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British Journal of Cancer Nov 2023Short-term infusions of dinutuximab beta plus isotretinoin and cytokines administered in previous immunotherapy studies in neuroblastoma were associated with severe...
BACKGROUND
Short-term infusions of dinutuximab beta plus isotretinoin and cytokines administered in previous immunotherapy studies in neuroblastoma were associated with severe pain. Here, long-term, continuous infusion of single-agent dinutuximab beta was evaluated in patients with relapsed/refractory neuroblastoma.
METHODS
In this open-label, single-arm, Phase 2 study, patients with either refractory or relapsed high-risk neuroblastoma received dinutuximab beta by continuous infusion over 10 days of each cycle, for up to five cycles. The primary endpoint was objective response rate 24 weeks after the end of cycle 5. Secondary endpoints included adverse events, intravenous morphine use, best response, duration of response, and three-year progression-free and overall survival.
RESULTS
Of the 40 patients included, 38 had evaluable response. Objective response rate was 26% and best response rate 37%. Median duration of response was 238 days (IQR 108-290). Three-year progression-free and overall survival rates were 31% (95% CI 17-47) and 66% (95% CI 47-79), respectively. Prophylactic intravenous morphine use and duration of use decreased with increasing cycles. The most common grade 3 treatment-related adverse events were pain, diarrhea, and hypokalemia.
CONCLUSION
Long-term continuous infusion of single-agent dinutuximab beta is tolerable and associated with clinically meaningful responses in patients with relapsed/refractory high-risk neuroblastoma.
CLINICAL TRIAL REGISTRATION
The study is registered with ClinicalTrials.gov (NCT02743429) and EudraCT (2014-000588-42).
Topics: Humans; Morphine Derivatives; Neoplasm Recurrence, Local; Neuroblastoma; Pain
PubMed: 37813959
DOI: 10.1038/s41416-023-02457-x -
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 -
The Turkish Journal of Pediatrics 2023Dinutuximab is a monoclonal antibody that targets the GD2 antigen used in the treatment of high-risk neuroblastoma. Dinutuximab-associated rhombencephalitis and myelitis...
BACKGROUND
Dinutuximab is a monoclonal antibody that targets the GD2 antigen used in the treatment of high-risk neuroblastoma. Dinutuximab-associated rhombencephalitis and myelitis is a rare, steroid-responsive, serious, but reversible pathology. To date, three transverse myelitis cases and one rhombencephalitis case due to dinutuximab have already been reported. Moreover, a recently published article identified five inflammatory CNS demyelination cases (four myelitis and one rhombencephalitis). We present a 5-year-old patient with rhombencephalitis and myelitis following dinutuximab-beta treatment.
CASE
A 5-year-old patient with a left-sided retroperitoneal mass infiltrating the left kidney and multiple lytic bone lesions was diagnosed with neuroblastoma with a percutaneous biopsy from the abdominal mass. Surgery was performed after a prominent treatment response was detected on the abdominal CT. Radiotherapy was applied to the abdomen. While she was still undergoing maintenance treatment with 13-cis retinoic acid, a metaiodobenzylguanidine (MIBG) scan detected new bone lesions, and brain MRG identified pachymeningeal involvement. A new chemotherapy regimen was started and decreased MIBG uptake was seen in all previous bone lesions. However, newly developed eighth rib metastasis was seen in the following MIBG scan. Autologous stem cell transplantation was done. Soon after, dinutuximab-beta, together with temozolomide and irinotecan, was initiated. Following the third cycle hypotension, somnolence, paraparesis, and unilateral fixed dilated pupil were developed. Afterward, hemiballismus-like irregular limb movements were observed. Work-up studies were unremarkable, except for hypodensity in the brain stem on the brain CT. MRI revealed T2 hyperintensity of the brainstem and spinal cord extending from the cervicomedullary junction to the T7 level. Moreover, incomplete contrast enhancement and facilitated diffusion were observed. Imaging findings suggested demyelination. Steroids and intravenous immune globulin (IVIG) treatment were initiated. Both imaging abnormalities and clinical symptoms resolved partially at one month and disappeared at six months.
CONCLUSIONS
Awareness of the radiological findings of dinutuximab toxicity will lead to prompt diagnosis and treatment.
Topics: Female; Humans; Child, Preschool; 3-Iodobenzylguanidine; Hematopoietic Stem Cell Transplantation; Transplantation, Autologous; Antibodies, Monoclonal; Neuroblastoma; Myelitis; Demyelinating Diseases
PubMed: 37395971
DOI: 10.24953/turkjped.2022.598 -
Oncoimmunology 2023Pediatric patients with high-risk neuroblastoma often relapse with chemotherapy-resistant, incurable disease. Relapsed neuroblastomas harbor chemo-resistant mesenchymal...
Pediatric patients with high-risk neuroblastoma often relapse with chemotherapy-resistant, incurable disease. Relapsed neuroblastomas harbor chemo-resistant mesenchymal tumor cells and increased expression/activity of the transcriptional co-regulator, the Yes-Associated Protein (YAP). Patients with relapsed neuroblastoma are often treated with immunotherapy such as the anti-GD2 antibody, dinutuximab, in combination with chemotherapy. We have previously shown that YAP mediates both chemotherapy and MEK inhibitor resistance in relapsed mutated neuroblastoma and so posited that YAP might also be involved in anti-GD2 antibody resistance. We now show that YAP genetic inhibition significantly enhances sensitivity of mesenchymal neuroblastomas to dinutuximab and gamma delta (γδ) T cells both and . Mechanistically, YAP inhibition induces increased GD2 cell surface expression through upregulation of , the gene encoding GD3 synthase and the rate-limiting enzyme in GD2 biosynthesis. The mechanism of suppression by YAP is independent of expression, a mesenchymal master transcription factor, suggesting YAP may be the downstream effector of mesenchymal GD2 resistance. These results therefore identify YAP as a therapeutic target to augment GD2 immunotherapy responses in patients with neuroblastoma.
Topics: Humans; Down-Regulation; Homeodomain Proteins; Immunotherapy; Neuroblastoma; YAP-Signaling Proteins; Animals; Sialyltransferases
PubMed: 37554309
DOI: 10.1080/2162402X.2023.2240678 -
Medicine Jan 2022Despite therapeutic advances, high-risk neuroblastoma is still associated with a poor long-term prognosis. Immunotherapy with the anti-GD2 antibody dinutuximab beta has...
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.
Topics: Adolescent; Adult; Antibodies, Monoclonal; Female; Follow-Up Studies; Humans; Immunologic Factors; Male; Middle Aged; Neuroblastoma; Retrospective Studies; Slovakia; Treatment Outcome; Young Adult
PubMed: 35089239
DOI: 10.1097/MD.0000000000028716 -
Annals of the New York Academy of... Feb 2022Triple-negative breast cancer (TNBC) is a heterogeneous disease characterized by lack of hormone receptor expression and is known for high rates of recurrence, distant... (Review)
Review
Triple-negative breast cancer (TNBC) is a heterogeneous disease characterized by lack of hormone receptor expression and is known for high rates of recurrence, distant metastases, and poor clinical outcomes. TNBC cells lack targetable receptors; hence, there is an urgent need for targetable markers for the disease. Breast cancer stem-like cells (BCSCs) are a fraction of cells in primary tumors that are associated with tumorigenesis, metastasis, and resistance to chemotherapy. Targeting BCSCs is thus an effective strategy for preventing cancer metastatic spread and sensitizing tumors to chemotherapy. The CD44 CD24 phenotype is a well-established phenotype for identification of BCSCs, but CD44 and CD24 are not targetable markers owing to their expression in normal tissues. The ganglioside GD2 has been shown to be upregulated in primary TNBC tumors compared with normal breast tissue and has been shown to identify BCSCs. In this review, we discuss GD2 as a BCSC- and tumor-specific marker in TNBC; epithelial-to-mesenchymal transition and the signaling pathways that are upstream and downstream of GD2 and the role of these pathways in tumorigenesis and metastasis in TNBC; direct and indirect approaches for targeting GD2; and ongoing clinical trials and treatments directed against GD2 as well as future directions for these strategies.
Topics: Biomarkers, Tumor; Carcinogenesis; Epithelial-Mesenchymal Transition; Female; Gangliosides; Humans; Neoplastic Stem Cells; Triple Negative Breast Neoplasms
PubMed: 34596246
DOI: 10.1111/nyas.14700 -
International Journal of Cancer Jan 2023Anti-G monoclonal antibodies (mAb) improve the prognosis of high-risk neuroblastoma (HR-NB). Worldwide experience almost exclusively involves toddlers and older patients...
Anti-G monoclonal antibodies (mAb) improve the prognosis of high-risk neuroblastoma (HR-NB). Worldwide experience almost exclusively involves toddlers and older patients treated after multimodality or second-line therapies, that is, many months postdiagnosis. In contrast, at our center, infants received anti-G mAbs because this immunotherapy started during or immediately after induction chemotherapy. We now report on the feasibility, safety, and long-term survival in this vulnerable age group. Thirty-three HR-NB patients were <19 months old when started on 3F8 (murine mAb; n = 21) or naxitamab (humanized-3F8; n = 12), with 30″ to 90″ intravenous infusions. Patients received analgesics and antihistamines. Common toxicities (pain, urticaria, cough) were manageable, allowing outpatient treatment. Capillary leak, posterior reversible encephalopathy syndrome, and mAb-related long-term toxicities did not occur. Two 3F8 cycles were aborted due to bradycardia (a preexisting condition) and asthmatic symptoms, respectively. One patient received ½ dose of Day 1 naxitamab because of hypotension; full doses were subsequently administered. Post-mAb treatments included chemotherapy, radiotherapy, and anti-NB vaccine. Among 3F8 patients, 17/21 are in complete remission off all treatment at 5.6+ to 24.1+ (median 13.4+) years from diagnosis. Among naxitamab patients, 10/12 remain relapse-free post-mAb at 1.7+ to 4.3+ (median 3.1+) years from diagnosis. Toxicity was similar with short outpatient infusions and matched that observed with these and other anti-G mAbs in older patients. These findings were reassuring given that naxitamab is dosed >2.5× higher (~270 mg/m /cycle) than 3F8, dinutuximab, and dinutuximab beta (70-100 mg/m /cycle). HR-NB in infants proved to be highly curable.
Topics: Humans; Infant; Mice; Animals; Aged; Posterior Leukoencephalopathy Syndrome; Neoplasm Recurrence, Local; Antibodies, Monoclonal; Neuroblastoma; Immunotherapy; Immunologic Factors; Antineoplastic Agents
PubMed: 35913764
DOI: 10.1002/ijc.34233 -
Frontiers in Immunology 2020Neuroblastoma (NB) is the most common extracranial solid tumor in children and, in the high-risk group, has a 5-year mortality rate of ~50%. The high mortality rate and... (Review)
Review
Neuroblastoma (NB) is the most common extracranial solid tumor in children and, in the high-risk group, has a 5-year mortality rate of ~50%. The high mortality rate and significant treatment-related morbidities associated with current standard of care therapies belie the critical need for more tolerable and effective treatments for this disease. While the monoclonal antibody dinutuximab has demonstrated the potential for immunotherapy to improve overall NB outcomes, the 5-year overall survival of high-risk patients has not yet substantially changed. The frequency and type of invariant natural killer T cells (iNKTs) and natural killer cells (NKs) has been associated with improved outcomes in several solid and liquid malignancies, including NB. Indeed, iNKTs and NKs inhibit tumor associated macrophages (TAMs) and myeloid derived suppressor cells (MDSCs), kill cancer stem cells (CSCs) and neuroblasts, and robustly secrete cytokines to recruit additional immune effectors. These capabilities, and promising pre-clinical and early clinical data suggest that iNKT- and NK-based therapies may hold promise as both stand-alone and combination treatments for NB. In this review we will summarize the biologic features of iNKTs and NKs that confer advantages for NB immunotherapy, discuss the barriers imposed by the NB tumor microenvironment, and examine the current state of such therapies in pre-clinical models and clinical trials.
Topics: Animals; Child; Clinical Trials as Topic; Disease Models, Animal; Humans; Immunotherapy, Adoptive; Killer Cells, Natural; Natural Killer T-Cells; Neuroblastoma; Tumor Microenvironment
PubMed: 32457760
DOI: 10.3389/fimmu.2020.00873 -
Cancers Jun 2023Immunotherapies against high-risk neuroblastoma (NB), using the anti-GD2 antibody (Ab) dinutuximab beta (DB), significantly improved patient survival. Ab-dependent...
Immunotherapies against high-risk neuroblastoma (NB), using the anti-GD2 antibody (Ab) dinutuximab beta (DB), significantly improved patient survival. Ab-dependent cellular cytotoxicity (ADCC) is one of the main mechanisms of action and it is primarily mediated by NK cells. To further improve antitumor efficacy, we investigated here a combinatorial immunotherapy with DB and the double immune checkpoint blockade of T-cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) and programmed cell death ligand-1 (PD-L1). The effects of ADCC, mediated by DB against NB cells on NK-cell activity, and the expression of TIGIT and CD226 and their ligands CD112 and CD155, as well as of PD-1 and PD-L1 on NB and effector cells, were investigated using flow cytometry. ADCC was assessed with a calcein-AM-based cytotoxicity assay. The efficacy of a combinatorial immunotherapy with DB, given as a long-term treatment, and the double immune checkpoint blockade of TIGIT and PD-L1 was shown using a resistant murine model of NB, followed by an analysis of the tumor tissue. We detected both TIGIT ligands, CD112 and CD155, on all NB cell lines analyzed. Although ADCC by DB resulted in a strong activation of NK cells leading to an effective tumor cell lysis, a remarkable induction of PD-L1 expression on NB cells, and of TIGIT and PD-1 on effector cells, especially on NK cells, was observed. Additional anti-TIGIT or anti-PD-L1 treatments effectively inhibited tumor growth and improved survival of the mice treated with DB. The superior antitumor effects were observed in the "DB + double immune checkpoint blockade" group, showing an almost complete eradication of the tumors and the highest OS, even under resistant conditions. An analysis of tumor tissue revealed both TIGIT and TIGIT ligand expression on myeloid-derived suppressor cells (MDSCs), suggesting additional mechanisms of protumoral effects in NB. Our data show that the targeting of TIGIT and PD-L1 significantly improves the antitumor efficacy of anti-GD2 immunotherapy, with DB presenting a new effective combinatorial treatment strategy against high-risk tumors.
PubMed: 37444427
DOI: 10.3390/cancers15133317 -
Pediatric Blood & Cancer Dec 2023Dinutuximab β can be used to treat children with high-risk neuroblastoma (NB). Due to its high price, whether dinutuximab β is cost-effective for the treatment of...
BACKGROUND
Dinutuximab β can be used to treat children with high-risk neuroblastoma (NB). Due to its high price, whether dinutuximab β is cost-effective for the treatment of high-risk NB remains uncertain. Therefore, assessing the cost-effectiveness of dinutuximab β in children with high-risk NB is of high importance.
METHODS
The health utilities and economic outcomes in children with high-risk NB were projected using a partitioned survival model. The individual patient data (IPD) of add-on treatment with dinutuximab β (GD2 group) were derived from the literature, while the IPD of traditional therapy (TT group) were obtained from retrospective data of Shanghai Children's Medical Center. Treatment costs included drugs, adverse event-related expenses, and medical resource use. Utility values were obtained from the literature. Costs and quality-adjusted life-years (QALYs) were measured over a 10-year time horizon. Deterministic sensitivity analyses (DSA) and probabilistic sensitivity analyses (PSA) were also conducted.
RESULTS
Compared with the TT group, QALY increased in the GD2 group by 0.72 with an increased cost of $171,269.70, leading to an incremental cost-effectiveness ratio of 236,462.75$/QALY. DSA showed that the price of dinutuximab β was the main factor on the results than other parameters. Compared with the TT group, the GD2 group could not be cost-effective in the PSA at the $37,920/QALY threshold.
CONCLUSION
Results found that dinutuximab β is not a cost-effective treatment option for children with high-risk NB unless its price is significantly reduced.
PubMed: 37715719
DOI: 10.1002/pbc.30680