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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 -
Frontiers in Oncology 2023Prognosis in children with refractory and relapsed high-risk neuroblastoma is poor. Only a minority of patients obtain remission when treated with second-line...
Prognosis in children with refractory and relapsed high-risk neuroblastoma is poor. Only a minority of patients obtain remission when treated with second-line chemotherapy regimens. Chemotherapy combined with anti-GD2 antibodies has previously been shown to increase response and survival rates. We retrospectively analyzed a cohort of 25 patients with relapsed or refractory high-risk neuroblastoma who were treated with irinotecan/temozolomide chemotherapy in combination with the anti-GD2 antibody dinutuximab beta. The therapy resulted in an objective response rate of 64%, with 32% of patients achieving a complete response. Response to treatment was observed in patients with refractory disease (n=5) and those with first (n=12) or consecutive (n=8) relapses, including patients with progressing disease. In four patients, best response was achieved after more than 5 cycles, suggesting that some patients may benefit from prolonged chemotherapy and dinutuximab beta treatment. Fourteen of our 25 patients had previously received dinutuximab beta, four of whom achieved complete response and six partial response (objective response rate 71%). The therapy was well tolerated, even in heavily pre-treated patients and those who had previously received dinutuximab beta treatment. Toxicities were comparable to those previously reported for the individual therapies, and no discontinuations due to toxicities occurred. Combination of chemotherapy with dinutuximab beta is a promising treatment option for patients with relapsed or refractory high-risk neuroblastoma and should be further explored in clinical studies.
PubMed: 36816982
DOI: 10.3389/fonc.2023.1082771 -
Cancers Jan 2023Anti-disialoganglioside GD2 antibody ch14.18/CHO (dinutuximab beta, DB) improved the outcome of patients with high-risk neuroblastoma (HR-NB) in the maintenance phase....
Anti-disialoganglioside GD2 antibody ch14.18/CHO (dinutuximab beta, DB) improved the outcome of patients with high-risk neuroblastoma (HR-NB) in the maintenance phase. We investigated chemotherapeutic compounds used in newly diagnosed patients in combination with DB. Vincristine, etoposide, carboplatin, cisplatin, and cyclophosphamide, as well as DB, were used at concentrations achieved in pediatric clinical trials. The effects on stress ligand and checkpoint expression by neuroblastoma cells and on activation receptors of NK cells were determined by using flow cytometry. NK-cell activity was measured with a CD107a/IFN-γ assay. Long-term cytotoxicity was analyzed in three spheroid models derived from GD2-positive neuroblastoma cell lines (LAN-1, CHLA 20, and CHLA 136) expressing a fluorescent near-infrared protein. Chemotherapeutics combined with DB in the presence of immune cells improved cytotoxic efficacy up to 17-fold compared to in the controls, and the effect was GD2-specific. The activating stress and inhibitory checkpoint ligands on neuroblastoma cells were upregulated by the chemotherapeutics up to 9- and 5-fold, respectively, and activation receptors on NK cells were not affected. The CD107a/IFN-γ assay revealed no additional activation of NK cells by the chemotherapeutics. The synergistic effect of DB with chemotherapeutics seems primarily attributed to the combined toxicity of antibody-dependent cellular cytotoxicity and chemotherapy, which supports further clinical evaluation in frontline induction therapy.
PubMed: 36765861
DOI: 10.3390/cancers15030904 -
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 -
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 -
Cancers Dec 2022Neuroblastoma (NBL) and medulloblastoma (MB) are aggressive pediatric cancers which can benefit from therapies targeting gangliosides. Therefore, we compared the...
Neuroblastoma (NBL) and medulloblastoma (MB) are aggressive pediatric cancers which can benefit from therapies targeting gangliosides. Therefore, we compared the ganglioside profile of 9 MB and 14 NBL samples by thin layer chromatography and mass spectrometry. NBL had the highest expression of GD2 (median 0.54 nmol GD2/mg protein), and also expressed complex gangliosides. GD2-low samples expressed GD1a and were more differentiated. MB mainly expressed GD2 (median 0.032 nmol GD2/mg protein) or GM3. Four sonic hedgehog-activated (SHH) as well as one group 4 and one group 3 MBs were GD2-positive. Two group 3 MB samples were GD2-negative but GM3-positive. N-glycolyl neuraminic acid-containing GM3 was neither detected in NBL nor MB by mass spectrometry. Furthermore, a GD2-phenotype predicting two-gene signature ( and ) was applied to RNA-Seq datasets, including 86 MBs and validated by qRT-PCR. The signature values were decreased in group 3 and wingless-activated (WNT) compared to SHH and group 4 MBs. These results suggest that while NBL is GD2-positive, only some MB patients can benefit from a GD2-directed therapy. The expression of genes involved in the ganglioside synthesis may allow the identification of GD2-positive MBs. Finally, the ganglioside profile may reflect the differentiation status in NBL and could help to define MB subtypes.
PubMed: 36551537
DOI: 10.3390/cancers14246051 -
Targeted Oncology Jan 2023The anti-GD2 antibody dinutuximab beta (Qarziba) has been added to the present standard of care for patients with high-risk neuroblastoma in Europe based on the positive... (Review)
Review
The anti-GD2 antibody dinutuximab beta (Qarziba) has been added to the present standard of care for patients with high-risk neuroblastoma in Europe based on the positive results obtained in different studies. In both the first-line and relapsed/refractory settings, treatment with dinutuximab beta attains objective clinical responses in children with high-risk neuroblastoma. Its incorporation has changed the outcome for these patients and optimized management should be guaranteed to minimize possible adverse effects. Most prevalent adverse events include pain, allergic reactions, fever and capillary leak syndrome. There are still no evidence-based clinical guidelines that include the latest published evidence to optimize its use, as it depends on the experience gained in each referral center. Topics such as the mode of preparation and administration, the concomitant use of interleukin-2, the recommended pediatric age and dose for its use, or the adequate management of possible toxicities are important aspects to review. The objective of this article was to update the clinical guide to management with dinutuximab beta of children with neuroblastoma based on the most recent published evidence and our own experience in clinical practice.
Topics: Child; Humans; Neuroblastoma; Antibodies, Monoclonal; Europe
PubMed: 36504394
DOI: 10.1007/s11523-022-00930-w -
Cancers Nov 2022(1) Background: High-risk neuroblastoma (HR-NB) is associated with a poor prognosis despite a multimodal high-intensity treatment regimen, including immunotherapy with...
(1) Background: High-risk neuroblastoma (HR-NB) is associated with a poor prognosis despite a multimodal high-intensity treatment regimen, including immunotherapy with anti-GD2 monoclonal antibodies (mAb). Here, we investigated the effects of an anti-idiotypic vaccine based on the mAb ganglidiomab that structurally mimics GD2. (2) Methods: Patients with HR-NB treated with anti-GD2 mAb dinutuximab beta and who achieved complete remission after frontline or salvage therapy were offered the vaccine (0.5 mg ganglidiomab adsorbed to Alhydrogel). Side effects (CTCAE v4.03) and immune responses were determined on each visit. We also evaluated the time to relapse or progression until the last follow-up. (3) Results: Seven HR-NB patients (five frontlines, two relapsed) received 6-22 subcutaneous injections every two weeks. Six of the seven patients showed an immune response. The non-responding patient had a haploidentical stem cell transplantation as part of the previous treatment. No fever, pain, neuropathy, or toxicities ≥ grade 3 occurred during or post-treatment. All immunized patients did not experience relapses or progressions of their neuroblastoma. (4) Conclusions: This is the first-in-man use of the ganglidiomab vaccine, which was well-tolerated, and all patients not pre-treated by haploidentical transplantation developed vaccine-specific immune responses. These findings provide an important basis for the design of prospective clinical trials.
PubMed: 36497290
DOI: 10.3390/cancers14235802 -
Paediatric Drugs Jan 2023The addition of anti-disialoganglioside-2 (GD2) monoclonal antibodies (mAbs) such as dinutuximab and naxitamab to standard therapies for high-risk (HR) neuroblastoma has...
The addition of anti-disialoganglioside-2 (GD2) monoclonal antibodies (mAbs) such as dinutuximab and naxitamab to standard therapies for high-risk (HR) neuroblastoma has significantly improved outcomes for children with this devastating disease. The care for these young patients receiving treatment for HR neuroblastoma is complex, with need for the involvement of a multidisciplinary team. Clinical implementation of anti-GD2 mAb treatment requires the same harmonized team approach. The authors share the development process of this coordinated team method and practical recommendations for administration of anti-GD2 mAbs and adverse event (AE) management. Successful collaboration between nurses and other team members ensures optimal treatment and comfort of patients and their families. The primary focus of this approach is to mitigate and manage AEs associated with anti-GD2 mAb treatments, such as pain, hypotension, allergic reactions, and hypertension, and to ensure safe and effective use of anti-GD2 mAbs. The two treatments approved for use in patients with neuroblastoma, dinutuximab for patients with HR disease following a partial response or better to frontline multimodal therapy and naxitamab for refractory or relapsed HR disease in the bone or bone marrow, were studied in different administration settings and follow different regimens and infusion schedules. Therefore, AE management requirements are specific to each treatment. The awareness of these differences and implementation of appropriate AE management strategies in clinical practice are important to ensure the best possible outcomes for patients with HR neuroblastoma.
Topics: Child; Humans; Neuroblastoma; Antineoplastic Agents; Immunotherapy; Combined Modality Therapy
PubMed: 36434427
DOI: 10.1007/s40272-022-00544-9 -
Cancers Oct 2022Treatment of high-risk neuroblastoma (NB) patients with the anti-GD antibody (Ab) dinutuximab beta (DB) improves survival by 15%. Ab-dependent cellular cytotoxicity...
Treatment of high-risk neuroblastoma (NB) patients with the anti-GD antibody (Ab) dinutuximab beta (DB) improves survival by 15%. Ab-dependent cellular cytotoxicity (ADCC) is the major mechanism of action and is primarily mediated by NK cells. Since IL-2 co-treatment did not show a therapeutic benefit but strongly induced Treg, we investigated here a DB-based immunotherapy combined with the immunocytokine FAP-IL-2v, which comprises a fibroblast activation protein α (FAP)-specific Ab linked to a mutated IL-2 variant (IL-2v) with abolished binding to the high-affinity IL-2 receptor, thus stimulating NK cells without induction of Treg. Effects of FAP-IL-2v on NK cells, Treg and ADCC mediated by DB, as well as FAP expression in NB, were investigated by flow cytometry, calcein-AM-based cytotoxicity assay and RT-PCR analysis. Moreover, the impact of soluble factors released from tumor cells on FAP expression by primary fibroblasts was assessed. Finally, a combined immunotherapy with DB and FAP-IL-2v was evaluated using a resistant syngeneic murine NB model. Incubation of leukocytes with FAP-IL-2v enhanced DB-specific ADCC without induction of Treg. FAP expression on NB cells and myeloid-derived suppressor cells (MDCS) in tumor tissue was identified. A tumor-cell-dependent enhancement in FAP expression by primary fibroblasts was demonstrated. Combination with DB and FAP-IL-2v resulted in reduced tumor growth and improved survival. Analysis of tumor tissue revealed increased NK and cytotoxic T cell numbers and reduced Treg compared to controls. Our data show that FAP-IL-2v is a potent immunocytokine that augments the efficacy of DB against NB, providing a promising alternative to IL-2.
PubMed: 36230765
DOI: 10.3390/cancers14194842