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Journal For Immunotherapy of Cancer May 2020Neuroblastoma (NB) is the most frequent extracranial solid tumor in children. More than 50% of patients present with widespread (stage M) or refractory disease. In these...
BACKGROUND
Neuroblastoma (NB) is the most frequent extracranial solid tumor in children. More than 50% of patients present with widespread (stage M) or refractory disease. In these patients, event-free and overall survival was improved by the addition of the anti-disialoganglioside antibody dinutuximab beta (DB) following multimodal conventional therapy. However, the prognosis of patients with refractory/relapsed NB remains poor. In the past decade, immunotherapy approaches with checkpoint inhibitors were approved for patients with certain malignant diseases such as melanoma or Hodgkin lymphoma. In preclinical models, DB resulted in an upregulation of the programmed cell death protein 1 (PD-1) checkpoint in NB cell lines and a combined treatment of DB with a murine anti-PD-1 checkpoint inhibitor showed a synergistic effect in a NB mouse model.
CASE PRESENTATIONS
Two patients were admitted with refractory metastatic NB. In the 4-year-old girl, NB was diagnosed in 2013. She completed her first-line therapy with a first remission in 2015, but suffered a relapse in 2017. Treatment with chemotherapy and DB resulted in progressive disease after transient improvement. In the 17-year-old young man, NB was first diagnosed in April 2010. After two local relapses in 2011 and 2014, a metastatic relapse and a large abdominal tumor bulk were found in 2018. Despite transient improvement with multimodal therapy, progressive metastatic disease was observed in May 2019. Both patients had a satisfactory quality of life. Therefore, treatment with DB and nivolumab was performed-in the girl from October 2018 until August 2019, in the young man since June 2019. Tolerance to treatment was excellent. The girl continues to be in complete remission 6 months after therapy was stopped. In the young man, the soft tissue lesions disappeared completely, the skeletal lesions regressed substantially after 9 months of his still ongoing treatment.
CONCLUSIONS
The combination of DB with the checkpoint inhibitor nivolumab led to complete and a very good partial remission in two patients with relapsed/refractory NB. Prospective trials are warranted to clarify the role of this novel approach in a larger number of patients.
Topics: Adolescent; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Child, Preschool; Drug Resistance, Neoplasm; Female; Humans; Male; Neoplasm Recurrence, Local; Neuroblastoma; Nivolumab; Prognosis; Salvage Therapy
PubMed: 32414861
DOI: 10.1136/jitc-2020-000540 -
Clinical Cancer Research : An Official... Aug 2019We determined whether elimination of CD105 cells in the tumor microenvironment (TME) with anti-CD105 antibodies enhanced anti-disialoganglioside (GD2) antibody...
PURPOSE
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.
EXPERIMENTAL DESIGN
The effect of MSCs and monocytes on antibody-dependent cellular cytotoxicity (ADCC) mediated by dinutuximab with aNK cells against neuroblastoma cells was determined . 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.
RESULTS
ADCC mediated by dinutuximab with aNK cells against neuroblastoma cells 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.
CONCLUSIONS
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.
Topics: Animals; Antibodies, Monoclonal; Antibody-Dependent Cell Cytotoxicity; Antineoplastic Agents; Cell Line, Tumor; Endoglin; Gangliosides; Humans; Immunotherapy; Killer Cells, Natural; Mice; Mice, Inbred NOD; Mice, SCID; Neuroblastoma; Xenograft Model Antitumor Assays
PubMed: 31068371
DOI: 10.1158/1078-0432.CCR-18-3358 -
Oncoimmunology 2019An effective therapy regimen for relapsed/refractory high-risk neuroblastoma (NB) includes the anti-GD2 monoclonal antibody, dinutuximab, in combination with...
An effective therapy regimen for relapsed/refractory high-risk neuroblastoma (NB) includes the anti-GD2 monoclonal antibody, dinutuximab, in combination with temozolomide and irinotecan, supporting a role for chemo-immunotherapy in NB. γδ T cells are an attractive anti-tumor immunotherapy because of their direct cytotoxic activity mediated through cell surface receptors NKG2D and CD16. NKG2D facilitates the innate recognition of stress-induced ligands whereas CD16 recognizes antibody bound to tumors and activates mechanisms of antibody-dependent cellular cytotoxicity (ADCC). This study demonstrates an efficient method for expanding and storing γδ T cells from NB patient-derived apheresis products at clinically relevant amounts. The expanded patient-derived γδ T cells were cytotoxic against the K562 cell line and multiple NB cell lines. Combining γδ T cells with dinutuximab led to a 30% increase in tumor cell lysis compared to γδ T cells alone. Furthermore, low-dose temozolomide in combination with expanded γδ T cells and dinutuximab resulted in increased IFNγ secretion and increased γδ T-cell surface expression of FasL and CD107a. IMR5 NB cell line xenografts established subcutaneously in NSG mice were treated with a regimen of dinutuximab, temozolomide, and γδ T cells. This combination caused targeted killing of NB xenografts in vivo, reducing tumor burden and prolonging survival. These data support the continued preclinical testing of dinutuximab and temozolomide in conjunction with γδ T-cell immunotherapy for patients with recurrent/refractory NB.
PubMed: 31413905
DOI: 10.1080/2162402X.2019.1593804 -
Journal of Biomedical Materials... Aug 2021Neuroblastoma is the most common extracranial solid tumor of childhood and is associated with poor survival in high risk patients. Recently, dinutuximab (DNX) has...
Neuroblastoma is the most common extracranial solid tumor of childhood and is associated with poor survival in high risk patients. Recently, dinutuximab (DNX) has emerged as an effective immunotherapy to treat patients with high risk neuroblastoma. DNX works through the induction of cell lysis via complement-dependent cytotoxicity (CDC) or antibody dependent cellular cytotoxicity (ADCC). However, one third of patients who undergo DNX treatment exhibit tumor relapse and the therapy is dose limited by side effects such as severe pain. To overcome delivery challenges of DNX, including large size and dose limiting side effects, we fabricated a delivery system capable of sustained local delivery of bioactive DNX utilizing silk fibroin. We evaluated the impact of silk properties (MW, crystallinity, and concentration) on release properties and confirmed the bioactivity of the release product. Additionally, we observed that the effectiveness of CDC induction by DNX could be correlated to the GD2 expression level of the target cells, with both the intravenous DNX formulation and the released DNX. Collectively, these data highlights a strategy to overcome delivery challenges and potentially improve therapeutic efficacy in cells expressing heterogenous levels of GD2.
Topics: Animals; Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Bombyx; Cell Death; Cell Line, Tumor; Delayed-Action Preparations; Drug Delivery Systems; Fibroins; Gangliosides; Neuroblastoma
PubMed: 33252182
DOI: 10.1002/jbm.a.37131 -
Frontiers in Pharmacology 2020Treatment of HR-NB comprise induction, consolidation with autologous stem cell transplant (ASCT) followed by anti-GD2 immunotherapy and isotretinoin. Childrens Oncology...
Treatment of HR-NB comprise induction, consolidation with autologous stem cell transplant (ASCT) followed by anti-GD2 immunotherapy and isotretinoin. Childrens Oncology Group and SIOPEN studies used dinutuximab and cytokines to treat patients in complete remission or refractory Bone/Bone marrow (B/BM) disease after ASCT. HR-NB patients referred to Hospital Sant Joan de Déu for anti-GD2 immunotherapy were eligible for two consecutive studies (dinutuximab for EudraCT 2013-004864-69 and naxitamab for 017-001829-40) and naxitamab/Sargramostim CU with or without prior ASCT. Patients enrolled in first complete remission or with primary refractory B/BM disease. We accrued a study population of two groups whose therapy, aside from ASCT, was similar. This is a retrospective analysis of their outcome calculated from study entry. From December 2014-2019, 67 patients were treated with dinutuximab and cytokines (n = 21) in the Hospital Sant Joan de Déu-HRNB-Ch14.18 study or with naxitamab and Sargramostim either in the Ymabs study 201 (n = 12) or CU (n = 34). 23 patients were treated with primary refractory disease in the B/BM (11 with dinutuximab and 12 with naxitamab), and 44 in first CR (10 with dinutuximab and 34 with naxitamab). Study patients included 13 (19.4%) treated following single ASCT and 54 following conventional chemotherapy. Median follow-up for all patients is 16.2 months. Two-year rates for ASCT and non-ASCT patients were, respectively, EFS 64.1% vs. 54.2% ( = 0.28), and OS 66.7% vs. 84.1% ( = 0.81). For the 44 pts in first CR, 2-years rates for ASCT and non-ASCT patients were, respectively, EFS 65.5% vs. 58.7% ( = 0.48), and OS 71.4% vs. 85.4% ( = 0.63). In this retrospective, single center study, ASCT did not provide survival benefit when anti-GD2 immunotherapy was used after induction chemotherapy.
PubMed: 33324208
DOI: 10.3389/fphar.2020.575009 -
Journal of Clinical Medicine Sep 2023GD2, a disialoganglioside, is present on the surface of most neuroblastomas, as well as on some other cancers, such as melanoma and osteogenic sarcoma. The anti-GD2...
GD2, a disialoganglioside, is present on the surface of most neuroblastomas, as well as on some other cancers, such as melanoma and osteogenic sarcoma. The anti-GD2 antibody ch14.18 (dinutuximab) has an FDA-registered indication for use as maintenance therapy for high-risk neuroblastoma with cytokines and 13-cis-retinoic acid after myeloablative therapy. Recent studies using immunohistochemistry of tumor or tumor cells in marrow have shown that some neuroblastomas are negative for GD2. Dinutuximab and other anti-GD2 antibodies are increasingly used in combination with cytotoxic chemotherapy for treating relapsed neuroblastoma, so it is important to be able to identify patients with tumor cells with low GD2 expression, as such patients may experience toxicity but not benefit from the antibody therapy. As the most common clinical samples available for relapsed neuroblastoma are bone marrow aspirates, we developed a method to quantify dinutuximab binding density and the frequency of neuroblastoma cells positive for the antibody in bone marrow aspirates. Here, we describe a multi-color flow cytometry assay that employs non-GD2 antibodies to identify neuroblastoma cells in a mixed population (tumor, bone marrow, or blood) and an anti-GD2 antibody to quantify both the frequency and density of GD2 expression on neuroblastoma cells.
PubMed: 37834874
DOI: 10.3390/jcm12196223 -
Case Reports in Pediatrics 2021Neuroblastoma is the most common extracranial solid tumor in children, accounting for 15% of all pediatric cancer deaths. High-risk neuroblastoma (HRNB) is a...
Neuroblastoma is the most common extracranial solid tumor in children, accounting for 15% of all pediatric cancer deaths. High-risk neuroblastoma (HRNB) is a particularly difficult-to-treat form of the disease that requires aggressive multimodality therapy, including induction chemotherapy, consolidation therapy with high-dose chemotherapy and autologous stem cell transplant, and maintenance therapy with dinutuximab beta. Despite treatment advances, the prognosis of these patients remains poor. As a better response to induction therapy has been associated with prolonged survival in patients with HRNB, we hypothesized that early use of dinutuximab beta-post-induction chemotherapy-may improve patient outcomes. We describe here our experience of administering at least one cycle of dinutuximab beta post-induction and prior to surgery in three children with HRNB who did not demonstrate a complete response to induction chemotherapy. All three patients achieved complete remission. Early use of dinutuximab beta may therefore have the potential to improve outcomes in patients with HRNB.
PubMed: 34239748
DOI: 10.1155/2021/6610955 -
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 -
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