Antitumor Activity and Tolerability of hu14.18-IL2 with GMCSF and Isotretinoin in Recurrent or Refractory Neuroblastoma: A Children's Oncology Group Phase II Study

Abstract

Purpose: Combining anti-GD2 (disialoganglioside) mAb with GM-CSF, IL2, and isotretinoin is now FDA-approved for high-risk neuroblastoma minimal residual disease (MRD) therapy. The humanized anti-GD2 antibody conjugated to IL2 (hu14.18-IL2) has clinical activity in neuroblastoma and is more effective in neuroblastoma-bearing mice than antibody and cytokine given separately. We therefore evaluated the safety, tolerability, and antitumor activity of hu14.18-IL2 given with GM-CSF and isotretinoin in a schedule similar to standard MRD therapy.Patients and Methods: Hu14.18-IL2 was given at the recommended phase II dose of 12 mg/m 2 /day on days 4-6 of a 28-day cycle with GM-CSF (250 mg/m 2 /dose, days 1-2 and 8-14) and isotretinoin (160 mg/m 2 /day, days 11-25). Tolerability was determined on the basis of the number of unacceptable toxicities observed. Response was evaluated separately for patients with disease measurable by standard radiologic criteria (stratum 1), and for patients with disease evaluable only by I 123 -metaiodobenzylguanidine (I 123 -MIBG) scan and/or bone marrow histology (stratum 2).Results: Fifty-two patients with recurrent or refractory neuroblastoma were enrolled; 51 were evaluable for toxicity and 45 were evaluable for response. Four patients had unacceptable toxicities, well below the protocol-defined rule for tolerability. Other grade 3 and 4 nonhematologic toxicities were expected and reversible. No responses were seen in stratum 1 (n ¼ 14). In stratum 2 (n ¼ 31), 5 objective responses were confirmed by central review (3 complete, 2 partial).Conclusions: Hu14.18-IL2 given in combination with GM-CSF and isotretinoin is safe and tolerable. Patients with MIBG and/or bone marrow-only disease had a 16.1% response rate, confirming activity of the combination.

The immune landscape of neuroblastoma: Challenges and opportunities for novel therapeutic strategies in pediatric oncology

“…Immunotherapy in neuroblastoma has already proven its efficacy with the introduction of the anti-GD2 antibody Dinutuximab into the standard treatment regimen, which significantly improved survival rates [6,9e13]. Even in patients with relapsed disease, Dinutuximab may have a treatment value [134,135]. The success of Dinutuximab has sparked investigations into combination therapy with cytotoxic compounds (NCT04385277, NCT03794349) [135e137], as well as cellular immunotherapy with (haploidentical) donor NK cells (NCT02573896, NCT03242603, NCT02100891, NCT04211675, NCT01807468) [138,139,148,140e147], the results of which are promising.…”

Targeting glycosphingolipids for cancer immunotherapy

“…To improve antitumor effects, hu14.18 was linked to IL-2. Clinical studies demonstrated that hu14.18-IL2 had some antitumor activities, but the maximal tolerable dosage was lower than ch14.18 due to IL2-associated toxicities [118].…”

Disialoganglioside GD2 Expression in Solid Tumors and Role as a Target for Cancer Therapy

“…Cytokines are added to antibody treatment regimens to augment effector cell function but can also produce dose-limiting systemic side effects ( 116 ). Conjugation, or fusion, of cytokines to mAbs (immunocytokines) may avoid this issue, as, for example, Hu14.18-IL-2 anti-GD2 immunocytokine ( 116 , 117 ). Other novel anti-GD2 therapies include targeted nanoparticles (presenting anticancer drugs at a sustained rate directly to tumor cells) ( 118 ), antibody–drug conjugates (allowing chemotherapeutic agents and other toxic drugs to be released into the microenvironment of the tumor via antibody targeting) ( 119 ), T-cell engaging bispecific antibodies (binding to two different antigens) ( 120 ), radiolabeled antibodies (delivering radiotherapy directly to the tumor environment) ( 121 ), and cell surface expression of chimeric antigen receptors (merging specific antigen binding with T-cell effector functions) ( 122 ).…”