-
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 -
Cancers Jun 2023The anti-disialoganglioside (GD2) monoclonal antibody dinutuximab beta is approved for the maintenance treatment of high-risk neuroblastoma. Dinutuximab beta combined...
Effect and Tolerance of N5 and N6 Chemotherapy Cycles in Combination with Dinutuximab Beta in Relapsed High-Risk Neuroblastoma Patients Who Failed at Least One Second-Line Therapy.
The anti-disialoganglioside (GD2) monoclonal antibody dinutuximab beta is approved for the maintenance treatment of high-risk neuroblastoma. Dinutuximab beta combined with different chemotherapy regimens is being investigated in various clinical settings. We conducted a retrospective clinical chart review of 25 patients with relapsed/refractory neuroblastoma who had failed ≥1 second-line therapy and received compassionate use treatment with dinutuximab beta long-term infusion combined with the induction chemotherapy regimens N5 (cisplatin, etoposide, vindesine) and N6 (vincristine, dacarbazine, ifosfamide, doxorubicin) recommended by the German Pediatric Oncology and Hematology Group [GPOH] guidelines. The treatment did not result in any unexpected severe toxicities or in any major treatment delays. Grade 3/4 pain was reported by 4/25 patients in cycle 1, decreasing to 0/9 patients in cycles 3 and 4. The median follow-up was 0.6 years. The best response in this group was 48% (12/25 patients), which included three patients with minor responses. At 1 year, the estimated event-free survival was 27% (95% confidence interval [CI] 8-47) and overall survival was 44% (95% CI 24-65). Combining long-term infusion of dinutuximab beta with N5 and N6 chemotherapy demonstrated an acceptable safety profile and encouraging objective response rates in heavily pretreated patients with high-risk neuroblastoma, warranting further evaluation in clinical trials.
PubMed: 37444475
DOI: 10.3390/cancers15133364 -
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 -
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 -
Frontiers in Pediatrics 2023The survival rates for pediatric patients with relapsed and refractory tumors are poor. Successful treatment strategies are currently lacking and there remains an unmet...
A phase 1, first-in-child, multicenter study to evaluate the safety and efficacy of the oncolytic herpes virus talimogene laherparepvec in pediatric patients with advanced solid tumors.
BACKGROUND
The survival rates for pediatric patients with relapsed and refractory tumors are poor. Successful treatment strategies are currently lacking and there remains an unmet need for novel therapies for these patients. We report here the results of a phase 1 study of talimogene laherparepvec (T-VEC) and explore the safety of this oncolytic immunotherapy for the treatment of pediatric patients with advanced non-central nervous system tumors.
METHODS
T-VEC was delivered by intralesional injection at 10 plaque-forming units (PFU)/ml on the first day, followed by 10 PFU/ml on the first day of week 4 and every 2 weeks thereafter. The primary objective was to evaluate the safety and tolerability as assessed by the incidence of dose-limiting toxicities (DLTs). Secondary objectives included efficacy indicated by response and survival per modified immune-related response criteria simulating the Response Evaluation Criteria in Solid Tumors (irRC-RECIST).
RESULTS
Fifteen patients were enrolled into two cohorts based on age: cohort A1 ( = 13) 12 to ≤21 years old (soft-tissue sarcoma, = 7; bone sarcoma, = 3; neuroblastoma, = 1; nasopharyngeal carcinoma, = 1; and melanoma, = 1) and cohort B1 ( = 2) 2 to <12 years old (melanoma, = 2). Overall, patients received treatment for a median (range) of 5.1 (0.1, 39.4) weeks. No DLTs were observed during the evaluation period. All patients experienced at least one treatment-emergent adverse event (TEAE), and 53.3% of patients reported grade ≥3 TEAEs. Overall, 86.7% of patients reported treatment-related TEAEs. No complete or partial responses were observed, and three patients (20%) overall exhibited stable disease as the best response.
CONCLUSIONS
T-VEC was tolerable as assessed by the observation of no DLTs. The safety data were consistent with the patients' underlying cancer and the known safety profile of T-VEC from studies in the adult population. No objective responses were observed.
TRIAL REGISTRATION
ClinicalTrials.gov: NCT02756845. https://clinicaltrials.gov/ct2/show/NCT02756845.
PubMed: 37292376
DOI: 10.3389/fped.2023.1183295 -
Neoplasia (New York, N.Y.) Aug 2023While immunotherapy for pediatric cancer has made great strides in recent decades, including the FDA approval of agents such as dinutuximab and tisgenlecleucel, these...
While immunotherapy for pediatric cancer has made great strides in recent decades, including the FDA approval of agents such as dinutuximab and tisgenlecleucel, these successes have rarely impacted children with pediatric central nervous system (CNS) tumors. As our understanding of the biological underpinnings of these tumors evolves, new immunotherapeutics are undergoing rapid clinical translation specifically designed for children with CNS tumors. Most recently, there have been notable clinical successes with oncolytic viruses, vaccines, adoptive cellular therapy, and immune checkpoint inhibition. In this article, the immunotherapy working group of the Pacific Pediatric Neuro-Oncology Consortium (PNOC) reviews the current and future state of immunotherapeutic CNS clinical trials with a focus on clinical trial development. Based on recent therapeutic trials, we discuss unique immunotherapy clinical trial challenges, including toxicity considerations, disease assessment, and correlative studies. Combinatorial strategies and future directions will be addressed. Through internationally collaborative efforts and consortia, we aim to direct this promising field of immuno-oncology to the next frontier of successful application against pediatric CNS tumors.
Topics: Child; Humans; Central Nervous System Neoplasms; Oncolytic Viruses; Immunotherapy
PubMed: 37244226
DOI: 10.1016/j.neo.2023.100909 -
Journal of Biomedical Optics Sep 2023Fluorescence-guided surgery (FGS) provides specific real-time visualization of tumors, but intensity-based measurement of fluorescence is prone to errors. Multispectral...
SIGNIFICANCE
Fluorescence-guided surgery (FGS) provides specific real-time visualization of tumors, but intensity-based measurement of fluorescence is prone to errors. Multispectral imaging (MSI) in the short-wave infrared (SWIR) has the potential to improve tumor delineation by enabling machine-learning classification of pixels based on their spectral characteristics.
AIM
Determine whether MSI can be applied to FGS and combined with machine learning to provide a robust method for tumor visualization.
APPROACH
A multispectral SWIR fluorescence imaging device capable of collecting data from six spectral filters was constructed and deployed on neuroblastoma (NB) subcutaneous xenografts ( ) after the injection of a NB-specific NIR-I fluorescent probe (Dinutuximab-IRDye800). We constructed image cubes representing fluorescence collected from to 1450 nm and compared the performance of seven learning-based methods for pixel-by-pixel classification, including linear discriminant analysis, -nearest neighbor classification, and a neural network.
RESULTS
The spectra of tumor and non-tumor tissue were subtly different and conserved between individuals. In classification, a combine principal component analysis and -nearest-neighbor approach with area under curve normalization performed best, achieving 97.5% per-pixel classification accuracy (97.1%, 93.5%, and 99.2% for tumor, non-tumor tissue and background, respectively).
CONCLUSIONS
The development of dozens of new imaging agents provides a timely opportunity for multispectral SWIR imaging to revolutionize next-generation FGS.
Topics: Humans; Neoplasms; Fluorescent Dyes; Neural Networks, Computer; Optical Imaging; Machine Learning
PubMed: 36993142
DOI: 10.1117/1.JBO.28.9.094804 -
Cancers Mar 2023The identification of novel therapeutic targets for specific cancer molecular subtypes is crucial for the development of precision oncology. In the last few years,...
The identification of novel therapeutic targets for specific cancer molecular subtypes is crucial for the development of precision oncology. In the last few years, CRISPR/Cas9 screens have accelerated the discovery and validation of new targets associated with different tumor types, mutations, and fusions. However, there are still many cancer vulnerabilities associated with specific molecular features that remain to be explored. Here, we used data from CRISPR/Cas9 screens in 954 cancer cell lines to identify gene dependencies associated with 16 common cancer genomic amplifications. We found that high-copy-number genomic amplifications generate multiple collateral dependencies within the amplified region in most cases. Further, to prioritize candidate targets for each chromosomal region amplified, we integrated gene dependency parameters with both druggability data and subcellular location. Finally, analysis of the relationship between gene expression and gene dependency led to the identification of genes, the expression of which may constitute predictive biomarkers of dependency. In conclusion, our study provides a set of druggable targets specific for each amplification, opening the possibility to specifically target amplified tumors on this basis.
PubMed: 36980521
DOI: 10.3390/cancers15061636 -
Cancer Research Jun 2023Fluorescence-guided surgery is set to play a pivotal role in the intraoperative management of pediatric tumors. Shortwave infrared imaging (SWIR) has advantages over...
UNLABELLED
Fluorescence-guided surgery is set to play a pivotal role in the intraoperative management of pediatric tumors. Shortwave infrared imaging (SWIR) has advantages over conventional near-infrared I (NIR-I) imaging with reduced tissue scattering and autofluorescence. Here, two NIR-I dyes (IRDye800CW and IR12), with long tails emitting in the SWIR range, were conjugated with a clinical-grade anti-GD2 monoclonal antibody (dinutuximab-beta) to compare NIR-I and SWIR imaging for neuroblastoma surgery. A first-of-its-kind multispectral NIR-I/SWIR fluorescence imaging device was constructed to allow an objective comparison between the two imaging windows. Conjugates were first characterized in vitro. Tissue-mimicking phantoms, imaging specimens of known geometric and material composition, were used to assess the sensitivity and depth penetration of the NIR-I/SWIR device, showing a minimum detectable volume of ∼0.9 mm3 and depth penetration up to 3 mm. In vivo, fluorescence imaging using the NIR-I/SWIR device showed a high tumor-to-background ratio (TBR) for both dyes, with anti-GD2-IR800 being significantly brighter than anti-GD2-IR12. Crucially, the system enabled higher TBR at SWIR wavelengths than at NIR-I wavelengths, verifying SWIR imaging enables high-contrast delineation of tumor margins. This work demonstrates that by combining the high specificity of anti-GD2 antibodies with the availability and translatability of existing NIR-I dyes, along with the advantages of SWIR in terms of depth and tumor signal-to-background ratio, GD2-targeted NIR-I/SWIR-guided surgery could improve the treatment of patients with neuroblastoma, warranting investigation in future clinical trials.
SIGNIFICANCE
Multispectral near-infrared I/shortwave infrared fluorescence imaging is a versatile system enabling high tumor-to-background signal for safer and more complete resection of pediatric tumors during surgery.
Topics: Child; Humans; Antineoplastic Agents; Optical Imaging; Neuroblastoma; Phantoms, Imaging; Coloring Agents; Fluorescent Dyes
PubMed: 36934744
DOI: 10.1158/0008-5472.CAN-22-2918 -
Journal of Clinical Oncology : Official... Jun 2023Patients with relapsed high-risk neuroblastoma (rHR-NB) have a poor prognosis. We hypothesized that graft-versus-neuroblastoma effects could be elicited by...
Anti-GD2 Antibody Dinutuximab Beta and Low-Dose Interleukin 2 After Haploidentical Stem-Cell Transplantation in Patients With Relapsed Neuroblastoma: A Multicenter, Phase I/II Trial.
PURPOSE
Patients with relapsed high-risk neuroblastoma (rHR-NB) have a poor prognosis. We hypothesized that graft-versus-neuroblastoma effects could be elicited by transplantation of haploidentical stem cells (haplo-SCT) exploiting cytotoxic functions of natural killer cells and their activation by the anti-GD2 antibody dinutuximab beta (DB). This phase I/II trial assessed safety, feasibility, and outcomes of immunotherapy with DB plus subcutaneous interleukin-2 (scIL2) after haplo-SCT in patients with rHR-NB.
METHODS
Patients age 1-21 years underwent T-/B-cell-depleted haplo-SCT followed by DB and scIL2. The primary end point 'success of treatment' encompassed patients receiving six cycles, being alive 180 days after end of trial treatment without progressive disease, unacceptable toxicity, acute graft-versus-host-disease (GvHD) ≥grade 3, or extensive chronic GvHD.
RESULTS
Seventy patients were screened, and 68 were eligible for immunotherapy. Median number of DB cycles was 6 (range, 1-9). Median number of scIL2 cycles was 3 (1-6). The primary end point was met by 37 patients (54.4%). Median observation time was 7.8 years. Five-year event-free survival (EFS) and overall survival from start of trial treatment were 43% (95% CI, 31 to 55) and 53% (95% CI, 41 to 65), respectively. Five-year EFS among patients in complete remission (CR; 52%; 95% CI, 31 to 69) or partial remission (44%; 95% CI, 27 to 60) before immunotherapy were significantly better compared with patients with nonresponse/mixed response/progressive disease (13%; 95% CI, 1 to 42; = .026). Overall response rate in 43 patients with evidence of disease after haplo-SCT was 51% (22 patients), with 15 achieving CR (35%). Two patients developed GvHD grade 2 and 3 each. No unexpected adverse events occurred.
CONCLUSION
DB therapy after haplo-SCT in patients with rHR-NB is feasible, with low risk of inducing GvHD, and results in long-term remissions likely attributable to increased antineuroblastoma activity by donor-derived effector cells.
Topics: Humans; Infant; Child, Preschool; Child; Adolescent; Young Adult; Adult; Interleukin-2; Neoplasm Recurrence, Local; Neuroblastoma; Hematopoietic Stem Cell Transplantation; Graft vs Host Disease
PubMed: 36854071
DOI: 10.1200/JCO.22.01630