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Cellular and Molecular Life Sciences :... Oct 2022The majority of current cancer therapies are aimed at reducing tumour growth, but there is lack of viable pharmacological options to reduce the formation of metastasis....
The majority of current cancer therapies are aimed at reducing tumour growth, but there is lack of viable pharmacological options to reduce the formation of metastasis. This is a paradox, since more than 90% of cancer deaths are attributable to metastatic progression. Integrin alpha9 (ITGA9) has been previously described as playing an essential role in metastasis; however, little is known about the mechanism that links this protein to this process, being one of the less studied integrins. We have now deciphered the importance of ITGA9 in metastasis and provide evidence demonstrating its essentiality for metastatic dissemination in rhabdomyosarcoma and neuroblastoma. However, the most translational advance of this study is to reveal, for the first time, the possibility of reducing metastasis by pharmacological inhibition of ITGA9 with a synthetic peptide simulating a key interaction domain of ADAM proteins, in experimental metastasis models, not only in childhood cancers but also in a breast cancer model.
Topics: ADAM Proteins; Humans; Integrin alpha Chains; Integrins; Neoplasm Metastasis; Neuroblastoma; Rhabdomyosarcoma
PubMed: 36221013
DOI: 10.1007/s00018-022-04557-y -
Children (Basel, Switzerland) Jun 2022To determine the potential benefits and feasibility of administering maintenance therapy with dinutuximab beta for high-risk neuroblastoma (HRNB) in clinical practice, a...
To determine the potential benefits and feasibility of administering maintenance therapy with dinutuximab beta for high-risk neuroblastoma (HRNB) in clinical practice, a retrospective review of charts of patients with HRNB treated at a single center in Croatia (2012-2021) was undertaken. Of 23 patients with HRNB, 11 received up to five cycles of dinutuximab beta as part of multimodal therapy; 12 patients did not (i.e., no immunotherapy). In the no immunotherapy group, one patient had complete remission (8%), and 11 patients died of tumor progression (92%). In the dinutuximab beta group, eight patients had complete remission (73%; median duration of response 5 years and 2 months), one had stable disease (9%), and two died of disease (18%). Patients who received dinutuximab beta had a higher median event-free survival (40.0 months [range: 12.5-83.0]) and median overall survival (56.0 months [range: 16.2-101.0]) than those who did not (12.9 months [range: 3.3-126.0] and 20.7 months [3.3-126.0], respectively). Dinutuximab beta was generally well tolerated; adverse events were manageable and as reported in clinical studies. These results confirm the benefits and feasibility of maintenance therapy with dinutuximab beta as part of multimodal therapy for patients with HRNB in real-world clinical practice.
PubMed: 35883927
DOI: 10.3390/children9070943 -
Journal of Clinical Oncology : Official... Dec 2022Postconsolidation immunotherapy including dinutuximab, granulocyte-macrophage colony-stimulating factor, and interleukin-2 improved outcomes for patients with high-risk...
PURPOSE
Postconsolidation immunotherapy including dinutuximab, granulocyte-macrophage colony-stimulating factor, and interleukin-2 improved outcomes for patients with high-risk neuroblastoma enrolled on the randomized portion of Children's Oncology Group study ANBL0032. After random assignment ended, all patients were assigned to immunotherapy. Survival and toxicities were assessed.
PATIENTS AND METHODS
Patients with a pre-autologous stem cell transplant (ASCT) response (excluding bone marrow) of partial response or better were eligible. Demographics, stage, tumor biology, pre-ASCT response, and adverse events were summarized using descriptive statistics. Event-free survival (EFS) and overall survival (OS) from time of enrollment (up to day +200 from last ASCT) were evaluated.
RESULTS
From 2009 to 2015, 1,183 patients were treated. Five-year EFS and OS for the entire cohort were 61.1 ± 1.9% and 71.9 ± 1.7%, respectively. For patients ≥ 18 months old at diagnosis with International Neuroblastoma Staging System stage 4 disease (n = 662) 5-year EFS and OS were 57.0 ± 2.4% and 70.9 ± 2.2%, respectively. EFS was superior for patients with complete response/very good partial response pre-ASCT compared with those with PR (5-year EFS: 64.2 ± 2.2% 55.4 ± 3.2%, = .0133); however, OS was not significantly different. Allergic reactions, capillary leak, fever, and hypotension were more frequent during interleukin-2-containing cycles than granulocyte-macrophage colony-stimulating factor-containing cycles ( < .0001). EFS was superior in patients with higher peak dinutuximab levels during cycle 1 ( = .034) and those with a high affinity FCGR3A genotype ( = .0418). Human antichimeric antibody status did not correlate with survival.
CONCLUSION
Analysis of a cohort assigned to immunotherapy after cessation of random assignment on ANBL0032 confirmed previously described survival and toxicity outcomes. EFS was highest among patients with end-induction complete response/very good partial response. Among patients with available data, higher dinutuximab levels and FCGR3A genotype were associated with superior EFS. These may be predictive biomarkers for dinutuximab therapy.
Topics: Child; Humans; Infant; Granulocyte-Macrophage Colony-Stimulating Factor; Interleukin-2; Research Design
PubMed: 35839426
DOI: 10.1200/JCO.21.02478 -
European Journal of Cancer (Oxford,... Sep 2022Novel effective therapies are urgently needed in recurrent osteosarcoma. GD2 is expressed in human osteosarcoma tumours and cell lines. This study evaluated the disease...
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.
PURPOSE
Novel 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.
METHODS
AOST1421 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/m/cycle) with granulocyte-macrophage colony-stimulating factor (GM-CSF). Two different dinutuximab infusion schedules were studied: 35 mg/m/day over 20 h (2 days) and 17.5 mg/m/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.
RESULTS
Thirty-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.
CONCLUSIONS
The 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.
Topics: Adolescent; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Child; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Neoplasm Recurrence, Local; Osteosarcoma; Young Adult
PubMed: 35809374
DOI: 10.1016/j.ejca.2022.05.035 -
FEBS Open Bio Sep 2022Dinutuximab (ch14.18) was the first approved monoclonal antibody against the tumor-associated antigen disialoganglioside GD2. Despite its success in treating...
Dinutuximab (ch14.18) was the first approved monoclonal antibody against the tumor-associated antigen disialoganglioside GD2. Despite its success in treating neuroblastoma (NB), it triggers a significant amount of neuropathic pain in patients, possibly through complement-dependent cytotoxicity (CDC). We hypothesized that modifying ch14.18 using antibody engineering techniques, such as humanization, affinity maturation, and Fc engineering, may enable the development of next-generation GD2-specific antibodies with reduced neuropathic pain and enhanced antitumor activity. In this study we developed the H3-16 IgG1m4 antibody from ch14.18 IgG1. H3-16 IgG1m4 exhibited enhanced binding activity to GD2 molecules and GD2-positive cell lines as revealed by ELISA, and its cross-binding activity to other gangliosides was not altered. The CDC activity of H3-16 IgG1m4 was decreased, and the antibody-dependent cellular cytotoxicity (ADCC) activity was enhanced. The pain response after H3-16 IgG1m4 antibody administration was also reduced, as demonstrated using the von Frey test in Sprague-Dawley (SD) rats. In summary, H3-16 IgG1m4 may have potential as a monoclonal antibody with reduced side effects.
Topics: Animals; Antibodies, Monoclonal; Gangliosides; Neuralgia; Rats; Rats, Sprague-Dawley
PubMed: 35792784
DOI: 10.1002/2211-5463.13464 -
Oncoimmunology 2022Neuroblastoma is a commonly lethal solid tumor of childhood and intensive chemoradiotherapy treatment cures ~50% of children with high-risk disease. The addition of...
Neuroblastoma is a commonly lethal solid tumor of childhood and intensive chemoradiotherapy treatment cures ~50% of children with high-risk disease. The addition of immunotherapy using dinutuximab, a monoclonal antibody directed against the GD2 disialoganglioside expressed on neuroblasts, improves survival when incorporated into front-line therapy and shows robust activity in regressing relapsed disease when combined with chemotherapy. Still, many children succumb to neuroblastoma progression despite receiving dinutuximab-based immunotherapy, and efforts to counteract the immune suppressive signals responsible are warranted. Animal models of human cancers provide useful platforms to study immunotherapies. transgenic mice are immunocompetent and develop neuroblastomas at autochthonous sites due to enforced expression in developing neural crest tissues. However, GD2-directed immunotherapy in this model has been underutilized due to the prevailing notion that neuroblasts express insufficient GD2 to be targeted. We demonstrate that neuroblasts in -driven tumors express GD2 at levels comparable to human neuroblastomas but rapidly lose GD2 expression when explanted ex vivo to establish tumor cell lines. This occurs in association with a transition from an adrenergic to mesenchymal differentiation state. Importantly, not only is GD2 expression retained on tumors in situ, treatment with a murine anti-GD2 antibody, 14G2a, markedly extends survival in such mice, including durable complete responses. Tumors in 14G2a-treated mice have fewer macrophage and myeloid-derived suppressor cells in their tumor microenvironment. Our findings support the utility of this model to inform immunotherapy approaches for neuroblastoma and potential opportunities to investigate drivers of adrenergic to mesenchymal fate decisions.
Topics: Adrenergic Agents; Animals; Antineoplastic Agents; Cell Line, Tumor; Gangliosides; Mice; N-Myc Proto-Oncogene Protein; Neuroblastoma; Tumor Microenvironment
PubMed: 35646475
DOI: 10.1080/2162402X.2022.2075204 -
Journal of Pediatric Hematology/oncology Aug 2022Despite multimodal therapy, the prognosis of patients with metastatic Ewing sarcoma (ES) remains poor, with new treatments urgently needed. The disialoganglioside GD2, a...
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.
Topics: Consolidation Chemotherapy; Humans; Neoplasm Recurrence, Local; Sarcoma; Sarcoma, Ewing; Soft Tissue Neoplasms
PubMed: 35622995
DOI: 10.1097/MPH.0000000000002488 -
Journal For Immunotherapy of Cancer Apr 2022Anti-GD2 monoclonal antibody immunotherapy has significantly improved the overall survival rate for high-risk neuroblastoma patients. However, 40% of patients fail to...
BACKGROUND
Anti-GD2 monoclonal antibody immunotherapy has significantly improved the overall survival rate for high-risk neuroblastoma patients. However, 40% of patients fail to respond or develop resistance to treatment, and the molecular mechanisms by which this occurs remain poorly understood. Tumor-derived small extracellular vesicles (sEVs) have emerged as critical regulators in modulating the response to immunotherapy. In this study, we investigated the role of neuroblastoma-derived sEVs in promoting resistance to the anti-GD2 monoclonal antibody dinutuximab. Moreover, to determine whether pharmacologic inhibition of sEV secretion sensitizes tumors to dinutuximab treatment, we combined dinutuximab with tipifarnib, a farnesyltransferase inhibitor that inhibits sEV secretion.
METHODS
We investigated the role of neuroblastoma-derived sEVs in modulating the response to dinutuximab by utilizing the syngeneic 9464D-GD2 mouse model. The effect of neuroblastoma-derived sEVs in modulating the tumor microenvironment (TME) and host immune system were evaluated by RNA-sequencing and flow cytometry. Importantly, we used this mouse model to investigate the efficacy of tipifarnib in sensitizing neuroblastoma tumors to dinutuximab. The effect of tipifarnib on both the TME and host immune system were assessed by flow cytometry.
RESULTS
We demonstrated that neuroblastoma-derived sEVs significantly attenuated the efficacy of dinutuximab and modulated tumor immune cell infiltration upon dinutuximab treatment to create an immunosuppressive TME that contains more tumor-associated macrophages and fewer tumor-infiltrating NK cells. In addition, we demonstrated that neuroblastoma-derived sEVs suppress splenic NK cell maturation and dinutuximab-induced NK cell-mediated antibody-dependent cellular cytotoxicity . Importantly, tipifarnib drastically enhanced the efficacy of dinutuximab-mediated inhibition of tumor growth and prevented the immunosuppressive effects of neuroblastoma-derived sEVs .
CONCLUSIONS
These preclinical findings uncover a novel mechanism by which neuroblastoma-derived sEVs modulate the immune system to promote resistance to dinutuximab and suggest that tipifarnib-mediated inhibition of sEV secretion may serve as a viable treatment strategy to enhance the antitumor efficacy of anti-GD2 immunotherapy in high-risk neuroblastoma patients.
Topics: Animals; Antibodies, Monoclonal; Antineoplastic Agents; Extracellular Vesicles; Humans; Immunologic Factors; Immunotherapy; Mice; Neuroblastoma; Quinolones; Tumor Microenvironment
PubMed: 35483745
DOI: 10.1136/jitc-2021-004399 -
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 -
Oncoimmunology 2022γδ T lymphocytes represent an emerging class of cellular immunotherapy with preclinical promise to treat cancer, notably neuroblastoma. The innate-like immune cell...
γδ T lymphocytes represent an emerging class of cellular immunotherapy with preclinical promise to treat cancer, notably neuroblastoma. The innate-like immune cell subset demonstrates inherent cytoxicity toward tumor cells independent of MHC recognition, enabling allogeneic administration of healthy donor-derived γδ T cell therapies. A current limitation is the substantial interindividual γδ T cell expansion variation among leukocyte collections. Overcoming this limitation will enable realization of the full potential of allogeneic γδ T-based cellular therapy. Here, we characterize γδ T cell expansions from healthy adult donors and observe that highly potent natural killer (NK) lymphocytes expand with γδ T cells under zoledronate and IL-2 stimulation. The presence of NK cells correlates with both the expansion potential of γδ T cells and the overall potency of the γδ T cell therapy. However, the potency of the cell therapy in combination with an antibody-based immunotherapeutic, dinutuximab, appears to be independent of γδ T/NK cell content both and , which minimizes the implication of interindividual expansion differences toward efficacy. Collectively, these studies highlight the utility of maintaining the NK cell population within expanded γδ T cell therapies and suggest a synergistic action of combined innate cell immunotherapy toward neuroblastoma.
Topics: Cell Proliferation; Cell- and Tissue-Based Therapy; Humans; Immunotherapy; Neuroblastoma; Receptors, Antigen, T-Cell, gamma-delta
PubMed: 35371623
DOI: 10.1080/2162402X.2022.2057012