Anti-GD2 antibody and Vorinostat immunocombination therapy is highly effective in an aggressive orthotopic neuroblastoma model.
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SUBMITTER: van den Bijgaart RJE
PROVIDER: S-EPMC7781842 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:PurposeImmunotherapy with IL2, GM-CSF, and an anti-disialoganglioside (GD2) antibody significantly increases event-free survival in children with high-risk neuroblastoma. However, therapy failure in one third of these patients and IL2-related toxicities pose a major challenge. We compared the immunoadjuvant effects of IL15 with those of IL2 for enhancing antibody-dependent cell-mediated cytotoxicity (ADCC) in neuroblastoma.Experimental designWe tested ADCC against neuroblastoma patient-derived xenografts (PDX) in vitro and in vivo and examined the functional and migratory properties of NK cells activated with IL2 and IL15.ResultsIn cell culture, IL15-activated NK cells induced higher ADCC against two GD+ neuroblastoma PDXs than did IL2-activated NK cells (P < 0.001). This effect was dose-dependent (P < 0.001) and was maintained across several effector-to-tumor ratios. As compared with IL2, IL15 also improved chemotaxis of NK cells, leading to higher numbers of tumorsphere-infiltrating NK cells in vitro (P = 0.002). In an orthotopic PDX model, animals receiving chemoimmunotherapy with an anti-GD2 antibody, GM-CSF, and a soluble IL15/IL15Rα complex had greater tumor regression than did those receiving chemotherapy alone (P = 0.012) or combined with anti-GD2 antibody and GM-CSF with (P = 0.016) or without IL2 (P = 0.035). This was most likely due to lower numbers of immature tumor-infiltrating NK cells (DX5+CD27+) after IL15/IL15Rα administration (P = 0.029) and transcriptional upregulation of Gzmd.ConclusionsThe substitution of IL15 for IL2 leads to significant tumor regression in vitro and in vivo and supports clinical testing of IL15 for immunotherapy in pediatric neuroblastoma.
| S-EPMC6911623 | biostudies-literature
Project description:Neuroblastoma (NBL) is a childhood malignancy of the sympathetic nervous system. For high-risk NBL patients, the mortality rate is still over 50%, despite intensive multimodal treatment. Anti-GD2 monoclonal antibody (mAB) in combination with systemic cytokine immunotherapy has shown clinical efficacy in high-risk NBL patients. Targeted therapy using histone deacetylase inhibitors (HDACi) is currently being explored in cancer treatment and already shows promising results. Using our recently developed transplantable TH-MYCN NBL model, we here report that the HDAC inhibitor Vorinostat synergizes with anti-GD2 mAb therapy in reducing NBL tumor growth. Further mechanistic studies uncovered multiple mechanisms for the observed synergy, including Vorinostat-induced specific NBL cell death and upregulation of the tumor antigen GD2 on the cell surface of surviving NBL cells. Moreover, Vorinostat created a permissive tumor microenvironment (TME) for tumor-directed mAb therapy by increasing macrophage effector cells expressing high levels of Fc-receptors (FcR) and decreasing the number and function of myeloid-derived suppressor cells (MDSC). Collectively, these data imply further testing of other epigenetic modulators with immunotherapy and provide a strong basis for clinical testing of anti-GD2 plus Vorinostat combination therapy in NBL patients.
| S-EPMC4938306 | biostudies-literature
Project description:Gamma delta T lymphocytes (??T cells) have pleiotropic properties including innate cytotoxicity, which make them attractive effectors for cancer immunotherapy. Combination treatment with zoledronic acid and IL-2 can activate and expand the most common subset of blood ??T, which express the V?9V?2 T cell receptor (TCR) (V?2 T cells). V?9V?2 T cells are equipped for antibody-dependent cell-mediated cytotoxicity (ADCC) through expression of the low-affinity Fc?R CD16. GD2 is a highly ranked tumor associated antigen for immunotherapy due to bright expression on the cell surface, absent expression on normal tissues and availability of therapeutic antibodies with known efficacy in neuroblastoma. To explore the hypothesis that zoledronic acid, IL-2 and anti-GD2 antibodies will synergize in a therapeutic combination, we evaluated in vitro cytotoxicity and tumor growth inhibition in the GD2 expressing cancers neuroblastoma and Ewing's sarcoma. V?2 T cells exert ADCC against GD2-expressing Ewing's sarcoma and neuroblastoma cell lines, an effect which correlates with the brightness of GD2 expression. In an immunodeficient mouse model of small established GD2-expressing Ewing's sarcoma or neuroblastoma tumors, the combination of adoptively transferred V?2+ T cells, expanded in vitro with zoledronic acid and IL-2, with anti-GD2 antibody ch14.18/CHO, and with systemic zoledronic acid, significantly suppressed tumor growth compared to antibody or ??T cell-free controls. Combination treatment using ch14.18/CHO, zoledronic acid and IL-2 is more effective than their use in isolation. The already-established safety profiles of these agents make testing of the combination in GD2 positive cancers such as neuroblastoma or Ewing's sarcoma both rational and feasible.
| S-EPMC4760299 | biostudies-other
Project description:Survival outcomes for patients with high-risk neuroblastoma (NB) have significantly improved with anti-disialoganglioside GD2 mAb therapy, which promotes NK cell activation through antibody-dependent cell-mediated cytotoxicity. NK cell activation requires an interaction between inhibitory killer cell immunoglobulin-like receptors (KIRs) and HLA class I ligands. NK cells lacking KIRs that are specific for self HLA are therefore "unlicensed" and hyporesponsive. mAb-treated NB patients lacking HLA class I ligands for their inhibitory KIRs have significantly higher survival rates, suggesting that NK cells expressing KIRs for non-self HLA are mediating tumor control in these individuals. We found that, in the presence of mAb, both licensed and unlicensed NK cells are highly activated in vitro. However, HLA class I expression on NB cell lines selectively inhibited licensed NK cell activity, permitting primarily unlicensed NK cells to mediate antibody-dependent cell-mediated cytotoxicity. These results indicate that unlicensed NK cells play a key antitumor role in patients undergoing mAb therapy via antibody-dependent cell-mediated cytotoxicity, thus explaining the potent "missing KIR ligand" benefit in patients with NB.
| S-EPMC3428088 | biostudies-literature
Project description:Current therapeutic approaches for high-risk neuroblastoma (HR-NB) include high-dose chemotherapy, surgery and radiotherapy; interventions that are associated with long and short-term toxicities. Effective immunotherapy holds particular promise for improving survival and quality of life by reducing exposure to cytotoxic agents. GD2, a surface glycolipid is the most common target for immunotherapy. Areas covered: We review the status of anti-GD2 immunotherapies currently in clinical use for neuroblastomas and novel GD2-targeted strategies in preclinical development. Expert commentary: Anti-GD2 monoclonal antibodies are associated with improved survival in patients in their first remission and are increasingly being used for chemorefractory and relapsed neuroblastoma. As protein engineering technology has become more accessible, newer antibody constructs are being tested. GD2 is also being targeted by natural killer cells and T-cells. Active immunity can be elicited by anti-GD2 vaccines. The rational combination of currently available and soon-to-emerge immunotherapeutic approaches, and their integration into conventional multimodality therapies will require further investigation to optimize their use for HR-NB.
| S-EPMC6082365 | biostudies-literature
Project description:BackgroundPreclinical and preliminary clinical data indicate that ch14.18, a monoclonal antibody against the tumor-associated disialoganglioside GD2, has activity against neuroblastoma and that such activity is enhanced when ch14.18 is combined with granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-2. We conducted a study to determine whether adding ch14.18, GM-CSF, and interleukin-2 to standard isotretinoin therapy after intensive multimodal therapy would improve outcomes in high-risk neuroblastoma.MethodsPatients with high-risk neuroblastoma who had a response to induction therapy and stem-cell transplantation were randomly assigned, in a 1:1 ratio, to receive standard therapy (six cycles of isotretinoin) or immunotherapy (six cycles of isotretinoin and five concomitant cycles of ch14.18 in combination with alternating GM-CSF and interleukin-2). Event-free survival and overall survival were compared between the immunotherapy group and the standard-therapy group, on an intention-to-treat basis.ResultsA total of 226 eligible patients were randomly assigned to a treatment group. In the immunotherapy group, a total of 52% of patients had pain of grade 3, 4, or 5, and 23% and 25% of patients had capillary leak syndrome and hypersensitivity reactions, respectively. With 61% of the number of expected events observed, the study met the criteria for early stopping owing to efficacy. The median duration of follow-up was 2.1 years. Immunotherapy was superior to standard therapy with regard to rates of event-free survival (66±5% vs. 46±5% at 2 years, P=0.01) and overall survival (86±4% vs. 75±5% at 2 years, P=0.02 without adjustment for interim analyses).ConclusionsImmunotherapy with ch14.18, GM-CSF, and interleukin-2 was associated with a significantly improved outcome as compared with standard therapy in patients with high-risk neuroblastoma. (Funded by the National Institutes of Health and the Food and Drug Administration; ClinicalTrials.gov number, NCT00026312.)
| S-EPMC3086629 | biostudies-literature
Project description:BackgroundAnti-GD2 antibody is a proven therapy for GD2-positive neuroblastoma. Monoclonal antibodies against GD2, such as chimeric mAb ch14.18, have become benchmarks for neuroblastoma therapies. Pain, however, can limit immunotherapy with anti-GD2 therapeutic antibodies like ch14.18. This adverse effect is attributed to acute inflammation via complement activation on GD2-expressing nerves. Thus, new strategies are needed for the development of treatment intensification strategies to improve the outcome of these patients.Methodology/principal findingsWe established the mouse-human chimeric antibody c.8B6 specific to OAcGD2 in order to reduce potential immunogenicity in patients and to fill the need for a selective agent that can kill neuroblastoma cells without inducing adverse neurological side effects caused by anti-GD2 antibody immunotherapy. We further analyzed some of its functional properties compared with anti-GD2 ch14.18 therapeutic antibody. With the exception of allodynic activity, we found that antibody c.8B6 shares the same anti-neuroblastoma attributes as therapeutic ch14.18 anti-GD2 mAb when tested in cell-based assay and in vivo in an animal model.Conclusion/significanceThe absence of OAcGD2 expression on nerve fibers and the lack of allodynic properties of c.8B6-which are believed to play a major role in mediating anti-GD2 mAb dose-limiting side effects-provide an important rationale for the clinical application of c.8B6 in patients with high-risk neuroblastoma.
| S-EPMC3919714 | biostudies-literature
Project description:PurposeWe 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 designThe 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.ResultsADCC 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.ConclusionsImmunotherapy 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.
| S-EPMC6738573 | biostudies-literature
Project description:BackgroundNeuroblastoma is a rare malignant disease that primarily affects children. The tumours mainly develop in the adrenal medullary tissue, and an abdominal mass is the most common presentation. High-risk disease is characterised by metastasis and other primary tumour characteristics resulting in increased risk for an adverse outcome. The GD2 carbohydrate antigen is expressed on the cell surface of neuroblastoma tumour cells and is thus a promising target for anti-GD2 antibody-containing immunotherapy.ObjectivesTo assess the efficacy of anti-GD2 antibody-containing postconsolidation immunotherapy after high-dose chemotherapy (HDCT) and autologous haematopoietic stem cell transplantation (HSCT) compared to standard therapy after HDCT and autologous HSCT in people with high-risk neuroblastoma. Our primary outcomes were overall survival and treatment-related mortality. Our secondary outcomes were progression-free survival, event-free survival, early toxicity, late non-haematological toxicity, and health-related quality of life.Search methodsWe searched the electronic databases CENTRAL (2018, Issue 9), MEDLINE (PubMed), and Embase (Ovid) on 20 September 2018. We searched trial registries and conference proceedings on 28 October 2018. Further searches included reference lists of recent reviews and relevant articles as well as contacting experts in the field. There were no limits on publication year or language.Selection criteriaRandomised controlled trials evaluating anti-GD2 antibody-containing immunotherapy after HDCT and autologous HSCT in people with high-risk neuroblastoma.Data collection and analysisTwo review authors independently performed study selection, abstracted data on study and participant characteristics, and assessed risk of bias and GRADE. Any differences were resolved by discussion, with third-party arbitration unnecessary. We performed analyses according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. We used the five GRADE considerations, that is study limitations, consistency of effect, imprecision, indirectness, and publication bias, to judge the quality of the evidence.Main resultsWe identified one randomised controlled trial that included 226 people with high-risk neuroblastoma who were pre-treated with autologous HSCT. The study randomised 113 participants to receive immunotherapy including isotretinoin, granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2, and ch14.18, a type of anti-GD2 antibody also known as dinutuximab. The study randomised another 113 participants to receive standard therapy including isotretinoin.The results on overall survival favoured the dinutuximab-containing immunotherapy group (hazard ratio (HR) 0.50, 95% confidence interval (CI) 0.31 to 0.80; P = 0.004). The results on event-free survival also favoured the dinutuximab-containing immunotherapy group (HR 0.61, 95% CI 0.41 to 0.92; P = 0.020). Randomised data on adverse events were not reported separately. The study did not report progression-free survival, late non-haematological toxicity, and health-related quality of life as separate endpoints. We graded the quality of the evidence as moderate.Authors' conclusionsThe evidence base favours dinutuximab-containing immunotherapy compared to standard therapy concerning overall survival and event-free survival in people with high-risk neuroblastoma pre-treated with autologous HSCT. Randomised data on adverse events are lacking, therefore more research is needed before definitive conclusions can be made regarding this outcome.
| S-EPMC6479178 | biostudies-literature
Project description:Although anti-disialoganglioside (GD2) antibodies are successfully used for neuroblastoma therapy, a third of patients with neuroblastoma experience treatment failure or serious toxicity. Various strategies have been employed in the clinic to improve antibody-dependent cell-mediated cytotoxicity (ADCC), such as the addition of interleukin (IL)-2 to enhance natural killer (NK) cell function, adoptive transfer of allogeneic NK cells to exploit immune surveillance, and retinoid-induced differentiation therapy. Nevertheless, these mechanisms are not fully understood. We developed a quantitative assay to test ADCC induced by the anti-GD2 antibody Hu14.18K322A in nine neuroblastoma cell lines and dissociated cells from orthotopic patient-derived xenografts (O-PDXs) in culture. IL-2 improved ADCC against neuroblastoma cells, and differentiation with all-trans retinoic acid stabilized GD2 expression on tumor cells and enhanced ADCC as well. Degranulation was highest in licensed NK cells that expressed CD158b (P?<?0.001) and harbored a killer-cell immunoglobulin-like receptor (KIR) mismatch against the tumor-specific human leukocyte antigen (HLA; P?=?0.016). In conclusion, IL-2 is an important component of immunotherapy because it can improve the cytolytic function of NK cells against neuroblastoma cells and could lower the antibody dose required for efficacy, thereby reducing toxicity. The effect of IL-2 may vary among individuals and a biomarker would be useful to predict ADCC following IL-2 activation. Sub-populations of NK cells may have different levels of activity dependent on their licensing status, KIR expression, and HLA-KIR interaction. Better understanding of HLA-KIR interactions and the molecular changes following retinoid-induced differentiation is necessary to delineate their role in ADCC.
| S-EPMC5862751 | biostudies-literature