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Journal of Research in Medical Sciences... 2023Dinutuximab, which is a monoclonal antibody targeting GD2 expressed in neuroblasts, improves survival when included in the therapy regimen. This article reviews the... (Review)
Review
Dinutuximab, which is a monoclonal antibody targeting GD2 expressed in neuroblasts, improves survival when included in the therapy regimen. This article reviews the importance of dinutuximab in managing neuroblastoma (NB). Dinutuximab targets high levels of GD2 expression in NB cells, thus increasing event-free survival when used in the maintenance therapy of high-risk patients with NB. Although several collaborative studies have set the standard of care for maintenance therapy, the long-term follow-up and continuous evaluation of the use of antibodies and the co-administration of other pharmacological or immunomodulatory drugs remain to be studied. Trials have shown that the use of dinutuximab for maintenance therapy can prolong the time before the first relapse and improve overall survival. However, there is uncertainty in the function of cytokines co-administered with dinutuximab, which may lead to increased toxicity without additional benefits. Recent studies on relapsed and refractory NB have shown the potential efficacy of dinutuximab. Further research is required to properly incorporate Dinutuximab in current treatment modalities.
PubMed: 38116487
DOI: 10.4103/jrms.jrms_727_22 -
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 -
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 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 -
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 -
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 -
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 -
European Journal of Cancer (Oxford,... May 2024Addition of anti-GD2 antibodies to temozolomide-based chemotherapy has demonstrated increased antitumor activity and progression-free survival in patients with...
BACKGROUND
Addition of anti-GD2 antibodies to temozolomide-based chemotherapy has demonstrated increased antitumor activity and progression-free survival in patients with relapsed/progressive high-risk neuroblastoma. However, chemo-immunotherapy is not yet approved for this indication. This study presents the chemo-immunotherapy experience in patients with relapsed/progressive high-risk neuroblastoma treated within the off-label use program of the Neuroblastoma Committee of the French Society of Pediatric Oncology (SFCE).
METHODS
Dinutuximab beta (dB) was administered alongside temozolomide-topotecan (TOTEM) or temozolomide-irinotecan (TEMIRI) at first disease relapse/progression or topotecan-cyclophosphamide (TopoCyclo) at further relapse/progression. Real-world data on demographics, treatment, antitumor activity and safety was collected from all patients after inclusion in SACHA-France (NCT04477681), a prospective national registry, which documents safety and efficacy data on innovative anticancer therapies prescribed to patients ≤ 25 years old as compassionate or off-label use.
RESULTS
Between February 2021 and July 2023, 39 patients with confirmed relapsed/progressive high-risk neuroblastoma (median age 6 years, range 1-24) were treated with dB+TopoCyclo (n = 24) or dB+TOTEM/TEMIRI (n = 15) across 17 centers. In total, 163 chemo-immunotherapy cycles were administered, main toxicities were mild or moderate, with higher incidence of hematological adverse drug reactions with dB+TopoCyclo than dB+TOTEM/TEMIRI. Objective response rate was 42% for dB+TopoCyclo (CI95% 22-63%) and 40% for dB+TOTEM/TEMIRI (CI95% 16-68%).
CONCLUSION
Similar objective response rates for dB+TopoCyclo and dB+TOTEM/TEMIRI in patients with relapsed/progressive high-risk neuroblastoma emphasize the importance of chemo-immunotherapy, irrespective of the chemotherapy backbone.
Topics: Child; Humans; Infant; Child, Preschool; Adolescent; Young Adult; Adult; Topotecan; Temozolomide; Prospective Studies; Disease-Free Survival; Antineoplastic Combined Chemotherapy Protocols; Neoplasm Recurrence, Local; Neuroblastoma; Cyclophosphamide; Irinotecan; Immunotherapy; Recurrence; Antibodies, Monoclonal
PubMed: 38489858
DOI: 10.1016/j.ejca.2024.114001