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Journal For Immunotherapy of Cancer Feb 2023In the Children's Oncology Group ANBL1221 phase 2 trial for patients with first relapse/first declaration of refractory high-risk neuroblastoma, irinotecan and...
KIR/KIR-ligand genotypes and clinical outcomes following chemoimmunotherapy in patients with relapsed or refractory neuroblastoma: a report from the Children's Oncology Group.
BACKGROUND
In the Children's Oncology Group ANBL1221 phase 2 trial for patients with first relapse/first declaration of refractory high-risk neuroblastoma, irinotecan and temozolomide (I/T) combined with either temsirolimus (TEMS) or immunotherapy (the anti-GD2 antibody dinutuximab (DIN) and granulocyte macrophage colony stimulating factory (GM-CSF)) was administered. The response rate among patients treated with I/T/DIN/GM-CSF in the initial cohort (n=17) was 53%; additional patients were enrolled to permit further evaluation of this chemoimmunotherapy regimen. Potential associations between immune-related biomarkers and clinical outcomes including response and survival were evaluated.
METHODS
Patients were evaluated for specific immunogenotypes that influence natural killer (NK) cell activity, including killer immunoglobulin-like receptors (KIRs) and their ligands, Fc gamma receptors, and NCR3. Total white cells and leucocyte subsets were assessed via complete blood counts, and flow cytometry of peripheral blood mononuclear cells was performed to assess the potential association between immune cell subpopulations and surface marker expression and clinical outcomes. Appropriate statistical tests of association were performed. The Bonferroni correction for multiple comparisons was performed where indicated.
RESULTS
Of the immunogenotypes assessed, the presence or absence of certain KIR and their ligands was associated with clinical outcomes in patients treated with chemoimmunotherapy rather than I/T/TEMS. While median values of CD161, CD56, and KIR differed in responders and non-responders, statistical significance was not maintained in logistic regression models. White cell and neutrophil counts were associated with differences in survival outcomes, however, increases in risk of event in patients assigned to chemoimmunotherapy were not clinically significant.
CONCLUSIONS
These findings are consistent with those of prior studies showing that KIR/KIR-ligand genotypes are associated with clinical outcomes following anti-GD2 immunotherapy in children with neuroblastoma. The current study confirms the importance of KIR/KIR-ligand genotype in the context of I/T/DIN/GM-CSF chemoimmunotherapy administered to patients with relapsed or refractory disease in a clinical trial. These results are important because this regimen is now widely used for treatment of patients at time of first relapse/first declaration of refractory disease. Efforts to assess the role of NK cells and genes that influence their function in response to immunotherapy are ongoing.
TRIAL REGISTRATION NUMBER
NCT01767194.
Topics: Humans; Child; Ligands; Granulocyte-Macrophage Colony-Stimulating Factor; Leukocytes, Mononuclear; Neuroblastoma; Genotype; Receptors, KIR; Histocompatibility Antigens; Irinotecan; Immunotherapy; Recurrence
PubMed: 36822669
DOI: 10.1136/jitc-2022-006530 -
European Journal of Cancer (Oxford,... Mar 2022Cancer in neonates and infants is a rare but challenging entity. Treatment is complicated by marked physiological changes during the first year of life, excess rates of... (Review)
Review
Cancer in neonates and infants is a rare but challenging entity. Treatment is complicated by marked physiological changes during the first year of life, excess rates of toxicity, mortality, and late effects. Dose optimisation of chemotherapeutics may be an important step to improving outcomes. Body size-based dosing is used for most anticancer drugs used in infants. However, dose regimens are generally not evidence based, and dosing strategies are frequently inconsistent between tumour types and treatment protocols. In this review, we collate available pharmacological evidence supporting dosing regimens in infants for a wide range of cytotoxic drugs. A systematic review was conducted, and available data ranked by a level of evidence (1-5) and a grade of recommendation (A-D) provided on a consensus basis, with recommended dosing approaches indicated as appropriate. For 9 of 29 drugs (busulfan, carboplatin, cyclophosphamide, daunorubicin, etoposide, fludarabine, isotretinoin, melphalan and vincristine), grade A was scored, indicating sufficient pharmacological evidence to recommend a dosing algorithm for infants. For busulfan and carboplatin, sufficient data were available to recommend therapeutic drug monitoring in infants. For eight drugs (actinomycin D, blinatumomab, dinutuximab, doxorubicin, mercaptopurine, pegaspargase, thioguanine and topotecan), some pharmacological evidence was available to guide dosing (graded as B). For the remaining drugs, including commonly used agents such as cisplatin, cytarabine, ifosfamide, and methotrexate, pharmacological evidence for dosing in infants was limited or non-existent: grades C and D were scored for 10 and 2 drugs, respectively. The review provides clinically relevant evidence-based dosing guidance for cytotoxic drugs in neonates and infants.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Carboplatin; Etoposide; Humans; Infant; Infant, Newborn
PubMed: 34865945
DOI: 10.1016/j.ejca.2021.11.001 -
Frontiers in Immunology 2024The clinical success of chimeric antigen receptor-modified T cells (CAR-T cells) for hematological malignancies has not been reproduced for solid tumors, partly due to...
INTRODUCTION
The clinical success of chimeric antigen receptor-modified T cells (CAR-T cells) for hematological malignancies has not been reproduced for solid tumors, partly due to the lack of cancer-type specific antigens. In this work, we used a novel combinatorial approach consisting of a versatile anti-FITC CAR-T effector cells plus an FITC-conjugated neuroblastoma (NB)-targeting linker, an FITC-conjugated monoclonal antibody (Dinutuximab) that recognizes GD2.
METHODS
We compared cord blood (CB), and CD45RA-enriched peripheral blood leukapheresis product (45RA) as allogeneic sources of T cells, using peripheral blood (PB) as a control to choose the best condition for anti-FITC CAR-T production. Cells were manufactured under two cytokine conditions (IL-2 IL-7+IL-15+IL-21) with or without CD3/CD28 stimulation. Immune phenotype, vector copy number, and genomic integrity of the final products were determined for cell characterization and quality control assessment. Functionality and antitumor capacity of CB/45RA-derived anti-FITC CAR-T cells were analyzed in co-culture with different anti-GD2-FITC labeled NB cell lines.
RESULTS
The IL-7+IL-15+IL-21 cocktail, in addition to co-stimulation signals, resulted in a favorable cell proliferation rate and maintained less differentiated immune phenotypes in both CB and 45RA T cells. Therefore, it was used for CAR-T cell manufacturing and further characterization. CB and CD45RA-derived anti-FITC CAR-T cells cultured with IL-7+IL-15+IL-21 retained a predominantly naïve phenotype compared with controls. In the presence of the NB-FITC targeting, CD4+ CB-derived anti-FITC CAR-T cells showed the highest values of co-stimulatory receptors OX40 and 4-1BB, and CD8+ CAR-T cells exhibited high levels of PD-1 and 4-1BB and low levels of TIM3 and OX40, compared with CAR-T cells form the other sources studied. CB-derived anti-FITC CAR-T cells released the highest amounts of cytokines (IFN-γ and TNF-α) into co-culture supernatants. The viability of NB target cells decreased to 30% when co-cultured with CB-derived CAR-T cells during 48h.
CONCLUSION
CB and 45RA-derived T cells may be used as allogeneic sources of T cells to produce CAR-T cells. Moreover, ex vivo culture with IL-7+IL-15+IL-21 could favor CAR-T products with a longer persistence in the host. Our strategy may complement the current use of Dinutuximab in treating NB through its combination with a targeted CAR-T cell approach.
Topics: Humans; T-Lymphocytes; Receptors, Chimeric Antigen; Interleukin-15; Interleukin-7; Fluorescein-5-isothiocyanate; Cytokines; Neuroblastoma
PubMed: 38601159
DOI: 10.3389/fimmu.2024.1375833 -
International Journal of Molecular... Jan 2023Ganglioside GD2 is a well-established target expressed on multiple solid tumors, many of which are characterized by low treatment efficiency. Antibody-drug conjugates...
Ganglioside GD2 is a well-established target expressed on multiple solid tumors, many of which are characterized by low treatment efficiency. Antibody-drug conjugates (ADCs) have demonstrated marked success in a number of solid tumors, and GD2-directed drug conjugates may also hold strong therapeutic potential. In a recent study, we showed that ADCs based on the approved antibody dinutuximab and the drugs monomethyl auristatin E (MMAE) or F (MMAF) manifested potent and selective cytotoxicity in a panel of tumor cell lines and strongly inhibited solid tumor growth in GD2-positive mouse cancer models. Here, we employed two different GD2-binding moieties-minibodies and scFv fragments that carry variable antibody domains identical to those of dinutuximab, and site-directly conjugated them to MMAE or MMAF by thiol-maleimide chemistry with drug-to-antibody ratios (DAR) of 2 and 1, respectively. Specific binding of the antibody fragment-drug conjugates (FDCs) to GD2 was confirmed in direct ELISA, flow cytometry, and confocal microscopy. Selective cytotoxic and cytostatic effects of the conjugates were observed in GD2-positive but not GD2-negative neuroblastoma and melanoma cell lines. Minibody-based FDCs demonstrated more pronounced cytotoxic effects and stronger antigen binding compared to scFv-based FDCs. The developed molecules may offer considerable practical benefit, since antibody fragment-drug conjugates are capable of enhancing therapeutic efficacy of ADCs by improving their pharmacokinetic characteristics and reducing side effects.
Topics: Animals; Mice; Immunoglobulin Fragments; Cell Line, Tumor; Antineoplastic Agents; Immunoconjugates; Neuroblastoma; Disease Models, Animal; Gangliosides
PubMed: 36674755
DOI: 10.3390/ijms24021239 -
Clinical Cancer Research : An Official... Jan 2019Immunotherapy of neuroblastoma that remains after myeloablative chemotherapy with anti-GD2 antibody dinutuximab has increased the two-year event-free and overall...
PURPOSE
Immunotherapy of neuroblastoma that remains after myeloablative chemotherapy with anti-GD2 antibody dinutuximab has increased the two-year event-free and overall survival of high-risk neuroblastoma patients; however, 40% of patients develop recurrent disease during or after this treatment. To determine the potential of such antibody-based immunotherapy earlier in treatment, a mouse model was developed in which surgical resection of the primary tumor was followed by therapy of residual disease with dinutuximab combined with -activated human natural killer (aNK) cells.
EXPERIMENTAL DESIGN
The effect of combining dinutuximab with human aNK cells was determined with cellular cytotoxicity and Matrigel invasion assays. The efficacy of dinutuximab and aNK cells against neuroblastoma was assessed following resection of primary tumors formed by two cell lines or a patient-derived xenograft (PDX) in immunodeficient NOD-scid gamma mice.
RESULTS
, the combination of aNK cells and dinutuximab caused cytotoxicity and decreased invasiveness of three human neuroblastoma cell lines. Treatment of mice with dinutuximab combined with aNK cells after surgical resection of primary intrarenal tumors formed by two cell lines or a PDX decreased tumor cells in liver and bone marrow as evaluated by histopathology and bioluminescence imaging. Survival of mice after resection of these tumors was most significantly increased by treatment with dinutuximab combined with aNK cells compared with that of untreated mice.
CONCLUSIONS
The combination of dinutuximab and adoptively transferred human aNK cells following surgical resection of primary neuroblastomas significantly improves survival of immunodeficient mice.
Topics: Animals; Antibodies, Anti-Idiotypic; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Cytotoxicity, Immunologic; Disease Models, Animal; Heterografts; Humans; Immunotherapy; Killer Cells, Natural; Mice; N-Acetylgalactosaminyltransferases; Neuroblastoma
PubMed: 30232225
DOI: 10.1158/1078-0432.CCR-18-1317 -
Frontiers in Oncology 2020The introduction of immunotherapy using an anti-GD2 antibody (dinutuximab, ch14.18) has significantly improved survival rates for high-risk neuroblastoma patients....
The introduction of immunotherapy using an anti-GD2 antibody (dinutuximab, ch14.18) has significantly improved survival rates for high-risk neuroblastoma patients. However, this improvement in survival is accompanied by a substantial immunotherapy-related toxicity burden. The primary objective of this study was to describe treatment-related toxicities during immunotherapy with dinutuximab, IL-2, GM-CSF, and isotretinoin. A retrospective, single center analysis of immunotherapy-related toxicities was performed in twenty-six consecutive high-risk neuroblastoma patients who received immunotherapy as maintenance therapy in the Princess Máxima Center (Utrecht, Netherlands). Toxicities were recorded and graded according to the CTCAE. Particular attention was drawn to pain and fever management and toxicities leading to dose modifications of dinutuximab and IL-2. Twenty-three patients (88%) completed all six courses of immunotherapy. Disease progression, isotretinoin-associated liver toxicity, and catheter-related infection in combination with peripheral neuropathy were reasons for immunotherapy discontinuation. The most common grade ≥3 toxicities for courses 1-5, respectively, were pain, catheter-related infections, and fever. In total, 310 grade ≥3 toxicities were recorded in 124 courses. Thirty-three grade 4 toxicities in 19/26 patients and no grade 5 toxicities (death) were seen. Fifty-nine percent of grade ≥3 toxicities were recorded in the two courses with IL-2. Catheter-related bloodstream infections were identified in 81% of patients. Four of these episodes led to intensive care admission followed by full recovery (grade 4).
PubMed: 33680926
DOI: 10.3389/fonc.2020.601076 -
Journal of Clinical Medicine Sep 2023GD2, a disialoganglioside, is present on the surface of most neuroblastomas, as well as on some other cancers, such as melanoma and osteogenic sarcoma. The anti-GD2...
GD2, a disialoganglioside, is present on the surface of most neuroblastomas, as well as on some other cancers, such as melanoma and osteogenic sarcoma. The anti-GD2 antibody ch14.18 (dinutuximab) has an FDA-registered indication for use as maintenance therapy for high-risk neuroblastoma with cytokines and 13-cis-retinoic acid after myeloablative therapy. Recent studies using immunohistochemistry of tumor or tumor cells in marrow have shown that some neuroblastomas are negative for GD2. Dinutuximab and other anti-GD2 antibodies are increasingly used in combination with cytotoxic chemotherapy for treating relapsed neuroblastoma, so it is important to be able to identify patients with tumor cells with low GD2 expression, as such patients may experience toxicity but not benefit from the antibody therapy. As the most common clinical samples available for relapsed neuroblastoma are bone marrow aspirates, we developed a method to quantify dinutuximab binding density and the frequency of neuroblastoma cells positive for the antibody in bone marrow aspirates. Here, we describe a multi-color flow cytometry assay that employs non-GD2 antibodies to identify neuroblastoma cells in a mixed population (tumor, bone marrow, or blood) and an anti-GD2 antibody to quantify both the frequency and density of GD2 expression on neuroblastoma cells.
PubMed: 37834874
DOI: 10.3390/jcm12196223 -
F1000Research 2019Ewing sarcoma is a small round blue cell malignancy arising from bone or soft tissue and most commonly affects adolescents and young adults. Metastatic and relapsed... (Review)
Review
Ewing sarcoma is a small round blue cell malignancy arising from bone or soft tissue and most commonly affects adolescents and young adults. Metastatic and relapsed Ewing sarcoma have poor outcomes and recurrences remain common. Owing to the poor outcomes associated with advanced disease and the need for a clear research strategy, the Children's Oncology Group Bone Tumor Committee formed the New Agents for Ewing Sarcoma Task Force to bring together experts in the field to evaluate and prioritize new agents for incorporation into clinical trials. This group's mission was to evaluate scientific and clinical challenges in moving new agents forward and to recommend agents and trial designs to the Bone Tumor Committee. The task force generated a framework for vetting prospective agents that included critical evaluation of each drug by using both clinical and non-clinical parameters. Representative appraisal of agents of highest priority, including eribulin, dinutuximab, cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, anti-angiogenic tyrosine kinase inhibitors, and poly-ADP-ribose polymerase (PARP) inhibitors, is described. The task force continues to analyze new compounds by using the paradigm established.
Topics: Adolescent; Antineoplastic Agents; Bone Neoplasms; Child; Humans; Neoplasm Recurrence, Local; Prospective Studies; Sarcoma, Ewing; Young Adult
PubMed: 31031965
DOI: 10.12688/f1000research.18139.1 -
Journal For Immunotherapy of Cancer May 2020Neuroblastoma (NB) is the most frequent extracranial solid tumor in children. More than 50% of patients present with widespread (stage M) or refractory disease. In these...
BACKGROUND
Neuroblastoma (NB) is the most frequent extracranial solid tumor in children. More than 50% of patients present with widespread (stage M) or refractory disease. In these patients, event-free and overall survival was improved by the addition of the anti-disialoganglioside antibody dinutuximab beta (DB) following multimodal conventional therapy. However, the prognosis of patients with refractory/relapsed NB remains poor. In the past decade, immunotherapy approaches with checkpoint inhibitors were approved for patients with certain malignant diseases such as melanoma or Hodgkin lymphoma. In preclinical models, DB resulted in an upregulation of the programmed cell death protein 1 (PD-1) checkpoint in NB cell lines and a combined treatment of DB with a murine anti-PD-1 checkpoint inhibitor showed a synergistic effect in a NB mouse model.
CASE PRESENTATIONS
Two patients were admitted with refractory metastatic NB. In the 4-year-old girl, NB was diagnosed in 2013. She completed her first-line therapy with a first remission in 2015, but suffered a relapse in 2017. Treatment with chemotherapy and DB resulted in progressive disease after transient improvement. In the 17-year-old young man, NB was first diagnosed in April 2010. After two local relapses in 2011 and 2014, a metastatic relapse and a large abdominal tumor bulk were found in 2018. Despite transient improvement with multimodal therapy, progressive metastatic disease was observed in May 2019. Both patients had a satisfactory quality of life. Therefore, treatment with DB and nivolumab was performed-in the girl from October 2018 until August 2019, in the young man since June 2019. Tolerance to treatment was excellent. The girl continues to be in complete remission 6 months after therapy was stopped. In the young man, the soft tissue lesions disappeared completely, the skeletal lesions regressed substantially after 9 months of his still ongoing treatment.
CONCLUSIONS
The combination of DB with the checkpoint inhibitor nivolumab led to complete and a very good partial remission in two patients with relapsed/refractory NB. Prospective trials are warranted to clarify the role of this novel approach in a larger number of patients.
Topics: Adolescent; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Child, Preschool; Drug Resistance, Neoplasm; Female; Humans; Male; Neoplasm Recurrence, Local; Neuroblastoma; Nivolumab; Prognosis; Salvage Therapy
PubMed: 32414861
DOI: 10.1136/jitc-2020-000540 -
European Journal of Cancer (Oxford,... Apr 2022There is an alarming delay in Europe for anticancer medicines becoming accessible for children. Following a paediatric European Union marketing authorisation, national...
BACKGROUND AND AIMS
There is an alarming delay in Europe for anticancer medicines becoming accessible for children. Following a paediatric European Union marketing authorisation, national Health Technology Assessment (HTA) agencies evaluate effectiveness, and safety of medicines to support decision on their cost and reimbursement. This study (a SIOPE Access to Medicines project) aimed to evaluate how these HTA evaluations take place for anticancer medicines indicated for paediatric use in Europe and to explore where the delays for market access originate.
METHODS
We obtained HTA reports from the public domain for nine European countries for blinatumomab, dinutuximab beta and tisagenlecleucel. We evaluated the time elapsed between marketing authorisation for a paediatric indication and a national HTA decision and the nature of the decision.
RESULTS
Out of 23 HTA decisions (four countries without blinatumomab report), 18 were positive, two with restrictions, three negative. For blinatumomab, tisagenlecleucel and dinutuximab beta, the median time to an HTA decision after regulatory approval for paediatric use was 353 days (range 193-751), 141 days (range 77-517) and 515 days (range 0-780), respectively, with variability between countries. Dinutuximab beta and tisagenlecleucel were first introduced in children, but did not result in shorter time to HTA decision. For blinatumomab, marketing authorisation followed 1008 days after the indication in adults, with HTA applications submitted a median of 167 days later, and a recommendation after 145 days.
CONCLUSIONS
This study reveals ample variability in HTA decision making in nine European Union countries. Collaboration and alignment of required evidence is needed to facilitate robust scientific HTA assessments, also considering methodological challenges in paediatric oncology.
Topics: Adolescent; Antineoplastic Agents; Child; Europe; Humans; Medical Oncology; Neoplasms; Technology Assessment, Biomedical
PubMed: 35235871
DOI: 10.1016/j.ejca.2022.01.034