Concerning 691 and 717, they show high levels of GD2 and resistance to NK cell-mediated killing that can be overcome by the administration of dinutuximab beta, the anti-GD2 monoclonal antibody applied in the clinic. NB is a heterogeneous tumor representing a further hurdle in NB immunotherapy. However, different from what was reported with NB commercial cells and independent of their MES/ADRN phenotype, the expression of GD2 and its displayed sensitivity to anti-GD2 mAb ADCC indicated the possible effectiveness of anti-GD2 immunotherapy.
6 months ago
Journal • IO biomarker
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WWTR1 (WW Domain Containing Transcription Regulator 1) • ENG (Endoglin)
P2, N=95, Active, not recruiting, Children's Oncology Group | Trial completion date: Jun 2024 --> Mar 2025 | Trial primary completion date: Jun 2024 --> Mar 2025
9 months ago
Trial completion date • Trial primary completion date
Anti-GD2-directed immunotherapy represents an additional therapeutic option in high-risk metastasized RB. Moreover, CD276 is another target of interest.
P1, N=82, Suspended, National Cancer Institute (NCI) | Trial completion date: Jun 2026 --> Dec 2032 | Trial primary completion date: Jun 2026 --> Dec 2032
11 months ago
Trial completion date • Trial primary completion date
This comprehensive review summarizes clinical data regarding efficacy and safety of GM-CSF, recombinant human granulocyte colony-stimulating factor (G-CSF) or no cytokine in combination with anti-GD2 monoclonal antibodies (ie, dinutuximab, dinutuximab beta or naxitamab) for immunotherapy of patients with high-risk neuroblastoma...Suboptimal efficacy outcomes with G-CSF raise concerns about its suitability as an alternative to GM-CSF as an adjuvant in immunotherapy for patients with high-risk neuroblastoma. While programs exist to facilitate obtaining GM-CSF and anti-GD2 monoclonal antibodies in regions where they are not commercially available, continued work is needed to ensure equitable therapeutic options are available globally.
Thereafter, we evaluate efficacy of rapamycin, irinotecan and dinutuximab beta in single drug approach in each model and proceed to combination assessments to understand their impact on OTS cell proliferation and migration and enable the selection the potential therapeutic combo to use. Clearly, we were able to show in patient biopsies, as well as in our patient-derived models that the 3 targets were largely expressed and might be efficiently inhibited to prevent OTS cell proliferation and migration.
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.
DB holds promise for the treatment of insulinoma. The study should be supported by in vivo studies.
1 year ago
Journal
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AKT2 (V-akt murine thymoma viral oncogene homolog 2) • PTHLH (Parathyroid Hormone Like Hormone) • ATF2 (Activating Transcription Factor 2) • CA 19-9 (Cancer antigen 19-9) • ELK1 (ETS Transcription Factor ELK1) • HSP90AA1 (Heat Shock Protein 90 Alpha Family Class A Member 1Heat Shock Protein 90 Alpha Family Class A Member 1) • KCNN4 (Potassium Calcium-Activated Channel Subfamily N Member 4)
Treatment was generally well tolerated, including in patients with co-morbidities and those who had experienced toxicities with previous therapies. These findings demonstrate that the use of dinutuximab beta is feasible and beneficial as a first-line or R/R treatment in routine clinical practice in Poland.
Using the ICER Matrix to grade orphan therapies according to their treatment benefit and certainty is feasible. However, the assessment involves subjective judgements based on heterogenous evidence. Tools such as the ICER Matrix might aid decision makers to evaluate treatment benefit and its certainty when comparing therapies across indications.
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. 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.
An analysis of tumor tissue revealed both TIGIT and TIGIT ligand expression on myeloid-derived suppressor cells (MDSCs), suggesting additional mechanisms of protumoral effects in NB. Our data show that the targeting of TIGIT and PD-L1 significantly improves the antitumor efficacy of anti-GD2 immunotherapy, with DB presenting a new effective combinatorial treatment strategy against high-risk tumors.
over 1 year ago
Journal • PD(L)-1 Biomarker • IO biomarker
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PD-1 (Programmed cell death 1) • TIGIT (T Cell Immunoreceptor With Ig And ITIM Domains 2) • PVR (PVR Cell Adhesion Molecule) • NECTIN2 (Nectin Cell Adhesion Molecule 2)
Here, two NIR-I dyes (IRDye800CW and IR12), with long tails emitting in the SWIR range, were conjugated with a clinical-grade anti-GD2 monoclonal antibody (dinutuximab-beta) to compare NIR-I and SWIR imaging for neuroblastoma surgery...Crucially, the system enabled higher TBR at SWIR wavelengths than at NIR-I wavelengths, verifying SWIR imaging enables high-contrast delineation of tumor margins. This work demonstrates that by combining the high-specificity of anti-GD2 antibodies with the availability and translatability of existing NIR-I dyes, along with the advantages of SWIR in terms of depth and tumor signal-to-background ratio, GD2-targeted NIR-I/SWIR-guided surgery could improve the treatment of neuroblastoma patients, warranting investigation in future clinical trials.
In the pseudometastatic model and in five orthotopic NB mouse models, weekly iv treatments with 1 mg/kg MGC018 for 3 weeks resulted in delayed tumor growth and increased survival rates compared to animals treated with an irrelevant (anti-CD20) duocarmycin-ADC or an anti-GD2 antibody (dinutuximab beta). A 4-week course of treatment further ameliorated MGC018 antitumor effect in both the orthotopic and resected NB models and increased the survival of NB-bearing mice co-treated with TOpotecan-TEMozolomide (TOTEM), the standard-of-care therapy for relapsed disease. MGC018 exerts relevant antitumor activity in pre-clinical NB models and may represent a potential candidate for future NB clinical translation.
DB therapy after haplo-SCT in patients with rHR-NB is feasible, with low risk of inducing GvHD, and results in long-term remissions likely attributable to increased antineuroblastoma activity by donor-derived effector cells.
Vincristine, etoposide, carboplatin, cisplatin, and cyclophosphamide, as well as DB, were used at concentrations achieved in pediatric clinical trials. The CD107a/IFN-γ assay revealed no additional activation of NK cells by the chemotherapeutics. The synergistic effect of DB with chemotherapeutics seems primarily attributed to the combined toxicity of antibody-dependent cellular cytotoxicity and chemotherapy, which supports further clinical evaluation in frontline induction therapy.
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.
Analysis of tumor tissue revealed increased NK and cytotoxic T cell numbers and reduced Treg compared to controls. Our data show that FAP-IL-2v is a potent immunocytokine that augments the efficacy of DB against NB, providing a promising alternative to IL-2.
Haploidentical stem cell transplantation (haplo SCT) in Stage IV neuroblastoma relapsed patients has been proven efficacious, while immunotherapy utilizing the anti-GD2 antibody dinutuximab beta has become a standard treatment for neuroblastoma...No impact of FcGR polymorphism on event-free and overall survival was found. Collectively, this study has shown that in-patient functional immunomonitoring is feasible and valuable in contributing to the understanding of anti-cancer combinatorial treatments such as haplo SCT and antibody immunotherapy.
3 years ago
Clinical • Clinical Trial,Phase I • Clinical Trial,Phase II • Journal • IO biomarker
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IL6 (Interleukin 6) • TNFA (Tumor Necrosis Factor-Alpha) • IL2 (Interleukin 2) • FCGR2A (Fc fragment of IgG receptor IIa)
Here we provide proof-of-concept for EKTOMUN preclinical efficacy against neuroblastoma, presenting this bispecific trAb as a promising new agent to fight neuroblastoma.
over 3 years ago
Preclinical • Journal
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CD8 (cluster of differentiation 8) • CD4 (CD4 Molecule)
No difference in outcome was observed between rCOJEC and MSKCC-N5; however, acute toxicity was less with rCOJEC, and therefore rCOJEC is the preferred induction regimen for International Society of Pediatric Oncology European Neuroblastoma Group.
Clinical parameters (body temperature, vital signs, Lansky performance score), laboratory values [C-reactive protein, IFN-γ, IL-6, and IL-18 (cycle 1)], and requirement of i.v. co-medication (e.g., morphine, metamizole) were systematically assessed. Patients receiving regimen B showed a shorter time to achieve normal vital parameters and required less co-medication compared to patients in regimen A that resulted in a shorter median time period to discharge and to achieve a potential outpatient status (6d regimen A and 3-5d regimen B after start of antibody infusion, respectively). This study shows that omitting IL-2 from immunotherapy with DB allows reduced co-medication and hospitalization time and therefore results in improved quality of life in patients with high-risk neuroblastoma.