Impact of IL-2 on Treatment Tolerance in Patients With High-Risk Neuroblastoma Treated With Dinutuximab Beta-Based Immunotherapy

Abstract

Patients with high-risk neuroblastoma treated with continuous long-term infusion of anti-GD2 antibody dinutuximab beta (DB) in combination with IL-2 show an acceptable safety profile. Here, we compared treatment tolerance with and without IL-2. Ninety-nine patients with high-risk neuroblastoma received up to five cycles of DB given as long-term infusion (10 mg/m2/d, 100 mg/m2; per cycle) with IL-2 (53 patients; regimen A; 6 × 106 IU/m2/d; 60 × 106 IU/m2/cycle) and without IL-2 (46 patients; regimen B) in a single-center compassionate use program. 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 with stable clinical parameters and that did not require co-medication were defined as potential “outpatient candidates.” Patients showed higher levels of body temperature and CRP in regimen A compared to B. However, IL-6 serum concentrations were similar in pts of both cohorts in the first cycle. 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.

Immunomonitoring of Stage IV Relapsed Neuroblastoma Patients Undergoing Haploidentical Hematopoietic Stem Cell Transplantation and Subsequent GD2 (ch14.18/CHO) Antibody Treatment

“…Administration of dinutuximab beta led to a highly significant increase in activated NK cells and elevated serum marker of inflammation (IL2, TNFa, IL6, and CrP) which is in line with previous findings in the autologous setting (10). Additional administration of IL-2 neither boosted NK-cell activity nor increased the inflammatory response which may result from the massive cytokine secretion induced by the antibody infusion itself, thus giving no rationale for IL-2 application in subsequent studies, which have been proposed in a trial with continuous long-term infusion of dinutuximab (33). To complement in-patient monitoring, NK-cell activity was analyzed ex vivo.…”

The quest to develop an effective therapy for neuroblastoma

“…In another study, using Dinutuximab and NK cell immunotherapy in an experimental mouse model of NB (Zobel et al, 2020) this combination promoted prolonged survival when the treatment was started before resection of primary tumors. In another NB clinical trial, omitting IL-2 from dinutuximab beta immunotherapy regimens resulted in a clear increase in drug tolerance, earlier hospital discharge, and better quality of life for treated patients (Cicek et al, 2020). Taken together these clinical observations support the use of dinutuximab treatment for high-risk NB patients in a clinical setting.…”

Immunotherapy by anti-GD2 antibodies in patients with primary high-risk neuroblastoma, primary resistant and relapsed disease: Raisa Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation, First Pavlov State Medical University of St. Petersburg experience

“…Вероятно, меньшие, чем в сходных когортах [35], число и степень наиболее серьезных осложнений (гипотензия, синдром повышенной проницаемости капилляров, реакции гиперчувствительности) объяснялись особенностями режима введения препарата с применением 24-часовой инфузии [14,31], а также отсутствием в схеме лечения ИЛ-2 [15]. Препараты ИЛ-2 не применялись с учетом данных SIOPEN о сравнимой эффективности схемы лечения, не включающей в себя ИЛ-2 [36], при меньшей токсичности данной терапии [16]. В целом проявления токсичности эффективно купировались на фоне проведения сопроводительной терапии.…”

“…В рамках первых крупных когорт пациентов, получавших антитела к GD2, побочные эффекты терапии III-IV степени развились более чем у 50 % пациентов [11]. В дальнейшем токсичность ИТ удалось в значительной степени снизить как за счет изменения режима введения антител [15], так и модификации режима сопроводительной терапии [16]. Кроме того, постепенно меняется спектр используемых препаратов с заменой мышиных антител химерными, а в последующем и полностью гуманизированными [17], что позволяет снизить число побочных эффектов терапии за счет менее выраженной активации механизмов комплемент-опосредованного лизиса.…”