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Frontiers in Oncology 2022Relapsed/refractory high-risk neuroblastoma has a dismal prognosis. Anti-GD2-mediated chemo-immunotherapy has a notable anti-tumor activity in patients with...
BACKGROUND
Relapsed/refractory high-risk neuroblastoma has a dismal prognosis. Anti-GD2-mediated chemo-immunotherapy has a notable anti-tumor activity in patients with relapsed/refractory high-risk neuroblastoma. The purpose of this study was to analyze the efficacy and safety of the combination of immunotherapy with dinutuximab beta (DB) and chemotherapy in patients with relapsed/refractory high-risk neuroblastoma.
METHODS
All patients received the Turkish Pediatric Oncology Group NB 2009 national protocol for HR-NB treatment at the time of diagnosis. Salvage treatments were administered after progression or relapse. The patients who could not achieve remission in primary or metastatic sites were included in the study. The most common chemotherapy scheme was irinotecan and temozolomide. DB was administered intravenously for 10 days through continuous infusion with 10 mg/m per day. The patients received 2 to 14 successive cycles with duration of 28 days each. Disease assessment was performed after cycles 2, 4, and 6 and every 2 to 3 cycles thereafter.
RESULTS
Between January 2020 and March 2022, nineteen patients received a total of 125 cycles of DB and chemotherapy. Objective responses were achieved in 12/19 (63%) patients, including complete remission in 6/19 and partial response in 6/19. Stable disease was observed in two patients. The remaining five patients developed bone/bone marrow and soft tissue progression after 2-4 cycles of treatment. The most common Grade ≥3 toxicities were leukopenia, thrombocytopenia, hypertransaminasemia, fever, rash/itching and capillary leak syndrome, respectively.
CONCLUSION
Our study results suggest that DB-based chemo-immunotherapy seems to be suitable with encouraging response rates in patients with relapsed/refractory high-risk neuroblastoma.
PubMed: 36620564
DOI: 10.3389/fonc.2022.1041443 -
Journal of Immunology Research 2017Target selection is a key feature in cancer immunotherapy, a promising field in cancer research. In this respect, gangliosides, a broad family of structurally related... (Review)
Review
Target selection is a key feature in cancer immunotherapy, a promising field in cancer research. In this respect, gangliosides, a broad family of structurally related glycolipids, were suggested as potential targets for cancer immunotherapy based on their higher abundance in tumors when compared with the matched normal tissues. GD2 is the first ganglioside proven to be an effective target antigen for cancer immunotherapy with the regulatory approval of dinutuximab, a chimeric anti-GD2 therapeutic antibody. Although the therapeutic efficacy of anti-GD2 monoclonal antibodies is well documented, neuropathic pain may limit its application. -Acetyl-GD2, the -acetylated-derivative of GD2, has recently received attention as novel antigen to target GD2-positive cancers. The present paper examines the role of -acetyl-GD2 in tumor biology as well as the available preclinical data of anti--acetyl-GD2 monoclonal antibodies. A discussion on the relevance of -acetyl-GD2 in chimeric antigen receptor T cell therapy development is also included.
Topics: Acetylation; Animals; Antibodies, Anti-Idiotypic; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antigens, Neoplasm; Clinical Trials as Topic; Gangliosides; Humans; Immunotherapy; Neoplasms; Receptors, Antigen, T-Cell
PubMed: 28154831
DOI: 10.1155/2017/5604891 -
Journal For Immunotherapy of Cancer Dec 2020Immunotherapy with anti-disialoganglioside dinutuximab has improved survival for children with high-risk neuroblastoma (NB) when given after induction chemotherapy and...
BACKGROUND
Immunotherapy with anti-disialoganglioside dinutuximab has improved survival for children with high-risk neuroblastoma (NB) when given after induction chemotherapy and surgery. However, disease recurrence and resistance persist. Dinutuximab efficacy has not been evaluated when initiated before primary tumor removal. Using a surgical mouse model of human NB, we examined if initiating dinutuximab plus ex vivo-activated natural killer (aNK) cells before resection of the primary tumor improves survival.
METHODS
In vitro, human NB cells (SMS-KCNR-Fluc, CHLA-255-Fluc) were treated with dinutuximab and/or aNK cells and cytotoxicity was measured. In vivo, NB cells (SMS-KCNR-Fluc, CHLA-255-Fluc, or COG-N-415x PDX) were injected into the kidney of NOD-scid gamma mice. Mice received eight intravenous infusions of aNK cells plus dinutuximab beginning either 12 days before or 2 days after resection of primary tumors. Tumors in control mice were treated by resection alone or with immunotherapy alone. Disease was quantified by bioluminescent imaging and survival was monitored. aNK cell infiltration into primary tumors was quantified by flow cytometry and immunohistochemistry at varying timepoints.
RESULTS
In vitro, aNK cells and dinutuximab were more cytotoxic than either treatment alone. In vivo, treatment with aNK cells plus dinutuximab prior to resection of the primary tumor was most effective in limiting metastatic disease and prolonging survival. aNK cell infiltration into xenograft tumors was observed after 1 day and peaked at 5 days following injection.
CONCLUSION
Dinutuximab plus aNK cell immunotherapy initiated before resection of primary tumors decreases disease burden and prolongs survival in an experimental mouse model of NB. These findings support the clinical investigation of this treatment strategy during induction therapy in patients with high-risk NB.
Topics: Animals; Antibodies, Monoclonal; Humans; Immunotherapy; Killer Cells, Natural; Mice; Neuroblastoma; Survival Analysis
PubMed: 33428582
DOI: 10.1136/jitc-2020-001560 -
MAbs 2014The commercial pipeline of monoclonal antibodies is highly dynamic, with a multitude of transitions occurring during the year as product candidates advance through the...
The commercial pipeline of monoclonal antibodies is highly dynamic, with a multitude of transitions occurring during the year as product candidates advance through the clinical phases and onto the market. The data presented here add to that provided in the extensive "Antibodies to watch in 2014" report published in the January/February 2014 issue of mAbs. Recent phase transition data suggest that 2014 may be a banner year for first approvals of antibody therapeutics. As of May 2014, three products, ramucirumab (Cyramza®), siltuximab (Sylvant®) and vedolizumab (Entyvio™), had been granted first approvals in the United States, and four additional antibody therapeutics (secukinumab, dinutuximab, nivolumab, pembrolizumab) are undergoing regulatory review in either the US or the European Union. Other notable events include the start of first Phase 3 studies for seven antibody therapeutics (dupilumab, SA237, etrolizumab, MPDL3280A, bavituximab, clivatuzumab tetraxetan, blinatumomab). Relevant data for these product candidates are summarized, and metrics for antibody therapeutics development are discussed.
Topics: Animals; Antibodies, Monoclonal; Drug Approval; Humans; Periodicals as Topic; United States
PubMed: 24846335
DOI: 10.4161/mabs.29282 -
Journal of Clinical Oncology : Official... Jan 2021Anti-GD2 monoclonal antibody (mAb) has proven efficacy in high-risk neuroblastoma (HR-NB). A small phase I GD2/GD3 vaccine trial (n = 15) described long-term survival...
PURPOSE
Anti-GD2 monoclonal antibody (mAb) has proven efficacy in high-risk neuroblastoma (HR-NB). A small phase I GD2/GD3 vaccine trial (n = 15) described long-term survival and a favorable safety profile among patients with a history of disease progression (PD). The kinetics of mounting antibody response to vaccine and its prognostic impact on survival are now investigated in a phase II study (ClinicalTrials.gov identifier: NCT00911560).
PATIENTS AND METHODS
One hundred two patients with HR-NB who achieved remission after salvage therapies were enrolled in this trial. They received seven subcutaneous injections of GD2/GD3 vaccine spanning 1 year plus oral β-glucan starting at week 6 after the third dose of vaccine. Serum anti-vaccine antibody titers were quantified by enzyme-linked immunosorbent assay. Single nucleotide polymorphisms (SNPs) were determined by quantitative polymerase chain reaction. Kaplan-Meier and landmark Cox Regression models were used for survival estimates.
RESULTS
Patients had a history of one (63%), two (21%), or three to six (16%) episodes of PD. 82% of them progressed following anti-GD2 mAb (m3F8/dinutuximab/naxitamab) therapy. Vaccine-related toxicities were self-limited injection-associated local reactions and fever without any > grade 3 toxicities. The progression-free survival (PFS) was 32% ± 6%, and the overall survival (OS) was 71% ± 7% at 5 years. Serum anti-GD2 (immunoglobulin G1 [IgG1] and IgM) and anti-GD3 (IgG1) titers showed notable increases following the initiation of β-glucan at week 6. There was an association between IgG1 titer and SNP rs3901533 of dectin-1, the β-glucan receptor. Multivariable analyses showed that anti-GD2-IgG1 titer ≥ 150 ng/mL by week 8 was associated with favorable PFS and OS, while having prior episodes of PD and the time from last PD to vaccine were associated with PFS.
CONCLUSION
GD2/GD3 vaccine plus β-glucan elicited robust antibody responses in patients with HR-NB with prior PD. Higher anti-GD2-IgG1 titer was associated with improved survival.
Topics: Adjuvants, Immunologic; Biomarkers; Brain Neoplasms; Cancer Vaccines; Child; Child, Preschool; Disease Progression; Female; Gangliosides; Glioblastoma; Humans; Immunogenicity, Vaccine; Immunoglobulin G; Infant; Lectins, C-Type; Male; Polymorphism, Single Nucleotide; Progression-Free Survival; Time Factors; beta-Glucans
PubMed: 33326254
DOI: 10.1200/JCO.20.01892 -
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 -
Cancer Dec 2017Early-phase trials in patients with recurrent neuroblastoma historically used an objective "response" of measureable disease (Response Evaluation Criteria In Solid... (Meta-Analysis)
Meta-Analysis Review
Historical time to disease progression and progression-free survival in patients with recurrent/refractory neuroblastoma treated in the modern era on Children's Oncology Group early-phase trials.
BACKGROUND
Early-phase trials in patients with recurrent neuroblastoma historically used an objective "response" of measureable disease (Response Evaluation Criteria In Solid Tumors [RECIST], without bone/bone marrow assessment) to select agents for further study. Historical cohorts may be small and potentially biased; to the authors' knowledge, disease recurrence studies from international registries are outdated. Using a large recent cohort of patients with recurrent/refractory neuroblastoma from Children's Oncology Group (COG) modern-era early-phase trials, the authors determined outcome and quantified parameters for designing future studies.
METHODS
The first early-phase COG trial enrollment (sequential) of 383 distinct patients with recurrent/refractory neuroblastoma on 23 phase 1, 3 phase 1/2, and 9 phase 2 trials (August 2002 to January 2014) was analyzed for progression-free survival (PFS), overall survival (OS), and time to disease progression (TTP). Planned frontline therapy for patients with high-risk neuroblastoma included hematopoietic stem cell transplantation (approximately two-thirds of patients underwent ≥1 hematopoietic stem cell transplantation); 13.2% of patients received dinutuximab.
RESULTS
From the time of the patient's first early-phase trial enrollment (383 patients), the 1-year and 4-year PFS rates ( ± standard error) were 21% ± 2% and 6% ± 1%, respectively, whereas the 1-year and 4-year OS rates were 57% ± 3% and 20% ± 2%, respectively. The median TTP was 58 days (interquartile range, 31-183 days [350 patients]); the median follow-up was 25.3 months (33 patients were found to be without disease recurrence/progression). The median time from diagnosis to first disease recurrence/progression was 18.7 months (range, 1.4-64.8 months) (176 patients). MYCN amplification and 11q loss of heterozygosity were prognostic of worse PFS and OS (P = .003 and P<.0001, respectively, and P = .02 and P = .03, respectively) after early-phase trial enrollment.
CONCLUSIONS
This recent COG cohort of patients with recurrent/refractory neuroblastoma is inclusive and representative. To the authors' knowledge, the current study is the first meta-analysis of PFS, TTP, and OS within the context of modern therapy. These results will inform the design of future phase 2 studies by providing a) historical context during the search for more effective agents; and, b) factors prognostic of PFS and OS after disease recurrence to stratify randomization. Cancer 2017;123:4914-23. © 2017 American Cancer Society.
Topics: Adolescent; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Cause of Death; Child; Child, Preschool; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Combined Modality Therapy; Disease Progression; Disease-Free Survival; Female; Follow-Up Studies; Humans; Infant; Male; Medical Oncology; Neoplasm Recurrence, Local; Neuroblastoma; Response Evaluation Criteria in Solid Tumors; Risk Assessment; Treatment Outcome; United States
PubMed: 28885700
DOI: 10.1002/cncr.30934 -
P & T : a Peer-reviewed Journal For... May 2015Filgrastim-sndz (Zarxio) to help prevent infections related to chemotherapy, dinutuximab (Unituxin) for high-risk pediatric neuroblastoma, and panobinostat (Farydak) for...
Filgrastim-sndz (Zarxio) to help prevent infections related to chemotherapy, dinutuximab (Unituxin) for high-risk pediatric neuroblastoma, and panobinostat (Farydak) for multiple myeloma.
PubMed: 25987820
DOI: No ID Found -
Orphanet Journal of Rare Diseases Jul 2023The evaluation of clinical evidence takes account of health benefit (efficacy and safety) and the degree of certainty in the estimate of benefit. In orphan indications...
Exploring the feasibility of using the ICER Evidence Rating Matrix for Comparative Clinical Effectiveness in assessing treatment benefit and certainty in the clinical evidence on orphan therapies for paediatric indications.
BACKGROUND
The evaluation of clinical evidence takes account of health benefit (efficacy and safety) and the degree of certainty in the estimate of benefit. In orphan indications practical and ethical challenges in conducting clinical trials, particularly in paediatric patients, often limit the available evidence, rendering structured evaluation challenging. While acknowledging the paucity of evidence, regulators and reimbursement authorities compare the efficacy and safety of alternative treatments for a given indication, often in the context of the benefits of other treatments for similar or different conditions. This study explores the feasibility of using the Institute for Clinical and Economic Review (ICER) Evidence Rating Matrix for Comparative Clinical Effectiveness in structured assessment of both the magnitude of clinical benefit (net health benefit, NHB) and the certainty of the effect estimate in a sample of orphan therapies for paediatric indications.
RESULTS
Eleven systemic therapies with European Medicines Agency (EMA) orphan medicinal product designation, licensed for 16 paediatric indications between January 2017 and March 2020 were identified using OrphaNet and EMA databases and were selected for evaluation with the ICER Evidence Rating Matrix: burosumab; cannabidiol; cerliponase alfa; chenodeoxycholic acid (CDCA); dinutuximab beta; glibenclamide; metreleptin; nusinersen; tisagenlecleucel; velmanase alfa; and vestronidase alfa. EMA European Public Assessment Reports, PubMed, EMBASE, the Cochrane Library, Clinical Key, and conference presentations from January 2016 to April 2021 were searched for evidence on efficacy and safety. Two of the identified therapies were graded as "substantial" NHB: dinutuximab beta (neuroblastoma maintenance) and nusinersen (Type I SMA), and one as "comparable" NHB (CDCA). The NHB grade of the remaining therapies fell between "comparable" and "substantial". No therapies were graded as having negative NHB. The certainty of the estimate ranged from "high" (dinutuximab beta in neuroblastoma maintenance) to "low" (CDCA, metreleptin and vestronidase alfa). The certainty of the other therapies was graded between "low" and "high". The ICER Evidence Rating Matrix overall rating "A" (the highest) was given to two therapies, "B+" to 6 therapies, "C+" to five therapies, and "I" (the lowest) to three therapies. The scores varied between rating authors with mean agreement over all indications of 71.9% for NHB, 56.3% for certainty and 68.8% for the overall rating.
CONCLUSIONS
Using the ICER Matrix to grade orphan therapies according to their treatment benefit and certainty is feasible. However, the assessment involves subjective judgements based on heterogenous evidence. Tools such as the ICER Matrix might aid decision makers to evaluate treatment benefit and its certainty when comparing therapies across indications.
Topics: Child; Humans; Feasibility Studies; Neuroblastoma; Treatment Outcome
PubMed: 37474954
DOI: 10.1186/s13023-023-02701-w -
Immunotherapy Sep 2016Tumor-specific monoclonal antibodies (mAbs) have demonstrated efficacy in the clinic, becoming an important approach for cancer immunotherapy. Due to its limited... (Review)
Review
Tumor-specific monoclonal antibodies (mAbs) have demonstrated efficacy in the clinic, becoming an important approach for cancer immunotherapy. Due to its limited expression on normal tissue, the GD2 disialogangloside expressed on neuroblastoma cells is an excellent candidate for mAb therapy. In 2015, dinutuximab (an anti-GD2 mAb) was approved by the US FDA and is currently used in a combination immunotherapeutic regimen for the treatment of children with high-risk neuroblastoma. Here, we review the extensive preclinical and clinical development of anti-GD2 mAbs and the different mechanisms by which they mediate tumor cell killing. In addition, we discuss different mAb-based strategies that capitalize on the targeting ability of anti-GD2 mAbs to potentially deliver, as monotherapy, or in combination with other treatments, improved antitumor efficacy.
Topics: Animals; Antibodies, Monoclonal; Antineoplastic Agents; Clinical Trials as Topic; Drug Evaluation, Preclinical; Drug Therapy, Combination; Gangliosides; Humans; Immunotherapy; Neuroblastoma; Treatment Outcome
PubMed: 27485082
DOI: 10.2217/imt-2016-0021