anti-GD2 Antibody Dinutuximab Research Articles

Yoga as a non-pharmacologic therapy to reduce dinutuximab-induced pain in patients with neuroblastoma.

Anti-GD2 antibodies are key components of treatment for high-risk neuroblastoma; however, they cause neuropathic pain. Yoga therapy may help reduce pain and distress associated with anti-GD2 therapy. Children 3years of age or older with neuroblastoma participated in individualized yoga therapy while receiving the anti-GD2 antibody dinutuximab (DIN). Yoga therapy was deemed feasible if patients participated during 60% or more of DIN admissions. Patients and caregivers assessed pain/distress before and after yoga therapy with a distress thermometer (DT) and Wong-Baker FACES pain rating scale and completed questionnaires regarding satisfaction with yoga therapy. Therapy was deemed efficacious if there was a ≥1 point pain score change and reduction in distress after yoga. Eighteen patients were enrolled; 52 encounters (admissions for DIN) were evaluable. Ten of 18 were female, three of 18 were Hispanic, and 10/18 were White. Median age at enrollment was 5.5years (range: 3-11). Yoga therapy was feasible in 39/52 (75%) encounters. Significant reductions in caregiver-reported pain and distress and reductions in patient-reported pain and distress after yoga therapy were reported. Twelve of 18 caregivers completed questionnaires: seven agreed/strongly agreed that yoga was valuable, and nine agreed/strongly agreed to continued participation in yoga. Thirty-four of 36 clinicians reported that they would recommend yoga therapy for other patients receiving DIN. Yoga therapy was feasible during DIN therapy and may be effective in reducing DIN-associated pain and distress. Future studies are needed to evaluate changes in opioid usage with the addition of yoga therapy during anti-GD2 antibody therapy.

Single-agent activity of the anti-GD2 antibody dinutuximab beta given as a long-term infusion in relapsed and refractory neuroblastoma (APN311-304).

10034 Background: Severe pain is a common side effect associated with short-term infusions of anti-GD2 antibodies in combination with cytokines and isotretinoin and was reduced by the long-term infusison (LTI) strategy. We investigated efficacy and tolerability of a single-agent dinutuximab beta (DB)-LTI in patients with primary refractory or relapsed (R/R) stage 4 neuroblastoma (NB). Methods: Patients with R/R-NB were enrolled into an open label phase II trial. Previous anti-GD2 antibody therapies were allowed, if anti-DB antibody could not be detected. Patients received 5 cycles of DB-LTI (100 mg/m2/10 days). The primary endpoint was objective INRC response 24 weeks after the end of cycle 5. A sample size of 40 patients provides at least 80% power to reject the null hypothesis of an objective response in < 10% of patients if the true objective response rate observed was 25% (overall 1-sided significance level 0.05, exact binomial test). Secondary endpoints included safety, morphine use, best response and duration of response, pharmacodynamics and pharmacokinetics, 3-year progression-free (PFS) and overall survival (OS). Results: 40 patients were treated and 38 patients had evaluable response. The objective response rate 24 weeks after the end of cycle 5 was 26% (10/38) (CR/PR) (p = 0.0034) and 32% (12/38) (CR/PR/MR), with a higher response rate in refractory vs. relapsed patients (50% vs 25%; p = 0.0159). The best response rate was 53% (20/38). Of 14 patients with bone marrow involvement, 13 patients responded (93%) (12 CR, 1 PR). The median duration of response (CR/PR) was 238 days (95% CI [108-290d]). The 3-year probability of PFS was 31% (95% CI [0.17–0.47]) and of OS was 66% (95% CI [0.47–0.79]). Survival was higher for patients with refractory compared to relapsed disease (PFS 47% vs 19%, OS 93% vs 50%; p = 0.015). Grade 3 treatment emergent adverse events (TEAE) were pain (18%), diarrhea (5%), and hypokalemia (5%) and grade 3 hypotension, capillary leak and neurotoxicity were not observed. In patients who experienced pain, mean pain scores (scale 0–10, where 0 is no pain) were low and decreased between cycles 1 and 2: pain score at rest decreased from 1.01 to 0.30, and at stress from 1.45 to 0.28. There were no grade 4 or 5 TEAEs. The morphine usage decreased from cycle 2 to 5 (C2 95%; C3 12%; C4 0%; C5 0%). DB peak serum concentration in cycle 1 was 10.8±0.7 µg/ml and patients showed 7- and 11-fold increase of antibody-dependent cell-mediated (ADCC) and complement-dependent cytotoxicity (CDC), respectively. Anti-DB antibodies were found in 24% of patients. There was no association and no trend between exposure to DB (area under the curve, peak ot trough level) and response rate or survival in this cohort. Conclusions: Single-agent treatment with single agent dinutuximab beta given as long LTI without cytokines and without isotretinoin is effective and highly tolerable in R/R-NB. Clinical trial information: NCT02743429 .

Dinutuximab beta combined with chemotherapy in patients with relapsed or refractory neuroblastoma.

Prognosis in children with refractory and relapsed high-risk neuroblastoma is poor. Only a minority of patients obtain remission when treated with second-line chemotherapy regimens. Chemotherapy combined with anti-GD2 antibodies has previously been shown to increase response and survival rates. We retrospectively analyzed a cohort of 25 patients with relapsed or refractory high-risk neuroblastoma who were treated with irinotecan/temozolomide chemotherapy in combination with the anti-GD2 antibody dinutuximab beta. The therapy resulted in an objective response rate of 64%, with 32% of patients achieving a complete response. Response to treatment was observed in patients with refractory disease (n=5) and those with first (n=12) or consecutive (n=8) relapses, including patients with progressing disease. In four patients, best response was achieved after more than 5 cycles, suggesting that some patients may benefit from prolonged chemotherapy and dinutuximab beta treatment. Fourteen of our 25 patients had previously received dinutuximab beta, four of whom achieved complete response and six partial response (objective response rate 71%). The therapy was well tolerated, even in heavily pre-treated patients and those who had previously received dinutuximab beta treatment. Toxicities were comparable to those previously reported for the individual therapies, and no discontinuations due to toxicities occurred. Combination of chemotherapy with dinutuximab beta is a promising treatment option for patients with relapsed or refractory high-risk neuroblastoma and should be further explored in clinical studies.

KIR/KIR-ligand genotypes and clinical outcomes following chemoimmunotherapy in patients with relapsed or refractory neuroblastoma: a report from the Children’s Oncology Group

BackgroundIn the Children’s Oncology Group ANBL1221 phase 2 trial for patients with first relapse/first declaration of refractory high-risk neuroblastoma, irinotecan and temozolomide (I/T) combined with either temsirolimus (TEMS) or immunotherapy...

Chemotherapeutics Used for High-Risk Neuroblastoma Therapy Improve the Efficacy of Anti-GD2 Antibody Dinutuximab Beta in Preclinical Spheroid Models.

Anti-disialoganglioside GD2 antibody ch14.18/CHO (dinutuximab beta, DB) improved the outcome of patients with high-risk neuroblastoma (HR-NB) in the maintenance phase. We investigated chemotherapeutic compounds used in newly diagnosed patients in combination with DB. Vincristine, etoposide, carboplatin, cisplatin, and cyclophosphamide, as well as DB, were used at concentrations achieved in pediatric clinical trials. The effects on stress ligand and checkpoint expression by neuroblastoma cells and on activation receptors of NK cells were determined by using flow cytometry. NK-cell activity was measured with a CD107a/IFN-γ assay. Long-term cytotoxicity was analyzed in three spheroid models derived from GD2-positive neuroblastoma cell lines (LAN-1, CHLA 20, and CHLA 136) expressing a fluorescent near-infrared protein. Chemotherapeutics combined with DB in the presence of immune cells improved cytotoxic efficacy up to 17-fold compared to in the controls, and the effect was GD2-specific. The activating stress and inhibitory checkpoint ligands on neuroblastoma cells were upregulated by the chemotherapeutics up to 9- and 5-fold, respectively, and activation receptors on NK cells were not affected. 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.

Recent Evidence-Based Clinical Guide for the Use of Dinutuximab Beta in Pediatric Patients with Neuroblastoma.

The anti-GD2 antibody dinutuximab beta (Qarziba®) has been added to the present standard of care for patients with high-risk neuroblastoma in Europe based on the positive results obtained in different studies. In both the first-line and relapsed/refractory settings, treatment with dinutuximab beta attains objective clinical responses in children with high-risk neuroblastoma. Its incorporation has changed the outcome for these patients and optimized management should be guaranteed to minimize possible adverse effects. Most prevalent adverse events include pain, allergic reactions, fever and capillary leak syndrome. There are still no evidence-based clinical guidelines that include the latest published evidence to optimize its use, as it depends on the experience gained in each referral center. 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.

The Immunocytokine FAP-IL-2v Enhances Anti-Neuroblastoma Efficacy of the Anti-GD2 Antibody Dinutuximab Beta.

Simple SummarySince IL-2 co-treatment did not show any therapeutic benefit in the GD2-directed treatment of high-risk neuroblastoma (NB) but strongly induced regulatory T cells (Treg), we investigated here the immunocytokine FAP-IL-2v stimulating NK and cytotoxic T cells without induction of Treg. We first detected FAP on NB- and myeloid-derived suppressor cells (MDCS) in tumor tissue and showed a tumor-cell-dependent enhancement in FAP expression by fibroblasts. Treatment of leukocytes with FAP-IL-2v increased ADCC mediated by the anti-GD2 antibody dinutuximab beta (DB) against NB cells. We next evaluated the antitumor efficacy of a combinatorial immunotherapy by applying DB and FAP-IL-2v and observed strongly reduced tumor growth and improved survival in experimental mice. 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.Treatment of high-risk neuroblastoma (NB) patients with the anti-GD2 antibody (Ab) dinutuximab beta (DB) improves survival by 15%. Ab-dependent cellular cytotoxicity (ADCC) is the major mechanism of action and is primarily mediated by NK cells. Since IL-2 co-treatment did not show a therapeutic benefit but strongly induced Treg, we investigated here a DB-based immunotherapy combined with the immunocytokine FAP-IL-2v, which comprises a fibroblast activation protein α (FAP)-specific Ab linked to a mutated IL-2 variant (IL-2v) with abolished binding to the high-affinity IL-2 receptor, thus stimulating NK cells without induction of Treg. Effects of FAP-IL-2v on NK cells, Treg and ADCC mediated by DB, as well as FAP expression in NB, were investigated by flow cytometry, calcein-AM-based cytotoxicity assay and RT-PCR analysis. Moreover, the impact of soluble factors released from tumor cells on FAP expression by primary fibroblasts was assessed. Finally, a combined immunotherapy with DB and FAP-IL-2v was evaluated using a resistant syngeneic murine NB model. Incubation of leukocytes with FAP-IL-2v enhanced DB-specific ADCC without induction of Treg. FAP expression on NB cells and myeloid-derived suppressor cells (MDCS) in tumor tissue was identified. A tumor-cell-dependent enhancement in FAP expression by primary fibroblasts was demonstrated. Combination with DB and FAP-IL-2v resulted in reduced tumor growth and improved survival. 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.

Phase 2 study of anti-disialoganglioside antibody, dinutuximab, in combination with GM-CSF in patients with recurrent osteosarcoma: A report from the Children's Oncology Group

PurposeNovel effective therapies are urgently needed in recurrent osteosarcoma. GD2 is expressed in human osteosarcoma tumours and cell lines. This study evaluated the disease control rate (DCR) in patients with recurrent osteosarcoma treated with the anti-GD2 antibody dinutuximab plus cytokine therapy as compared to historical outcomes. MethodsAOST1421 was a single-arm Phase 2 study for patients with recurrent pulmonary osteosarcoma in complete surgical remission. Patients received up to five cycles of dinutuximab (70 mg/m2/cycle) with granulocyte-macrophage colony-stimulating factor (GM-CSF). Two different dinutuximab infusion schedules were studied: 35 mg/m2/day over 20 h (2 days) and 17.5 mg/m2/day over 10 h (4 days). Primary end point was DCR, defined as a proportion of patients event free at 12 months from enrolment. The historical benchmark was 12-month DCR of 20% (95% CI 10–34%). Dinutuximab would be considered effective if ≥ 16/39 patients remained event free. Secondary objectives included toxicity evaluation and pharmacokinetics. ResultsThirty-nine eligible patients were included in the outcome analysis. Dinutuximab did not demonstrate evidence of efficacy as 11/39 patients remained event free for a DCR of 28.2% (95% CI 15–44.9%). One of 136 administered therapy cycles met criteria for unacceptable toxicity when a patient experienced sudden death of unknown cause. Other ≥ Grade 3 toxicities included pain, diarrhoea, hypoxia, and hypotension. Pharmacokinetic parameters were similar in the two schedules. ConclusionsThe combination of dinutuximab with GM-CSF did not significantly improve DCR in recurrent osteosarcoma. Dinutuximab toxicity and pharmacokinetics in adolescent and young adult osteosarcoma patients were similar to younger patients. Other strategies for targeting GD2 in osteosarcoma are being developed.

First-line Anti-GD2 Therapy Combined With Consolidation Chemotherapy in 3 Patients With Newly Diagnosed Metastatic Ewing Sarcoma or Ewing-like Sarcoma.

Despite multimodal therapy, the prognosis of patients with metastatic Ewing sarcoma (ES) remains poor, with new treatments urgently needed. The disialoganglioside GD2, a well-established tumor-associated antigen, is expressed in 40% to 90% of ES cells, making it a suitable therapeutic target. Here we report 3 cases with newly diagnosed, metastatic, GD2-positive ES or Ewing-like sarcoma treated with the anti-GD2 antibody dinutuximab beta in addition to standard chemotherapeutic regimens. Treatment was well-tolerated, and all patients achieved complete remission, without evidence of relapse. First-line anti-GD2 immunotherapy in patients with metastatic, GD2-positive ES or Ewing-like sarcoma represents a promising therapeutic option that warrants further clinical evaluation.

Clinical Phenotype and Management of Severe Neurotoxicity Observed in Patients with Neuroblastoma Treated with Dinutuximab Beta in Clinical Trials.

Simple SummaryNeurotoxicity is an on-target side effect of GD2-directed immunotherapy due to the expression of GD2 on healthy cells. Patients with high-risk neuroblastoma who receive treatment with anti-GD2 immunotherapy, therefore, require close observation and supportive management to improve treatment tolerance and avoid the persistence of neurological symptoms. This study reports on the incidence, clinical course and management of patients who experienced neurotoxicity due to treatment with the anti-GD2 antibody dinutuximab beta, given with or without interleukin-2, in two clinical trials. The majority of severe neurotoxic events were observed in patients treated with dinutuximab beta combined with interleukin-2, with most patients recovering following supportive management. Given the increased risk of neurotoxic events and the lack of clinical benefit reported for the combination treatment in clinical trials, adding interleukin-2 to dinutuximab beta therapy is not recommended. The clinical experiences described here may aid clinicians in managing neurotoxicity associated with dinutuximab beta more effectively.Neurotoxicity is an off-tumour, on-target side effect of GD2-directed immunotherapy with monoclonal antibodies. Here, we report the frequency, management and outcome of patients enrolled in two prospective clinical trials who experienced severe neurotoxicity during immunotherapy with the anti-GD2 antibody dinutuximab beta (DB) administered as short-term infusion (HR-NBL1/SIOPEN study, randomisation R2, EudraCT 2006-001489-17) or as long-term infusion (HR-NBL1/SIOPEN study, randomisation R4, EudraCT 2006-001489-17 and LTI/SIOPEN study, EudraCT 2009-018077-31), either alone or with subcutaneous interleukin-2 (scIL-2). The total number of patients included in this analysis was 1102. Overall, 44/1102 patients (4.0%) experienced Grade 3/4 neurotoxicities (HR-NBL1 R2, 21/406; HR-NBL1 R4, 8/408; LTI study, 15/288), including 27 patients with severe neurotoxicities (2.5%). Events occurred predominantly in patients receiving combined treatment with DB and scIL-2. Neurotoxicity was treated using dexamethasone, prednisolone, intravenous immunoglobulins and, in two patients, plasmapheresis, which was highly effective. While neurological recovery was observed in 16 of 21 patients with severe neurotoxicities, 5/1102 (0.45%) patients experienced persistent and severe neurological deficits. In conclusion, severe neurotoxicity is most commonly observed in patients receiving DB with scIL-2. Considering the lack of clinical benefit for IL-2 in clinical trials so far, the administration of IL-2 alongside DB is not recommended.

Dinutuximab beta in the treatment of high-risk neuroblastoma: A follow-up of a case series in Bratislava.

Despite therapeutic advances, high-risk neuroblastoma is still associated with a poor long-term prognosis. Immunotherapy with the anti-GD2 antibody dinutuximab beta has recently been added to the standard of care for patients with high-risk neuroblastoma in our center in Bratislava, and our initial experience with dinutuximab beta has been reported previously. Here we provide a follow-up on the outcomes of 7 patients who were treated with dinutuximab beta under clinical practice conditions at our center.Medical records of 31 patients diagnosed with neuroblastoma between 2017 and 2020 at the Children's Hematology and Oncology Clinic in Bratislava were retrospectively reviewed and 7 patients with high-risk neuroblastoma who were treated with dinutuximab beta were identified. All 7 patients received dinutuximab beta as continuous infusion over 10 days at a dose of 10 mg/m2/day for 5 cycles, following induction and consolidation therapy. Supportive therapy was administered to manage adverse events. Clinical outcomes and treatment tolerance were evaluated.Six of 7 patients treated with dinutuximab beta achieved complete remission, with a median duration of response of 21.5 months as of January 2022, and 1 displayed stable disease 21 months after treatment completion. Treatment was tolerable in most patients, with the majority of adverse events managed with supportive care.Dinutuximab beta is an effective immunotherapy for patients with high-risk neuroblastoma in routine clinical practice when coupled with optimal supportive management of adverse events.

Managing Adverse Events Associated with Dinutuximab Beta Treatment in Patients with High-Risk Neuroblastoma: Practical Guidance.

Neuroblastoma is the most common extracranial solid tumour in children, accounting for 15% of all paediatric cancer deaths. High-risk neuroblastoma is a particularly challenging-to-treat form of disease that requires multimodality treatment, consisting of chemotherapy, surgery, high-dose chemotherapy with autologous haematopoietic stem cell rescue, radiotherapy and differentiation therapy. However, despite intense multimodal treatment regimens, the prognosis for this patient population remains poor. In recent years, immunotherapy with anti-disialoganglioside 2 (anti-GD2) antibodies was found to improve survival rates for patients with high-risk neuroblastoma. Based on studies led by the SIOPEN (International Society of Paediatric Oncology European Neuroblastoma) group, the anti-GD2 antibody dinutuximab beta was approved for use in high-risk neuroblastoma by the European Medicines Agency and has been implemented into the standard of care in many countries across Europe. However, immunotherapy with dinutuximab beta is associated with a number of adverse events that may be challenging for clinicians, such as pain, fever, hypersensitivity reactions and capillary leak syndrome. While these adverse events are considered manageable, there are currently no formal guidelines to support clinicians with their management. The aim of this article is to discuss the management of the most common adverse events encountered in clinical practice and to provide practical guidance to assist clinicians in minimising toxicity associated with dinutuximab beta.

CD47-SIRPα Checkpoint Inhibition Enhances Neutrophil-Mediated Killing of Dinutuximab-Opsonized Neuroblastoma Cells.

Simple SummaryCurrent immunotherapy for high-risk neuroblastoma patients involves treatment with anti-GD2 antibody dinutuximab, which has significantly improved the survival rate. Still, approximately half of the patients succumb to the tumor; therefore, efforts to improve their prognosis are urgently needed. Since T cell targeting immune checkpoint inhibitors in neuroblastoma are limited due to the low immunogenicity of these tumors, alternative immunotherapeutic approaches should be studied. The therapeutic targeting of the innate immune checkpoint CD47-SIRPα has the ability to enhance antitumor effects of myeloid cells, especially in the presence of cancer-opsonizing antibodies. Given that neutrophil ADCC is a dominant effector mechanism leading to the eradication of dinutuximab-opsonized neuroblastoma cells, we have investigated the therapeutic potential of anti-GD2 antibody in combination with CD47-SIRPα inhibition. We demonstrate here that the capacity of neutrophils to kill dinutuximab-opsonized neuroblastoma cells is controlled by the CD47-SIRPα axis and its disruption promotes their cytotoxic potential even further, significantly improving dinutuximab responsiveness.High-risk neuroblastoma, especially after recurrence, still has a very low survival rate. Immune checkpoint inhibitors targeting T cells have shown remarkable clinical efficacy in adult solid tumors, but their effects in pediatric cancers have been limited so far. On the other hand, targeting myeloid immune checkpoints, such as CD47-SIPRα, provide the opportunity to enhance antitumor effects of myeloid cells, including that of neutrophils, especially in the presence of cancer-opsonizing antibodies. Disialoganglioside (GD2)-expressing neuroblastoma cells targeted with anti-GD2 antibody dinutuximab are in part eradicated by neutrophils, as they recognize and bind the antibody targeted tumor cells through their Fc receptors. Therapeutic targeting of the innate immune checkpoint CD47-SIRPα has been shown to promote the potential of neutrophils as cytotoxic cells in different solid tumor indications using different cancer-targeting antibodies. Here, we demonstrate that the capacity of neutrophils to kill dinutuximab-opsonized neuroblastoma cells is also controlled by the CD47-SIRPα axis and can be further enhanced by antagonizing CD47-SIRPα interactions. In particular, CD47-SIRPa checkpoint inhibition enhanced neutrophil-mediated ADCC of dinutuximab-opsonized adrenergic neuroblastoma cells, whereas mesenchymal neuroblastoma cells may evade immune recognition by a reduction of GD2 expression. These findings provide a rational basis for targeting CD47-SIRPα interactions to potentiate dinutuximab responsiveness in neuroblastomas with adrenergic phenotype.

Anti-GD2 antibody dinutuximab inhibits triple-negative breast tumor growth by targeting GD2+ breast cancer stem-like cells

BackgroundTriple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype with no effective standard therapy. Breast cancer stem-like cells (BCSCs) in primary TNBCs are reported to be responsible for...

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

Immunotherapy holds great promise for the treatment of pediatric cancers. In neuroblastoma, the recent implementation of anti-GD2 antibody Dinutuximab into the standard of care has improved patient outcomes substantially. However, 5-year survival rates are still below 50% in patients with high-risk neuroblastoma, which has sparked investigations into novel immunotherapeutic approaches. T cell-engaging therapies such as immune checkpoint blockade, antibody-mediated therapy and adoptive T cell therapy have proven remarkably successful in a range of adult cancers but still meet challenges in pediatric oncology. In neuroblastoma, their limited success may be due to several factors. Neuroblastoma displays low immunogenicity due to its low mutational load and lack of MHC-I expression. Tumour infiltration by T and NK cells is especially low in high-risk neuroblastoma and is prognostic for survival. Only a small fraction of tumour-infiltrating lymphocytes shows tumour reactivity. Moreover, neuroblastoma tumours employ a variety of immune evasion strategies, including expression of immune checkpoint molecules, induction of immunosuppressive myeloid and stromal cells, as well as secretion of immunoregulatory mediators, which reduce infiltration and reactivity of immune cells. Overcoming these challenges will be key to the successful implementation of novel immunotherapeutic interventions. Combining different immunotherapies, as well as personalised strategies, may be promising approaches. We will discuss the composition, function and prognostic value of tumour-infiltrating lymphocytes (TIL) in neuroblastoma, reflect on challenges for immunotherapy, including a lack of TIL reactivity and tumour immune evasion strategies, and highlight opportunities for immunotherapy and future perspectives with regard to state-of-the-art developments in the tumour immunology space.

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

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.

Initiation of immunotherapy with activated natural killer cells and anti-GD2 antibody dinutuximab prior to resection of primary neuroblastoma prolongs survival in mice

BackgroundImmunotherapy with anti-disialoganglioside dinutuximab has improved survival for children with high-risk neuroblastoma (NB) when given after induction chemotherapy and surgery. However, disease recurrence and resistance persist. Dinutuximab efficacy has not...

Outcomes and toxicities in patients (pts) non-randomly assigned to immunotherapy Children’s Oncology Group (COG) ANBL0032.

10523 Background: Immunotherapy with the anti-GD2 antibody dinutuximab plus sargramostim (GM-CSF), aldesleukin (IL-2) and isotretinoin following consolidation therapy improved outcome for high-risk neuroblastoma (HRNBL) pts enrolled on COG ANBL0032. Randomization was halted in 2009; subsequent pts were non-randomly assigned to immunotherapy. Toxicities and survival were evaluated. Methods: HRNBL pts < 31 years old with a pre-autologous stem cell transplant (ASCT) response of ≥ partial response (PR) were eligible. Demographics, INSS stage, tumor biology, 1993 INRC pre-ASCT response and toxicities were summarized using descriptive statistics. Five-year (yr) EFS and OS from time of study enrollment were estimated. Results: From 2009-2015, 1,183 pts were non-randomly assigned to immunotherapy. 96.7% (n = 1,144) were ≥18 months old and 83.1% (n = 765/921) had stage 4 disease. 45.1% (n = 363/805) of tumors with known biology were MYCN amplified, 94.5% (n = 749/793) had unfavorable histology, and 54.9% (n = 397/723) were diploid. Pre-ASCT, 352 (29.8%) pts had complete response (CR), 418 (35.3%) had very good partial response (VGPR), and 413 (34.9%) had PR. 1,042 (88.1%) pts underwent a single and 141 (11.9%) underwent tandem ASCT. For the entire cohort, 5-yr EFS was 61.1±1.9% and 5-yr OS was 71.9±1.7%. 5-yr EFS and OS for pts ≥18 months of age with stage 4 disease (n = 746) were 58.4±2.3% and 71.0±2.1%. 5-yr EFS and OS were 82.3±4.8% and 86.7±4.2% among pts with stage 3 disease (n = 110). EFS but not OS was superior for those with a CR/VGPR pre-ASCT vs. PR (5-yr EFS: 64.2±2.2% vs. 55.4±3.2%, p = 0.0133; OS: 72.7±2.1% vs. 70.5±2.9%, p = 0.3811). There was a trend toward improved OS for those treated with tandem vs. single transplant (5-yr EFS: 65.9±4.3% vs. 60.4±2.1%, p = 0.1282; OS: 76.5±3.8% vs. 71.2±1.9%, p = 0.0704). Grade ≥3 toxicities ( > 10% of pts) during GM-CSF and IL-2-containing cycles, respectively, included pain (15.6/11.4%), fever (15.1/32.7%), anemia (18.9/21.7%), thrombocytopenia (13.9/17.4%), lymphopenia (12.3/16.0%), and hypokalemia (13.3/25.2%). Additional Grade ≥3 toxicities ( > 10% of pts) included hypoxia (10.1%) during GM-CSF-containing cycles, and anaphylaxis (12.0%), neutropenia (16.1%), hyponatremia (16.5%), and hypotension (13.8%) during IL-2-containing cycles. Conclusions: In this large cohort of HRNBL pts treated with immunotherapy, 5-yr EFS was 61.1%. Superior EFS was observed for pts with stage 3 disease and for those with CR/VGPR pre-ASCT. IL-2-containing cycles were associated with increased toxicity. Clinical trial information: NCT00026312.

Anti-CD105 Antibody Eliminates Tumor Microenvironment Cells and Enhances Anti-GD2 Antibody Immunotherapy of Neuroblastoma with Activated Natural Killer Cells.

We determined whether elimination of CD105+ cells in the tumor microenvironment (TME) with anti-CD105 antibodies enhanced anti-disialoganglioside (GD2) antibody dinutuximab therapy of neuroblastoma when combined with activated natural killer (aNK) cells. The effect of MSCs and monocytes on antibody-dependent cellular cytotoxicity (ADCC) mediated by dinutuximab with aNK cells against neuroblastoma cells was determined in vitro. ADCC with anti-CD105 mAb TRC105 and aNK cells against MSCs, monocytes, and endothelial cells, which express CD105, was evaluated. Anti-neuroblastoma activity in immunodeficient NSG mice of dinutuximab with aNK cells without or with anti-CD105 mAbs was determined using neuroblastoma cell lines and a patient-derived xenograft. ADCC mediated by dinutuximab with aNK cells against neuroblastoma cells in vitro was suppressed by addition of MSCs and monocytes, and dinutuximab with aNK cells was less effective against neuroblastomas formed with coinjected MSCs and monocytes in NSG mice than against those formed by tumor cells alone. Anti-CD105 antibody TRC105 with aNK cells mediated ADCC against MSCs, monocytes, and endothelial cells. Neuroblastomas formed in NSG mice by two neuroblastoma cell lines or a patient-derived xenograft coinjected with MSCs and monocytes were most effectively treated with dinutuximab and aNK cells when anti-human (TRC105) and anti-mouse (M1043) CD105 antibodies were added, which depleted human MSCs and murine endothelial cells and macrophages from the TME. Immunotherapy of neuroblastoma with anti-GD2 antibody dinutuximab and aNK cells is suppressed by CD105+ cells in the TME, but suppression is overcome by adding anti-CD105 antibodies to eliminate CD105+ cells.

Activated Natural Killer Cells in Combination with Anti-GD2 Antibody Dinutuximab Improve Survival of Mice after Surgical Resection of Primary Neuroblastoma.

Immunotherapy of neuroblastoma that remains after myeloablative chemotherapy with anti-GD2 antibody dinutuximab has increased the two-year event-free and overall survival of high-risk neuroblastoma patients; however, 40% of patients develop recurrent disease during or after this treatment. To determine the potential of such antibody-based immunotherapy earlier in treatment, a mouse model was developed in which surgical resection of the primary tumor was followed by therapy of residual disease with dinutuximab combined with ex vivo-activated human natural killer (aNK) cells. The effect of combining dinutuximab with human aNK cells was determined in vitro with cellular cytotoxicity and Matrigel invasion assays. The in vivo efficacy of dinutuximab and aNK cells against neuroblastoma was assessed following resection of primary tumors formed by two cell lines or a patient-derived xenograft (PDX) in immunodeficient NOD-scid gamma mice. In vitro, the combination of aNK cells and dinutuximab caused cytotoxicity and decreased invasiveness of three human neuroblastoma cell lines. Treatment of mice with dinutuximab combined with aNK cells after surgical resection of primary intrarenal tumors formed by two cell lines or a PDX decreased tumor cells in liver and bone marrow as evaluated by histopathology and bioluminescence imaging. Survival of mice after resection of these tumors was most significantly increased by treatment with dinutuximab combined with aNK cells compared with that of untreated mice. The combination of dinutuximab and adoptively transferred human aNK cells following surgical resection of primary neuroblastomas significantly improves survival of immunodeficient mice.