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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 -
Cancers Apr 2022Neurotoxicity is an off-tumour, on-target side effect of GD2-directed immunotherapy with monoclonal antibodies. Here, we report the frequency, management and outcome of...
Neurotoxicity is an off-tumour, on-target side effect of GD2-directed immunotherapy with monoclonal antibodies. Here, we report the frequency, management and outcome of patients enrolled in two prospective clinical trials who experienced severe neurotoxicity during immunotherapy with the anti-GD2 antibody dinutuximab beta (DB) administered as short-term infusion (HR-NBL1/SIOPEN study, randomisation R2, EudraCT 2006-001489-17) or as long-term infusion (HR-NBL1/SIOPEN study, randomisation R4, EudraCT 2006-001489-17 and LTI/SIOPEN study, EudraCT 2009-018077-31), either alone or with subcutaneous interleukin-2 (scIL-2). The total number of patients included in this analysis was 1102. Overall, 44/1102 patients (4.0%) experienced Grade 3/4 neurotoxicities (HR-NBL1 R2, 21/406; HR-NBL1 R4, 8/408; LTI study, 15/288), including 27 patients with severe neurotoxicities (2.5%). Events occurred predominantly in patients receiving combined treatment with DB and scIL-2. Neurotoxicity was treated using dexamethasone, prednisolone, intravenous immunoglobulins and, in two patients, plasmapheresis, which was highly effective. While neurological recovery was observed in 16 of 21 patients with severe neurotoxicities, 5/1102 (0.45%) patients experienced persistent and severe neurological deficits. In conclusion, severe neurotoxicity is most commonly observed in patients receiving DB with scIL-2. Considering the lack of clinical benefit for IL-2 in clinical trials so far, the administration of IL-2 alongside DB is not recommended.
PubMed: 35454826
DOI: 10.3390/cancers14081919 -
Pediatric Blood & Cancer Sep 2022Dinutuximab, an immune-mediated therapy indicated for high-risk neuroblastoma, targets the protein disialoganglioside (GD2) on neuroblastoma cells, neurons, and... (Observational Study)
Observational Study
BACKGROUND
Dinutuximab, an immune-mediated therapy indicated for high-risk neuroblastoma, targets the protein disialoganglioside (GD2) on neuroblastoma cells, neurons, and peripheral nerve fibers. Off-target effects lead to severe nerve pain. Pain regimens including continuous infusion opioids are required during treatment courses. Our institution utilizes a combination of intravenous (i.v.) lidocaine infusions and morphine for the treatment of dinutuximab-associated neuropathic pain.
OBJECTIVE
The primary outcome of this study was to compare morphine equivalents for cycle 1 of dinutuximab at an institution that uses i.v. lidocaine (primary) versus those that do not (comparison). Secondary outcomes included both dinutuximab infusion time and safety of i.v. lidocaine.
METHODS
A retrospective, multicentered, electronic chart review was performed at three tertiary academic medical centers. Patients between 0 and 18 years of age during their first course of dinutuximab were included to evaluate the primary outcome of adjuvant morphine equivalents needed.
RESULTS
Twenty-one patients were identified for inclusion. Total morphine equivalents at the primary institution were 1.87 mg/kg versus 1.79 mg/kg at the comparison institutions (P = 0.413). Dinutuximab infusion time was statistically significantly less at the primary institution: 610.5 minutes versus 676.23 minutes (P = 0.046). Only one patient at the primary institution experienced nausea, vomiting, and paresthesias.
CONCLUSIONS
This study did not find a statistically significant difference in morphine equivalents between patients receiving i.v. lidocaine and those who did not. Lidocaine use resulted in a statistically significant lower dinutuximab infusion time. Our data suggest it is a safe adjuvant medication, for use outside of the pediatric intensive care unit, in the treatment of dinutuximab-associated neuropathic pain.
Topics: Antibodies, Monoclonal; Child; Humans; Lidocaine; Morphine Derivatives; Neuralgia; Neuroblastoma; Retrospective Studies
PubMed: 35441791
DOI: 10.1002/pbc.29653 -
Oncoimmunology 2022γδ T lymphocytes represent an emerging class of cellular immunotherapy with preclinical promise to treat cancer, notably neuroblastoma. The innate-like immune cell...
γδ T lymphocytes represent an emerging class of cellular immunotherapy with preclinical promise to treat cancer, notably neuroblastoma. The innate-like immune cell subset demonstrates inherent cytoxicity toward tumor cells independent of MHC recognition, enabling allogeneic administration of healthy donor-derived γδ T cell therapies. A current limitation is the substantial interindividual γδ T cell expansion variation among leukocyte collections. Overcoming this limitation will enable realization of the full potential of allogeneic γδ T-based cellular therapy. Here, we characterize γδ T cell expansions from healthy adult donors and observe that highly potent natural killer (NK) lymphocytes expand with γδ T cells under zoledronate and IL-2 stimulation. The presence of NK cells correlates with both the expansion potential of γδ T cells and the overall potency of the γδ T cell therapy. However, the potency of the cell therapy in combination with an antibody-based immunotherapeutic, dinutuximab, appears to be independent of γδ T/NK cell content both and , which minimizes the implication of interindividual expansion differences toward efficacy. Collectively, these studies highlight the utility of maintaining the NK cell population within expanded γδ T cell therapies and suggest a synergistic action of combined innate cell immunotherapy toward neuroblastoma.
Topics: Cell Proliferation; Cell- and Tissue-Based Therapy; Humans; Immunotherapy; Neuroblastoma; Receptors, Antigen, T-Cell, gamma-delta
PubMed: 35371623
DOI: 10.1080/2162402X.2022.2057012 -
Cancer Reports (Hoboken, N.J.) Nov 2022Survival for patients with high-risk neuroblastoma (HRNB) remains poor despite aggressive multimodal therapies.
BACKGROUND
Survival for patients with high-risk neuroblastoma (HRNB) remains poor despite aggressive multimodal therapies.
AIMS
To study the feasibility and safety of incorporating a genomic-based targeted agent to induction therapy for HRNB as well as the feasibility and safety of adding difluoromethylornithine (DFMO) to anti-GD2 immunotherapy.
METHODS
Twenty newly diagnosed HRNB patients were treated on this multicenter pilot trial. Molecular tumor boards selected one of six targeted agents based on tumor-normal whole exome sequencing and tumor RNA-sequencing results. Treatment followed standard upfront HRNB chemotherapy with the addition of the selected targeted agent to cycles 3-6 of induction. Following consolidation, DFMO (750 mg/m twice daily) was added to maintenance with dinutuximab and isotretinoin, followed by continuation of DFMO alone for 2 years. DNA methylation analysis was performed retrospectively and compared to RNA expression.
RESULTS
Of the 20 subjects enrolled, 19 started targeted therapy during cycle 3 and 1 started during cycle 5. Eighty-five percent of subjects met feasibility criteria (receiving 75% of targeted agent doses). Addition of targeted agents did not result in toxicities requiring dose reduction of chemotherapy or permanent discontinuation of targeted agent. Following standard consolidation, 15 subjects continued onto immunotherapy with DFMO. This combination was well-tolerated and resulted in no unexpected adverse events related to DFMO.
CONCLUSION
This study demonstrates the safety and feasibility of adding targeted agents to standard induction therapy and adding DFMO to immunotherapy for HRNB. This treatment regimen has been expanded to a Phase II trial to evaluate efficacy.
Topics: Humans; Eflornithine; Pilot Projects; Induction Chemotherapy; Retrospective Studies; Neuroblastoma; Immunotherapy; Antineoplastic Agents; Immunologic Factors; Genomics; RNA
PubMed: 35355452
DOI: 10.1002/cnr2.1616 -
Biomolecules Feb 2022Neuroblastoma is one of the few childhood cancers that carries a tumor-specific antigen in the form of a glycolipid antigen known as GD2. It has restricted expression in... (Review)
Review
Neuroblastoma is one of the few childhood cancers that carries a tumor-specific antigen in the form of a glycolipid antigen known as GD2. It has restricted expression in normal tissue, such as peripheral afferent nerves. Monoclonal antibodies targeting GD2 have been applied clinically to high-risk neuroblastoma with significant success. However, there are different anti-GD2 products and administration regimens. For example, anti-GD2 has been used in combination with chemotherapy during the induction phase or with retinoic acid during the maintenance stage. Regimens also vary in the choice of whether to add cytokines (i.e., IL-2, GMCSF, or both). Furthermore, the addition of an immune enhancer, such as β-glucan, or allogeneic natural killer cells also becomes a confounder in the interpretation. The question concerning which product or method of administration is superior remains to be determined. So far, most studies agree that adding anti-GD2 to the conventional treatment protocol can achieve better short- to intermediate-term event-free and overall survival, but the long-term efficacy remains to be verified. How to improve its efficacy is another challenge. Late relapse and central nervous system metastasis have emerged as new problems. The methods to overcome the mechanisms related to immune evasion or resistance to immunotherapy represent new challenges to be resolved. The newer anti-GD2 strategies, such as bispecific antibody linking of anti-GD2 with activated T cells or chimeric antigen receptor T cells, are currently under clinical trials, and they may become promising alternatives. The use of anti-GD2/GD3 tumor vaccine is a novel and potential approach to minimizing late relapse. How to induce GD2 expression from tumor cells using the epigenetic approach is a hot topic nowadays. We expect that anti-GD2 treatment can serve as a model for the use of monoclonal antibody immunotherapy against cancers in the future.
Topics: Antibodies, Monoclonal; Child; Humans; Immunologic Factors; Immunotherapy; Neuroblastoma; Recurrence
PubMed: 35327550
DOI: 10.3390/biom12030358 -
Lung Cancer (Amsterdam, Netherlands) Apr 2022Topotecan is approved as second-line treatment for small cell lung cancer (SCLC). Irinotecan is also frequently used given its more convenient schedule and superior... (Randomized Controlled Trial)
Randomized Controlled Trial
Randomized phase 3 study of the anti-disialoganglioside antibody dinutuximab and irinotecan vs irinotecan or topotecan for second-line treatment of small cell lung cancer.
INTRODUCTION
Topotecan is approved as second-line treatment for small cell lung cancer (SCLC). Irinotecan is also frequently used given its more convenient schedule and superior tolerability. Preclinical studies support disialoganglioside (GD2) as an SCLC target and the combination of dinutuximab, an anti-GD2 antibody, plus irinotecan in this setting. We tested dinutuximab/irinotecan versus irinotecan or topotecan as second-line therapy in relapsed/refractory (RR) SCLC.
MATERIALS AND METHODS
Patients with RR SCLC and Eastern Cooperative Oncology Group performance status 0-1 were randomized 2:2:1 to receive dinutuximab 16-17.5 mg/m intravenous (IV)/irinotecan 350 mg/m IV (day 1), irinotecan 350 mg/m IV (day 1), or topotecan 1.5 mg/m IV (days 1-5) in 21-day cycles. The primary endpoint was overall survival (OS); secondary endpoints were progression-free survival (PFS), objective response rate (ORR; complete response [CR] + partial response [PR]), and clinical benefit rate (CBR; CR + PR + stable disease). Safety/tolerability were also assessed.
RESULTS
A total of 471 patients were randomized to dinutuximab/irinotecan (n = 187), irinotecan (n = 190), or topotecan (n = 94). Age, sex, performance status, prior therapies, and metastatic disease sites were similar between groups. Survival and response rates were not improved for patients receiving dinutuximab/irinotecan versus those receiving irinotecan or topotecan (median OS 6.9 vs 7.0 vs 7.4 months [p = 0.3132]; median PFS 3.5 vs 3.0 vs 3.4 months [p = 0.3482]; ORR confirmed 17.1% vs 18.9% vs 20.2% [p = 0.8043]; and CBR 67.4% vs 58.9% vs 68.1% [p = 0.0989]), respectively. Grade 3/4 adverse events (≥5% receiving dinutuximab/irinotecan) included neutropenia, anemia, diarrhea, and asthenia.
CONCLUSIONS
Dinutuximab/irinotecan treatment did not result in improved OS in RR SCLC versus irinotecan alone. Irinotecan administered every 21 days demonstrated comparable activity to topotecan administered daily × 5 every 21 days.
CLINICALTRIALS
gov Identifier. NCT03098030.
Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Humans; Irinotecan; Lung Neoplasms; Neoplasm Recurrence, Local; Small Cell Lung Carcinoma; Topotecan
PubMed: 35278766
DOI: 10.1016/j.lungcan.2022.03.003 -
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 -
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 -
Pediatric Blood & Cancer Apr 2022
Topics: Antibodies, Monoclonal; Humans; Neuroblastoma; Plasmapheresis
PubMed: 34913569
DOI: 10.1002/pbc.29465