcan.2022.03.003