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Paediatric Drugs Jan 2023The addition of anti-disialoganglioside-2 (GD2) monoclonal antibodies (mAbs) such as dinutuximab and naxitamab to standard therapies for high-risk (HR) neuroblastoma has...
The addition of anti-disialoganglioside-2 (GD2) monoclonal antibodies (mAbs) such as dinutuximab and naxitamab to standard therapies for high-risk (HR) neuroblastoma has significantly improved outcomes for children with this devastating disease. The care for these young patients receiving treatment for HR neuroblastoma is complex, with need for the involvement of a multidisciplinary team. Clinical implementation of anti-GD2 mAb treatment requires the same harmonized team approach. The authors share the development process of this coordinated team method and practical recommendations for administration of anti-GD2 mAbs and adverse event (AE) management. Successful collaboration between nurses and other team members ensures optimal treatment and comfort of patients and their families. The primary focus of this approach is to mitigate and manage AEs associated with anti-GD2 mAb treatments, such as pain, hypotension, allergic reactions, and hypertension, and to ensure safe and effective use of anti-GD2 mAbs. The two treatments approved for use in patients with neuroblastoma, dinutuximab for patients with HR disease following a partial response or better to frontline multimodal therapy and naxitamab for refractory or relapsed HR disease in the bone or bone marrow, were studied in different administration settings and follow different regimens and infusion schedules. Therefore, AE management requirements are specific to each treatment. The awareness of these differences and implementation of appropriate AE management strategies in clinical practice are important to ensure the best possible outcomes for patients with HR neuroblastoma.
Topics: Child; Humans; Neuroblastoma; Antineoplastic Agents; Immunotherapy; Combined Modality Therapy
PubMed: 36434427
DOI: 10.1007/s40272-022-00544-9 -
Frontiers in Immunology 2021Haploidentical stem cell transplantation (haplo SCT) in Stage IV neuroblastoma relapsed patients has been proven efficacious, while immunotherapy utilizing the anti-GD2...
Immunomonitoring of Stage IV Relapsed Neuroblastoma Patients Undergoing Haploidentical Hematopoietic Stem Cell Transplantation and Subsequent GD2 (ch14.18/CHO) Antibody Treatment.
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. The combinatorial therapy of haplo SCT and dinutuximab may potentiate the efficacy of the immunotherapy. To gain further understanding of the synergistic effects, functional immunomonitoring was assessed during the clinical trial CH14.18 1021 Antibody and IL2 After haplo SCT in Children with Relapsed Neuroblastoma (NCT02258815). Rapid immune reconstitution of the lymphoid compartment was confirmed, with clinically relevant dinutuximab serum levels found in all patients over the course of treatment. Only one patient developed human anti-chimeric antibodies (HACAs). In-patient monitoring revealed highly functional NK cell posttransplant capable of antibody-dependent cellular cytotoxicity (ADCC). Degranulation of NK cell subsets revealed a significant response increased by dinutuximab. This was irrespective of the KIR receptor-ligand constellation within the NK subsets, defined by the major KIR receptors CD158a, CD158b, and CD158e. Moreover, complement-dependent cytotoxicity (CDC) was shown to be an extremely potent effector-cell independent mechanism of tumor cell lysis, with a clear positive correlation to GD2 expression on the cancer cells as well as to the dinutuximab concentrations. The testing of patient-derived effector cells and the sera collected during dinutuximab therapy demonstrated both high functionality of the newly established lymphoid immune compartment and provided confidence that the antibody dosing regimen was sufficient over the duration of the dinutuximab therapy (up to nine cycles in a 9-month period). During the course of the dinutuximab therapy, proinflammatory cytokines and markers (sIL2R, TNFa, IL6, and C reactive protein) were significantly elevated indicating a strong anti-GD2 immune response. 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.
Topics: Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Cytokines; Feasibility Studies; Gangliosides; Hematopoietic Stem Cell Transplantation; Humans; Inflammation Mediators; Monitoring, Immunologic; Neoplasm Recurrence, Local; Neoplasm Staging; Neuroblastoma; Predictive Value of Tests; Prospective Studies; Time Factors; Transplantation, Haploidentical; Treatment Outcome
PubMed: 34367149
DOI: 10.3389/fimmu.2021.690467 -
Cancers Apr 2022Neurotoxicity is an off-tumour, on-target side effect of GD2-directed immunotherapy with monoclonal antibodies. Here, we report the frequency, management and outcome of...
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.
PubMed: 35454826
DOI: 10.3390/cancers14081919 -
Cancer Cell Apr 2017Cancer immunotherapies can be classified into agents that amplify natural immune responses (e.g., checkpoint inhibitors) versus synthetic immunotherapies designed to... (Review)
Review
Cancer immunotherapies can be classified into agents that amplify natural immune responses (e.g., checkpoint inhibitors) versus synthetic immunotherapies designed to initiate new responses (e.g., monoclonal antibodies [mAbs], chimeric antigen receptors [CARs]). Checkpoint inhibitors mediate unprecedented benefit in some adult cancers, but have not demonstrated significant activity in pediatric cancers, likely due their paucity of neoantigens. In contrast, synthetic immunotherapies such as mAbs and CAR T cells demonstrate impressive effects against childhood cancers. Intense efforts are underway to enhance the effectiveness of pediatric cancer immunotherapies through improved engineering of synthetic immunotherapies and by combining these with agents designed to amplify immune responses.
Topics: Antibodies, Bispecific; Antibodies, Monoclonal; Antigens, CD19; Humans; Immunotherapy; Mutation; Neoplasms; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Receptors, Antigen; Recombinant Proteins
PubMed: 28366678
DOI: 10.1016/j.ccell.2017.03.002 -
Journal of Nuclear Medicine : Official... Feb 2022The tumor-selective ganglioside antigene GD2 is frequently expressed on neuroblastomas and to a lesser extent on sarcomas and neuroendocrine tumors. The aim of our study...
The tumor-selective ganglioside antigene GD2 is frequently expressed on neuroblastomas and to a lesser extent on sarcomas and neuroendocrine tumors. The aim of our study was to evaluate the tumor targeting and biodistribution of I-labeled chimeric GD2-antibody clone 14/18 (I-GD2-ch14.18) in patients with late-stage disease in order to identify eligibility for radioimmunotherapy. Twenty patients (neuroblastoma, = 9; sarcoma, = 9; pheochromocytoma, = 1; and neuroendocrine tumor, = 1) were involved in this study. A 21- to 131-MBq dose (1-2 MBq/kg) of I-GD2-ch14.18 (0.5-1.0 mg) was injected intravenously. Planar scintigraphy was performed within 1 h from injection (day 0) and on days 1, 2, 3, and 6 or 7 to analyze tumor uptake and tracer biodistribution. Serial blood samples were collected in 4 individuals. Absorbed dose to tumor lesions and organs was calculated using OLINDA software. The tumor-targeting rate on a per-patient base was 65% (13/20), with 6 of 9 neuroblastomas showing uptake of I-GD2-ch14.18. Tumor lesions showed maximum uptake at 20-64 h after injection (effective half-life in tumors, 33-192 h). The tumor-absorbed dose varied between 0.52 and 30.2 mGy/MBq (median, 9.08 mGy/MBq; = 13). Visual analysis showed prominent blood-pool activity up to day 2 or 3 after injection. No pronounced uptake was observed in the bone marrow compartment or in the kidneys. Bone marrow dose was calculated at 0.09-0.18 mGy/MBq (median, 0.12 mGy/MBq), whereas blood dose was 1.1-4.7 mGy/MBq. Two patients (1 neuroblastoma and 1 pheochromocytoma) with particularly high tumor uptake underwent radioimmunotherapy using 2.3 and 2.9 GBq of I-GD2-ch14.18, both achieving stable disease. Overall survival was 17 and 6 mo, respectively. I-GD2-ch14.18 is cleared slowly from blood, not resulting in good tumor-to-background contrast until 2 d after application. With acceptable red marrow and organ dose, radioimmunotherapy is an option for patients with high tumor uptake. However, because of the variable GD2 expression, the decision should depend on pretherapeutic dosimetry.
Topics: Adrenal Gland Neoplasms; Antibodies, Monoclonal; Gangliosides; Humans; Iodine Radioisotopes; Neuroblastoma; Neuroendocrine Tumors; Pheochromocytoma; Radioimmunotherapy; Radionuclide Imaging; Tissue Distribution
PubMed: 34049985
DOI: 10.2967/jnumed.120.261854 -
BioRxiv : the Preprint Server For... May 2024Disialoganglioside 2 (GD2), overexpressed by cancers such as melanoma and neuroblastoma, is a tumor antigen for targeted therapy. The delivery of conventional IgG...
OBJECTIVES
Disialoganglioside 2 (GD2), overexpressed by cancers such as melanoma and neuroblastoma, is a tumor antigen for targeted therapy. The delivery of conventional IgG antibody technologies targeting GD2 is limited clinically by its co-expression on nerves that contributes to toxicity presenting as severe neuropathic pain. To improve the tumor selectivity of current GD2-targeting approaches, a next-generation bispecific antibody targeting GD2 and B7-H3 (CD276) was generated.
METHODS
Differential expression of human B7-H3 (hB7-H3) was transduced into GD2 B78 murine melanoma cells and confirmed by flow cytometry. We assessed the avidity and selectivity of our GD2-B7-H3 targeting bispecific antibodies (INV34-6, INV33-2, and INV36-6) towards GD2/hB7-H3 B78 cells relative to GD2/hB7-H3 B78 cells using flow cytometry and competition binding assays, comparing results an anti-GD2 antibody (dinutuximab, DINU). The bispecific antibodies, DINU, and a non-targeted bispecific control (bsAb CTRL) were conjugated with deferoxamine for radiolabeling with Zr-89 (t = 78.4 h). Using positron emission tomography (PET) studies, we evaluated the in vivo avidity and selectivity of the GD2-B7-H3 targeting bispecific compared to bsAb CTRL and DINU using GD2/hB7-H3 and GD2/hB7-H3 B78 tumor models.
RESULTS
Flow cytometry and competition binding assays showed that INV34-6 bound with high avidity to GD2/hB7-H3 B78 cells with high avidity but not GD2/hB7-H3 B78 cells. In comparison, no selectivity between cell types was observed for DINU. PET in mice bearing the GD2/hB7-H3 and GD2/hB7-H3 B78 murine tumor showed similar biodistribution in normal tissues for [Zr]Zr-Df-INV34-6, [Zr]Zr-Df-bsAb CTRL, and [Zr]Zr-Df-DINU. Importantly, [Zr]Zr-Df-INV34-6 tumor uptake was selective to GD2/hB7-H3 B78 over GD2/hB7-H3 B78 tumors, and substantially higher to GD2/hB7-H3 B78 than the non-targeted [Zr]Zr-Df-bsAb CTRL control. [Zr]Zr-Df-DINU displayed similar uptake in both GD2 tumor models, with uptake comparable to [Zr]Zr-Df-INV34-6 in the GD2/hB7-H3 B78 model.
CONCLUSION
The GD2-B7-H3 targeting bispecific antibodies successfully improved selectivity to cells expressing both antigens. This approach should address the severe toxicities associated with GD2-targeting therapies by reducing off-tumor GD2 binding in nerves. Continued improvements in bispecific antibody technologies will continue to transform the therapeutic biologics landscape.
PubMed: 38853889
DOI: 10.1101/2024.05.23.595624 -
Clinical Cancer Research : An Official... Jan 2018In 2010, a Children's Oncology Group (COG) phase III randomized trial for patients with high-risk neuroblastoma (ANBL0032) demonstrated improved event-free survival...
In 2010, a Children's Oncology Group (COG) phase III randomized trial for patients with high-risk neuroblastoma (ANBL0032) demonstrated improved event-free survival (EFS) and overall survival (OS) following treatment with an immunotherapy regimen of dinutuximab, GM-CSF, IL2, and isotretinoin compared with treatment with isotretinoin alone. Dinutuximab, a chimeric anti-GD2 monoclonal antibody, acts in part via natural killer (NK) cells. Killer immunoglobulin-like receptors (KIR) on NK cells and their interactions with KIR-ligands can influence NK cell function. We investigated whether KIR/KIR-ligand genotypes were associated with EFS or OS in this trial. We genotyped patients from COG study ANBL0032 and evaluated the effect of KIR/KIR-ligand genotypes on clinical outcomes. Cox regression models and log-rank tests were used to evaluate associations of EFS and OS with KIR/KIR-ligand genotypes. In this trial, patients with the "all KIR-ligands present" genotype as well as patients with inhibitory KIR2DL2 with its ligand (HLA-C1) together with inhibitory KIR3DL1 with its ligand (HLA-Bw4) were associated with improved outcome if they received immunotherapy. In contrast, for patients with the complementary KIR/KIR-ligand genotypes, clinical outcome was not significantly different for patients who received immunotherapy versus those receiving isotretinoin alone. These data show that administration of immunotherapy is associated with improved outcome for neuroblastoma patients with certain KIR/KIR-ligand genotypes, although this was not seen for patients with other KIR/KIR-ligand genotypes. Further investigation of KIR/KIR-ligand genotypes may clarify their role in cancer immunotherapy and may enable KIR/KIR-ligand genotyping to be used prospectively for identifying patients likely to benefit from certain cancer immunotherapy regimens. .
Topics: Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Cell Line, Tumor; Clinical Trials, Phase III as Topic; Female; Genotype; Humans; Immunotherapy; Ligands; Male; Neuroblastoma; Receptors, KIR; Receptors, KIR2DL1; Receptors, KIR3DL1
PubMed: 28972044
DOI: 10.1158/1078-0432.CCR-17-1767 -
EJC Paediatric Oncology Dec 2023Racial/ethnic survival disparities in neuroblastoma were first reported more than a decade ago. We sought to investigate if these disparities have persisted with current...
BACKGROUND
Racial/ethnic survival disparities in neuroblastoma were first reported more than a decade ago. We sought to investigate if these disparities have persisted with current era therapy.
METHODS
Two patient cohorts were identified in the International Neuroblastoma Risk Group Data Commons (INRGdc) (Cohort 1: diagnosed 2001-2009, n=4359; Cohort 2: diagnosed 2010-2019, n=4891). Chi-squared tests were used to assess the relationship between race/ethnicity and clinical and biologic features. Survival was estimated by the Kaplan-Meier method. Cox proportional hazards regression analyses were performed to investigate the association between racial/ethnic groups and prognostic markers.
RESULTS
Significantly higher 5-year event-free survival (EFS) and overall survival (OS) were observed for Cohort 2 compared to Cohort 1 (P<0.001 and P<0.001, respectively). Compared to White patients, Black patients in both cohorts had a higher proportion of high-risk disease (Cohort 1: P<0.001; Cohort 2: P<0.001) and worse EFS (Cohort 1: P<0.001; Cohort 2 P<0.001) and OS (Cohort 1: P<0.001; Cohort 2: P<0.001). In Cohort 1, Native Americans also had a higher proportion of high-risk disease (P=0.03) and inferior EFS/OS. No significant survival disparities were observed for low- or intermediate-risk patients in either cohort or high-risk patients in Cohort 1. Hispanic patients with high-risk disease in Cohort 2 had significantly inferior OS (P=0.047). Significantly worse OS, but not EFS, (P=0.006 and P=0.02, respectively) was also observed among Black and Hispanic patients assigned to receive post-Consolidation dinutuximab on clinical trials (n=885).
CONCLUSION
Racial/ethnic survival disparities have persisted over time and were observed among high-risk patients assigned to receive post-Consolidation dinutuximab.
PubMed: 38213818
DOI: 10.1016/j.ejcped.2023.100022 -
Cancers Aug 2021High-risk neuroblastoma, especially after recurrence, still has a very low survival rate. Immune checkpoint inhibitors targeting T cells have shown remarkable clinical...
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.
PubMed: 34503071
DOI: 10.3390/cancers13174261 -
Frontiers in Immunology 2024Neuroblastoma (NB) is characterized by both adrenergic (ADRN) and undifferentiated mesenchymal (MES) subsets. The ganglioside sialic acid-containing glycosphingolipid...
BACKGROUND
Neuroblastoma (NB) is characterized by both adrenergic (ADRN) and undifferentiated mesenchymal (MES) subsets. The ganglioside sialic acid-containing glycosphingolipid (GD2) is widely overexpressed on tumors of neuroectodermal origin promoting malignant phenotypes. MES cells are greatly enriched in post-therapy and relapsing tumors and are characterized by decreased expression of GD2. This event may cause failure of GD2-based immunotherapy. NK cells represent a key innate cell subset able to efficiently kill tumors. However, the tumor microenvironment (TME) that includes tumor cells and tumor-associated (TA) cells could inhibit their effector function.
METHODS
We studied eight NB primary cultures that, in comparison with commercial cell lines, more faithfully reflect the tumor cell characteristics. We studied four primary NB-MES cell cultures and two pairs of MES/ADRN (691 and 717) primary cultures, derived from the same patient. In particular, in the six human NB primary cultures, we assessed their phenotype, the expression of GD2, and the enzymes that control its expression, as well as their interactions with NK cells, using flow cytometry, RT-qPCR, and cytotoxicity assays.
RESULTS
We identified mature (CD105/CD133) and undifferentiated (CD133/CD105) NB subsets that express high levels of the MES transcripts WWTR1 and SIX4. In addition, undifferentiated MES cells display a strong resistance to NK-mediated killing. On the contrary, mature NB-MES cells display an intermediate resistance to NK-mediated killing and exhibit some immunomodulatory capacities on NK cells but do not inhibit their cytolytic activity. Notably, independent from their undifferentiated or mature phenotype, NB-MES cells express GD2 that can be further upregulated in undifferentiated NB-MES cells upon co-culture with NK cells, leading to the generation of mature mesenchymal GD2 neuroblasts. 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.
CONCLUSIONS
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.
Topics: Humans; Cell Line, Tumor; Cytotoxicity, Immunologic; Gangliosides; Killer Cells, Natural; Mesenchymal Stem Cells; Neuroblastoma; Tumor Cells, Cultured; Tumor Escape; Tumor Microenvironment
PubMed: 38736882
DOI: 10.3389/fimmu.2024.1382931