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.

First, we demonstrate that 9464D-GD2 is nonresponsive to a preferred salvage regimen: anti-GD2 with temozolomide and irinotecan. Second, we have previously shown that adding agonist anti-CD40 mAb and CpG to a regimen of radiotherapy, anti-GD2/IL2 immunocytokine and anti-CTLA-4, cured a substantial fraction of mice bearing small 9464D-GD2 tumors; here, we further characterize this regimen by showing that radiotherapy and hu14.18-IL2 are necessary components, while anti-CTLA-4, anti-CD40, or CpG can individually be removed, and CpG and anti-CTLA-4 can be removed together, while maintaining efficacy. We have developed and characterized a regimen that can cure mice of a high-risk neuroblastoma that is refractory to the current clinical regimen for relapsed/refractory disease. Ongoing preclinical work is directed towards ways to potentially translate these findings to a regimen appropriate for clinical testing.

P3, N=478, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting

P1, N=82, Active, not recruiting, National Cancer Institute (NCI) | Suspended --> Active, not recruiting

P3, N=1449, Active, not recruiting, National Cancer Institute (NCI)

P2, N=24, Completed, Fundació Sant Joan de Déu | Unknown status --> Completed

P1, N=44, Recruiting, University Hospital Southampton NHS Foundation Trust | Trial completion date: Nov 2023 --> Jul 2025 | Trial primary completion date: Nov 2023 --> Sep 2024

P2, N=42, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2023 --> Sep 2024

Moreover, ex vivo culture with IL-7+IL-15+IL-21 could favor CAR-T products with a longer persistence in the host. Our strategy may complement the current use of Dinutuximab in treating NB through its combination with a targeted CAR-T cell approach.

P2, N=46, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Recruiting --> Active, not recruiting

P1, N=60, Recruiting, Y-mAbs Therapeutics | Trial completion date: Jan 2025 --> Apr 2027 | Trial primary completion date: Mar 2024 --> Mar 2027

P1, N=27, Active, not recruiting, National Cancer Institute (NCI)

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

P=N/A, N=40, Recruiting, University Hospital, Strasbourg, France

P1/2, N=31, Recruiting, Nationwide Children's Hospital | Trial primary completion date: Dec 2023 --> Dec 2024

P1, N=85, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Jan 2024 --> Jan 2025 | Trial primary completion date: Jan 2024 --> Jan 2025

P1, N=8, Completed, BeiGene | Active, not recruiting --> Completed

Anti-GD2-directed immunotherapy represents an additional therapeutic option in high-risk metastasized RB. Moreover, CD276 is another target of interest.

P2, N=153, Active, not recruiting, St. Jude Children's Research Hospital | Trial completion date: Dec 2023 --> Dec 2024

P2, N=24, Recruiting, Anna Raciborska | Not yet recruiting --> Recruiting

P1, N=82, Suspended, National Cancer Institute (NCI) | Trial completion date: Jun 2026 --> Dec 2032 | Trial primary completion date: Jun 2026 --> Dec 2032

Unexpectedly, her brain metastasis responded clinically, histologically, and by imaging to the treatment. We believe this is the first documented case of NBL of the brain responding to NAX.

P1/2, N=186, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Dec 2023 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Dec 2025

P3, N=478, Not yet recruiting, National Cancer Institute (NCI)

In a phase I clinical trial, administration of 3xTx (with an immunocytokine fusion of tumor-specific antibody and IL-2, hu14.18-IL2) to subjects with metastatic melanoma increases peripheral CD8 T cell effector polyfunctionality...NK cell depletion increases T infiltration, diminishing CD8 T cell-dependent antitumor response. These findings demonstrate that NK cells sustain and propagate CD8 T cell immunity following 3xTx.

P1/2, N=42, Recruiting, Margaret Gatti-Mays | Phase classification: P1b/2 --> P1/2

P1/2, N=42, Recruiting, Margaret Gatti-Mays

P=N/A, N=7, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Nov 2023 --> Nov 2024 | Trial primary completion date: Nov 2023 --> Nov 2024

P1b/2, N=42, Recruiting, Margaret Gatti-Mays | Not yet recruiting --> Recruiting

The externally controlled analyses presented show a relapse risk reduction in patients with HRNB treated with postimmunotherapy DFMO.

P2, N=41, Completed, National Cancer Institute (NCI) | Active, not recruiting --> Completed

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.

P1, N=13, Active, not recruiting, New Approaches to Neuroblastoma Therapy Consortium | Trial completion date: Sep 2023 --> Sep 2024 | Trial primary completion date: Sep 2023 --> Sep 2024

We investigated the combination of humanized anti-GD2 mAb naxitamab (Hu3F8), irinotecan (I), temozolomide (T), and sargramostim (GM-CSF)-HITS-against primary resistant HR-NB. Cohort 1 had a 3-year OS of 84.8% and EFS 54.4%, which are statistically significant improvements (EFS p = 0.0041 and OS p = 0.0037) compared to cohort 2. In conclusion, naxitamab-based chemo-immunotherapy is effective against primary chemo-resistant HR-NB, increasing long-term outcomes when administered early during the course of treatment.

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.

We observed excellent outcomes in 99 pts treated with proton radiotherapy for HR-NBL from 2010 through 2021, with 81% of patients alive and 92% free of LR. Our data suggest that LR is rare after GTR and 21.6 Gy, and uncommon among pts with STR treated with 36 Gy. A small number of pts received 21.6 Gy after STR, however, this experience suggests that a subset of pts with RD may require RT dose > 21.6 Gy. Further work is required to further characterize individual management of PS in pts with HR-NBL with regard to extent of RD and biologic disease features.

P2, N=34, Active, not recruiting, Children's Oncology Group | Trial completion date: Dec 2023 --> Sep 2024 | Trial primary completion date: Dec 2023 --> Jun 2023

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.

P4, N=62, Not yet recruiting, SciClone Pharmaceuticals

Results found that dinutuximab β is not a cost-effective treatment option for children with high-risk NB unless its price is significantly reduced.

P2, N=48, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Jun 2023 --> Jun 2024 | Trial primary completion date: Jun 2023 --> Jun 2024