Dinutuximab Research Articles

Transition to a mesenchymal state in neuroblastoma may be characterized by a high expression of GD2 and by the acquisition of immune escape from NK cells.

Neuroblastoma (NB) is characterized by both adrenergic (ADRN) and undifferentiated mesenchymal (MES) subsets. The ganglioside sialic acid-containing glycosphingolipid (GD2) is widely overexpressed on tumors of neuroectodermal origin promoting malignant phenotypes. MES cells are greatly enriched in post-therapy and relapsing tumors and are characterized by decreased expression of GD2. This event may cause failure of GD2-based immunotherapy. NK cells represent a key innate cell subset able to efficiently kill tumors. However, the tumor microenvironment (TME) that includes tumor cells and tumor-associated (TA) cells could inhibit their effector function. We studied eight NB primary cultures that, in comparison with commercial cell lines, more faithfully reflect the tumor cell characteristics. We studied four primary NB-MES cell cultures and two pairs of MES/ADRN (691 and 717) primary cultures, derived from the same patient. In particular, in the six human NB primary cultures, we assessed their phenotype, the expression of GD2, and the enzymes that control its expression, as well as their interactions with NK cells, using flow cytometry, RT-qPCR, and cytotoxicity assays. We identified mature (CD105+/CD133-) and undifferentiated (CD133+/CD105-) NB subsets that express high levels of the MES transcripts WWTR1 and SIX4. In addition, undifferentiated MES cells display a strong resistance to NK-mediated killing. On the contrary, mature NB-MES cells display an intermediate resistance to NK-mediated killing and exhibit some immunomodulatory capacities on NK cells but do not inhibit their cytolytic activity. Notably, independent from their undifferentiated or mature phenotype, NB-MES cells express GD2 that can be further upregulated in undifferentiated NB-MES cells upon co-culture with NK cells, leading to the generation of mature mesenchymal GD2bright neuroblasts. Concerning 691 and 717, they show high levels of GD2 and resistance to NK cell-mediated killing that can be overcome by the administration of dinutuximab beta, the anti-GD2 monoclonal antibody applied in the clinic. NB is a heterogeneous tumor representing a further hurdle in NB immunotherapy. However, different from what was reported with NB commercial cells and independent of their MES/ADRN phenotype, the expression of GD2 and its displayed sensitivity to anti-GD2 mAb ADCC indicated the possible effectiveness of anti-GD2 immunotherapy.

Tolerability and toxicity of induction chemoimmunotherapy with dinutuximab beta in newly diagnosed patients with high-risk neuroblastoma

Tolerability and toxicity of induction chemoimmunotherapy with dinutuximab beta in newly diagnosed patients with high-risk neuroblastoma

Chemo-immunotherapy with dinutuximab beta in patients with relapsed/progressive high-risk neuroblastoma: does chemotherapy backbone matter?

BackgroundAddition of anti-GD2 antibodies to temozolomide-based chemotherapy has demonstrated increased antitumor activity and progression-free survival in patients with relapsed/progressive high-risk neuroblastoma. However, chemo-immunotherapy is not yet approved for this indication. This study presents the chemo-immunotherapy experience in patients with relapsed/progressive high-risk neuroblastoma treated within the off-label use program of the Neuroblastoma Committee of the French Society of Pediatric Oncology (SFCE). MethodsDinutuximab beta (dB) was administered alongside temozolomide-topotecan (TOTEM) or temozolomide-irinotecan (TEMIRI) at first disease relapse/progression or topotecan-cyclophosphamide (TopoCyclo) at further relapse/progression. Real-world data on demographics, treatment, antitumor activity and safety was collected from all patients after inclusion in SACHA-France (NCT04477681), a prospective national registry, which documents safety and efficacy data on innovative anticancer therapies prescribed to patients ≤ 25 years old as compassionate or off-label use. ResultsBetween February 2021 and July 2023, 39 patients with confirmed relapsed/progressive high-risk neuroblastoma (median age 6 years, range 1–24) were treated with dB+TopoCyclo (n = 24) or dB+TOTEM/TEMIRI (n = 15) across 17 centers. In total, 163 chemo-immunotherapy cycles were administered, main toxicities were mild or moderate, with higher incidence of hematological adverse drug reactions with dB+TopoCyclo than dB+TOTEM/TEMIRI. Objective response rate was 42% for dB+TopoCyclo (CI95% 22–63%) and 40% for dB+TOTEM/TEMIRI (CI95% 16–68%). ConclusionSimilar objective response rates for dB+TopoCyclo and dB+TOTEM/TEMIRI in patients with relapsed/progressive high-risk neuroblastoma emphasize the importance of chemo-immunotherapy, irrespective of the chemotherapy backbone.

Yoga as a non-pharmacologic therapy to reduce dinutuximab-induced pain in patients with neuroblastoma.

Anti-GD2 antibodies are key components of treatment for high-risk neuroblastoma; however, they cause neuropathic pain. Yoga therapy may help reduce pain and distress associated with anti-GD2 therapy. Children 3years of age or older with neuroblastoma participated in individualized yoga therapy while receiving the anti-GD2 antibody dinutuximab (DIN). Yoga therapy was deemed feasible if patients participated during 60% or more of DIN admissions. Patients and caregivers assessed pain/distress before and after yoga therapy with a distress thermometer (DT) and Wong-Baker FACES pain rating scale and completed questionnaires regarding satisfaction with yoga therapy. Therapy was deemed efficacious if there was a ≥1 point pain score change and reduction in distress after yoga. Eighteen patients were enrolled; 52 encounters (admissions for DIN) were evaluable. Ten of 18 were female, three of 18 were Hispanic, and 10/18 were White. Median age at enrollment was 5.5years (range: 3-11). Yoga therapy was feasible in 39/52 (75%) encounters. Significant reductions in caregiver-reported pain and distress and reductions in patient-reported pain and distress after yoga therapy were reported. Twelve of 18 caregivers completed questionnaires: seven agreed/strongly agreed that yoga was valuable, and nine agreed/strongly agreed to continued participation in yoga. Thirty-four of 36 clinicians reported that they would recommend yoga therapy for other patients receiving DIN. Yoga therapy was feasible during DIN therapy and may be effective in reducing DIN-associated pain and distress. Future studies are needed to evaluate changes in opioid usage with the addition of yoga therapy during anti-GD2 antibody therapy.

Targeted therapies in retinoblastoma: GD2-directed immunotherapy following autologous stem cell transplantation and evaluation of alternative target B7-H3

BackgroundGD2-directed immunotherapy is highly effective in the treatment of high-risk neuroblastoma (NB), and might be an interesting target also in other high-risk tumors.MethodsThe German-Austrian Retinoblastoma Registry, Essen, was searched for patients, who were treated with anti-GD2 monoclonal antibody (mAb) dinutuximab beta (Db) in order to evaluate toxicity, response and outcome in these patients. Additionally, we evaluated anti-GD2 antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) in retinoblastoma cell lines in vitro. Furthermore, in vitro cytotoxicity assays directed against B7-H3 (CD276), a new identified potential target in RB, were performed.ResultsWe identified four patients with relapsed stage IV retinoblastoma, who were treated with Db following autologous stem cell transplantation (ASCT). Two out of two evaluable patients with detectable tumors responded to immunotherapy. One of these and another patient who received immunotherapy without residual disease relapsed 10 and 12 months after start of Db. The other patients remained in remission until last follow-up 26 and 45 months, respectively. In vitro, significant lysis of RB cell lines by ADCC and CDC with samples from patients and healthy donors and anti-GD2 and anti-CD276-mAbs were demonstrated.ConclusionAnti-GD2-directed immunotherapy represents an additional therapeutic option in high-risk metastasized RB. Moreover, CD276 is another target of interest.

GM-CSF, G-CSF or no cytokine therapy with anti-GD2 immunotherapy for high-risk neuroblastoma.

Colony-stimulating factors have been shown to improve anti-disialoganglioside 2 (anti-GD2) monoclonal antibody response in high-risk neuroblastoma by enhancing antibody-dependent cell-mediated cytotoxicity (ADCC). A substantial amount of research has focused on recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) as an adjuvant to anti-GD2 monoclonal antibodies. There may be a disparity in care among patients as access to GM-CSF therapy and anti-GD2 monoclonal antibodies is not uniform. Only select countries have approved these agents for use, and even with regulatory approvals, access to these agents can be complex and cost prohibitive. This comprehensive review summarizes clinical data regarding efficacy and safety of GM-CSF, recombinant human granulocyte colony-stimulating factor (G-CSF) or no cytokine in combination with anti-GD2 monoclonal antibodies (ie, dinutuximab, dinutuximab beta or naxitamab) for immunotherapy of patients with high-risk neuroblastoma. A substantial body of clinical data support the immunotherapy combination of anti-GD2 monoclonal antibodies and GM-CSF. In contrast, clinical data supporting the use of G-CSF are limited. No formal comparison between GM-CSF, G-CSF and no cytokine has been identified. The treatment of high-risk neuroblastoma with anti-GD2 therapy plus GM-CSF is well established. Suboptimal efficacy outcomes with G-CSF raise concerns about its suitability as an alternative to GM-CSF as an adjuvant in immunotherapy for patients with high-risk neuroblastoma. While programs exist to facilitate obtaining GM-CSF and anti-GD2 monoclonal antibodies in regions where they are not commercially available, continued work is needed to ensure equitable therapeutic options are available globally.

Long-term, continuous infusion of single-agent dinutuximab beta for relapsed/refractory neuroblastoma: an open-label, single-arm, Phase 2 study

BackgroundShort-term infusions of dinutuximab beta plus isotretinoin and cytokines administered in previous immunotherapy studies in neuroblastoma were associated with severe pain. Here, long-term, continuous infusion of single-agent dinutuximab beta was evaluated in patients with relapsed/refractory neuroblastoma.MethodsIn this open-label, single-arm, Phase 2 study, patients with either refractory or relapsed high-risk neuroblastoma received dinutuximab beta by continuous infusion over 10 days of each cycle, for up to five cycles. The primary endpoint was objective response rate 24 weeks after the end of cycle 5. Secondary endpoints included adverse events, intravenous morphine use, best response, duration of response, and three-year progression-free and overall survival.ResultsOf the 40 patients included, 38 had evaluable response. Objective response rate was 26% and best response rate 37%. Median duration of response was 238 days (IQR 108–290). Three-year progression-free and overall survival rates were 31% (95% CI 17–47) and 66% (95% CI 47–79), respectively. Prophylactic intravenous morphine use and duration of use decreased with increasing cycles. The most common grade 3 treatment-related adverse events were pain, diarrhea, and hypokalemia.ConclusionLong-term continuous infusion of single-agent dinutuximab beta is tolerable and associated with clinically meaningful responses in patients with relapsed/refractory high-risk neuroblastoma.Clinical trial registrationThe study is registered with ClinicalTrials.gov (NCT02743429) and EudraCT (2014-000588-42).

Exploring dual effects of dinutuximab beta on cell death and proliferation of insulinoma.

Insulinoma INS-1 cells are pancreatic beta cell tumors. Dinutuximab beta (DB) is a monoclonal antibody used in the treatment of neuroblastoma. The aim of this study is to investigate the effects of DB on pancreatic beta cell tumors at the molecular level. DB (Qarziba®) was available from EUSA Pharma. Streptozotocin (STZ) was used induce to cell cytotoxicity. DB was applied to the cells before or after the STZ application. KCND3, KCNN4, KCNK1, and PTHrP gene expression levels were analyzed by q-RT-PCR, and protein levels were analyzed by Western blotting. Analysis of glucose-stimulated insulin secretion was performed. Ca+2 and CA19-9 levels were determined by the ELISA kit. PERK, CHOP, HSP90, p-c-Jun, p-Atf2, and p-Elk1 protein levels were analyzed by simple WES. Decreased KCND3, KCNK1, and PTHrP protein levels and increased KCND3, KCNN4, KCNK1, and PTHrP gene expression levels were observed with DB applied after STZ application. Cell dysfunction was detected with DB applied before and after STZ application. Ca19-9 and Ca+2 levels were increased with DB applied after STZ application. PERK, CHOP, and p-Elk1 levels decreased, while HSP90 levels increased with DB applied after STZ application. CHOP, p-Akt-2, and p-c-Jun levels increased in the DB group. As a result, INS-1 cells go to cell death via the ERK signaling pathway without ER stress and release insulin with the decrease of K+ channels and an increase in Ca+2 levels with DB applied after STZ application. Moreover, the cells proliferate via JNK signaling with DB application. DB holds promise for the treatment of insulinoma. The study should be supported by in vivo studies.

Multimodal Therapy with Consolidating Haploidentical Stem Cell Transplantation and Dinutuximab Beta for Patients with High-Risk Neuroblastoma and Central Nervous System Relapse.

Despite highly intensive multimodality treatment regimens, the prognosis of patients with high-risk neuroblastoma (HRNB) and central nervous system (CNS) relapse remains poor. We retrospectively reviewed data from 13 patients with HRNB and CNS relapse who received multimodal therapy with consolidating haploidentical stem cell transplantation (haplo-SCT) followed by dinutuximab beta ± subcutaneous interleukin-2 (scIL-2). Following individual relapse treatment, patients aged 1-21 years underwent haplo-SCT with T/B-cell-depleted grafts followed by dinutuximab beta 20 mg/m2/day × 5 days for 5-6 cycles. If a response was demonstrated after cycle 5 or 6, patients received up to nine treatment cycles. After haplo-SCT, eight patients had a complete response, four had a partial response, and one had a stable disease. All 13 patients received ≥3 cycles of immunotherapy. At the end of the follow-up, 9/13 patients (66.7%) demonstrated complete response. As of July 2023, all nine patients remain disease-free, with a median follow-up time of 5.1 years since relapse. Estimated 5-year event-free and overall survival rates were 55.5% and 65.27%, respectively. Dinutuximab beta ± scIL-2 following haplo-SCT is a promising treatment option with a generally well-tolerated safety profile for patients with HRNB and CNS relapse.

Treatment of High-Risk Neuroblastoma with Dinutuximab and Chemotherapy Administered in all Cycles of Induction.

Administration of chemoimmunotherapy using concurrent chemotherapy and an anti-GD2 monoclonal antibody (mAb), dinutuximab (DIN), demonstrated efficacy for the treatment of relapsed and refractory neuroblastoma. Chemoimmunotherapy, using a humanized anti-GD2 mAb, demonstrated a signal of activity in a phase 2 study for the treatment of patients with newly diagnosed high-risk neuroblastoma (HRNBL). In this single-institution retrospective study, patients with HRNBL received an Induction chemotherapy regimen plus DIN in all Induction cycles. Toxicity and response data were abstracted from the electronic medical record. Toxicities were graded by CTCAE v.5.0. The end of Induction (EOI) objective response rate was determined using the Revised International Neuroblastoma Response Criteria. Twenty-seven patients with HRNBL (23 newly diagnosed, 16 females, median age 3.9 years) started Induction chemoimmunotherapy from 27 January 2017 to 28 December 2022. All patients received DIN with all cycles of Induction therapy, and all but one patient completed Induction therapy. The most common non-hematologic grade ≥ 3 toxicities included fever (44%), hypoxemia (20%), and hypoalbuminemia (11%). End of Induction responses included eighteen with a complete response (CR), seven with a partial response (PR), one with progressive disease (PD), and zero with a minor response or stable disease. Twenty-six of twenty-seven patients (96%) completed all Induction cycles and were evaluable for a response. The EOI response of PR or better in the evaluable cohort was 96%. Dinutuximab was well tolerated with all Induction cycles, demonstrated an encouraging EOI response rate, and should be evaluated in a randomized study.

Dinutuximab Beta Maintenance Therapy in Patients with High-Risk Neuroblastoma in First-Line and Refractory/Relapsed Settings-Real-World Data.

Dinutuximab beta is approved for the maintenance treatment of patients with high-risk neuroblastoma (HR-NB), including patients with relapsed/refractory (R/R) disease. However, the data on its use in real-world clinical practice is limited. We retrospectively reviewed the clinical records of 54 patients with HR-NB who received maintenance therapy with dinutuximab beta in first-line (37 patients) or R/R settings (17 patients) at three centers in Poland. Of the 37 patients who received first-line treatment, twenty-eight had a complete response, two had a partial response, three had progressive disease, and four relapsed at the end of treatment. The median overall survival (OS) was 24.37 months, and the three-year progression-free survival (PFS) and OS were 0.63 and 0.80, respectively. Of the 17 patients in the R/R group, 11 had a complete response, two had a partial response, one had stable disease, and three had progressive disease or relapsed at the end of treatment. The median OS was 33.1 months and the three-year PFS and OS were 0.75 and 0.86, respectively. Treatment was generally well tolerated, including in patients with co-morbidities and those who had experienced toxicities with previous therapies. These findings demonstrate that the use of dinutuximab beta is feasible and beneficial as a first-line or R/R treatment in routine clinical practice in Poland.

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

BackgroundThe 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.ResultsEleven 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.ConclusionsUsing 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.

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.

Combined Blockade of TIGIT and PD-L1 Enhances Anti-Neuroblastoma Efficacy of GD2-Directed Immunotherapy with Dinutuximab Beta.

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.

ОПЫТ ПРИМЕНЕНИЯ ИММУНОТЕРАПИИ АНТИ-GD2 МОНОКЛОНАЛЬНЫМИ АНТИТЕЛАМИ У ПАЦИЕНТОВ С НЕЙРОБЛАСТОМОЙ ГРУППЫ ВЫСОКОГО РИСКА В АМБУЛАТОРНЫХ УСЛОВИЯХ

Neuroblastoma (NB) is the most common extracranial solid tumor in childhood. Prior to the introduction of intensive multimodal therapy, overall survival (OS) in patients with high-risk NB was below 15%. The addition of immunotherapy with dinutuximab beta in post-consolidation to multimodal treatment can increase the 5-year event-free survival rate for patients with high-risk NB up to 56.6%, and the 5-year OS up to 73.2%. The purpose of the research was to study the efficacy and safety of dinutuximab beta therapy in high-risk NB patients. Materials and methods used: the study included 8 pediatric patients with high-risk NB who had been treated with dinutuximab beta immunotherapy during postconsolidation on the basis of the Morozov Children’s City Clinical Hospital (Moscow, Russia) in 2020 to 2022. In case a patient's vital parameters normalization coupled with the absence of the need for accompanying therapy for 24 hours in a hospital, the patient was then considered as a candidate for outpatient treatment with possible no need for admission in the hospital. Results: 6 patients (75%) completed the full course of therapy with dinutuximab beta. The course of immunotherapy was not completed in 2 patients due to further progression of the disease. The most common adverse events were recorded as follows: pain (100%), fever (100%), diarrhea (62.5%), edematous syndrome (37.5%), allergic reactions (25%), hematological toxicity (25%). The period of time to becoming the candidates for outpatient treatment was 10.38±2.56 days for the 1st cycle of therapy and 2.67±1.63 days for the last, 5th cycle of the immunotherapy. In 6 out of 8 cases described the immunotherapy with dinutuximab beta allowed maintaining the response to treatment achieved after the end of consolidation preventing further development of the disease. The overall good tolerance to the drug made it possible to carry out the immunotherapy on an outpatient basis using microinfusing pump. Conclusion: an adequate route of administration and accompanying treatment make dinutuximab beta toxicity profile sufficient for outpatient management of patients with high-risk NB.

ОПЫТ ПРИМЕНЕНИЯ ИММУНОТЕРАПИИ АНТИ-GD2 МОНОКЛОНАЛЬНЫМИ АНТИТЕЛАМИ У ПАЦИЕНТОВ С НЕЙРОБЛАСТОМОЙ ГРУППЫ ВЫСОКОГО РИСКА В АМБУЛАТОРНЫХ УСЛОВИЯХ

Neuroblastoma (NB) is the most common extracranial solid tumor in childhood. Prior to the introduction of intensive multimodal therapy, overall survival (OS) in patients with high-risk NB was below 15%. The addition of immunotherapy with dinutuximab beta in post-consolidation to multimodal treatment can increase the 5-year event-free survival rate for patients with high-risk NB up to 56.6%, and the 5-year OS up to 73.2%. The purpose of the research was to study the efficacy and safety of dinutuximab beta therapy in high-risk NB patients. Materials and methods used: the study included 8 pediatric patients with high-risk NB who had been treated with dinutuximab beta immunotherapy during postconsolidation on the basis of the Morozov Children’s City Clinical Hospital (Moscow, Russia) in 2020 to 2022. In case a patient's vital parameters normalization coupled with the absence of the need for accompanying therapy for 24 hours in a hospital, the patient was then considered as a candidate for outpatient treatment with possible no need for admission in the hospital. Results: 6 patients (75%) completed the full course of therapy with dinutuximab beta. The course of immunotherapy was not completed in 2 patients due to further progression of the disease. The most common adverse events were recorded as follows: pain (100%), fever (100%), diarrhea (62.5%), edematous syndrome (37.5%), allergic reactions (25%), hematological toxicity (25%). The period of time to becoming the candidates for outpatient treatment was 10.38±2.56 days for the 1st cycle of therapy and 2.67±1.63 days for the last, 5th cycle of the immunotherapy. In 6 out of 8 cases described the immunotherapy with dinutuximab beta allowed maintaining the response to treatment achieved after the end of consolidation preventing further development of the disease. The overall good tolerance to the drug made it possible to carry out the immunotherapy on an outpatient basis using microinfusing pump. Conclusion: an adequate route of administration and accompanying treatment make dinutuximab beta toxicity profile sufficient for outpatient management of patients with high-risk NB.

Single-agent activity of the anti-GD2 antibody dinutuximab beta given as a long-term infusion in relapsed and refractory neuroblastoma (APN311-304).

10034 Background: Severe pain is a common side effect associated with short-term infusions of anti-GD2 antibodies in combination with cytokines and isotretinoin and was reduced by the long-term infusison (LTI) strategy. We investigated efficacy and tolerability of a single-agent dinutuximab beta (DB)-LTI in patients with primary refractory or relapsed (R/R) stage 4 neuroblastoma (NB). Methods: Patients with R/R-NB were enrolled into an open label phase II trial. Previous anti-GD2 antibody therapies were allowed, if anti-DB antibody could not be detected. Patients received 5 cycles of DB-LTI (100 mg/m2/10 days). The primary endpoint was objective INRC response 24 weeks after the end of cycle 5. A sample size of 40 patients provides at least 80% power to reject the null hypothesis of an objective response in < 10% of patients if the true objective response rate observed was 25% (overall 1-sided significance level 0.05, exact binomial test). Secondary endpoints included safety, morphine use, best response and duration of response, pharmacodynamics and pharmacokinetics, 3-year progression-free (PFS) and overall survival (OS). Results: 40 patients were treated and 38 patients had evaluable response. The objective response rate 24 weeks after the end of cycle 5 was 26% (10/38) (CR/PR) (p = 0.0034) and 32% (12/38) (CR/PR/MR), with a higher response rate in refractory vs. relapsed patients (50% vs 25%; p = 0.0159). The best response rate was 53% (20/38). Of 14 patients with bone marrow involvement, 13 patients responded (93%) (12 CR, 1 PR). The median duration of response (CR/PR) was 238 days (95% CI [108-290d]). The 3-year probability of PFS was 31% (95% CI [0.17–0.47]) and of OS was 66% (95% CI [0.47–0.79]). Survival was higher for patients with refractory compared to relapsed disease (PFS 47% vs 19%, OS 93% vs 50%; p = 0.015). Grade 3 treatment emergent adverse events (TEAE) were pain (18%), diarrhea (5%), and hypokalemia (5%) and grade 3 hypotension, capillary leak and neurotoxicity were not observed. In patients who experienced pain, mean pain scores (scale 0–10, where 0 is no pain) were low and decreased between cycles 1 and 2: pain score at rest decreased from 1.01 to 0.30, and at stress from 1.45 to 0.28. There were no grade 4 or 5 TEAEs. The morphine usage decreased from cycle 2 to 5 (C2 95%; C3 12%; C4 0%; C5 0%). DB peak serum concentration in cycle 1 was 10.8±0.7 µg/ml and patients showed 7- and 11-fold increase of antibody-dependent cell-mediated (ADCC) and complement-dependent cytotoxicity (CDC), respectively. Anti-DB antibodies were found in 24% of patients. There was no association and no trend between exposure to DB (area under the curve, peak ot trough level) and response rate or survival in this cohort. Conclusions: Single-agent treatment with single agent dinutuximab beta given as long LTI without cytokines and without isotretinoin is effective and highly tolerable in R/R-NB. Clinical trial information: NCT02743429 .

Phase 1b/2 study of abemaciclib combined with chemoimmunotherapy in pediatric and young adult patients with relapsed/refractory neuroblastoma (JPCS Part C).

TPS10068 Background: Survival for high-risk neuroblastoma (NBL) remains poor with over 50% of patients experiencing disease relapse. The addition of dinutuximab (DIN) and granulocyte macrophage colony-stimulating factor (GM-CSF) to irinotecan (IRN) and temozolomide (TMZ) in patients with first relapse achieved an overall response rate of 42% in the study ANBL12211 and is now standard of care. However, there remains a significant unmet need to improve outcomes for children with relapsed/refractory NBL. Deregulation of the Cyclin D/cyclin-dependent kinase (CDK) 4 & 6 pathway has been observed in NBL, rendering CDK4 & 6 inhibition logical to explore. Abemaciclib is an orally administered, selective CDK4 & 6 inhibitor approved to treat breast cancer. JPCS (NCT04238819) is designed to assess the pharmacokinetics, safety, and tolerability of abemaciclib added to standard treatment regimens for relapsed/refractory pediatric solid tumors. Part A defined the recommended phase 2 dose (RP2D) of abemaciclib in combination with IRN and TMZ. In Part C, the addition of DIN + GM-CSF to the JPCS Part A regimen will be evaluated. The co-primary objectives of Part C are to determine the RP2D and to estimate the anti-tumor activity of abemaciclib added to the ANBL1221 chemoimmunotherapy backbone in patients with first relapse/refractory NBL. Methods: JPCS Part C is a two-stage, non-randomized, open-label, Phase 1b/2 study for patients < 21 years of age with first relapse/refractory NBL. Stage 1 aims to identify the maximum tolerated dose (MTD) of abemaciclib at a starting dose of 55 mg/m2 combined with DIN, GM-CSF, IRN and TMZ using a 3+3 design. One dose de-escalation (30 mg/m2) will be possible if the starting dose is not tolerated. Further tolerability and initial anti-tumor activity will be evaluated in an expansion cohort at the MTD. Up to 11 evaluable patients will enroll in Stage 1 at the MTD; the MTD will be declared the RP2D if adequate safety and tolerability are observed and ≥6 patients achieve minimal response or better per International Neuroblastoma Response Criteria (INRC). Following determination of the RP2D, Stage 2 will enroll 35 patients. If ≥26 of 46 total patients achieve an INRC minimum response or better, further investigation of this regimen could be warranted. As of 31 Jan 2023, Part C is open for enrollment at one site (US) and additional sites are being evaluated.

Dinutuximab beta-targeted therapy kills beta-cell tumors of the pancreas

PurposeDinutuximab beta is a monoclonal antibody used only in glioblastoma. Streptozotocin is an agent that is particularly toxic to pancreatic beta cells. Dinutuximab beta causes cytotoxicity through natural killer cells and neutrophils and shows effects. In this study, cytotoxicity was induced by streptozotocin without natural killer cells and neutrophils. Gaining the ability to show the effect of Dinutuximab beta without a natural killer was the first aim of this study. This will be especially important in cases where the immune system is deficient, such as cancer. The second aim of the study was to investigate the effects of Dinutuximab beta on cell viability and cell death in insulinoma under the conditions created.MethodsThe effect of Dinutuximab beta in the presence of natural killer cells in vivo was created by the application of Streptozotocin to Beta-cell tumors of the pancreas in vitro. The cell viability was determined with WST-1 assay. Reactive oxygen species were measured by using dichlorofluorescein diacetate as a spectrophotometer. The cells were marked with DAPI to indicate apoptotic markers (nuclear condensation and fragmentation) with the confocal microscope. GLUT2 (Glucose transporter 2), IR (Insulin receptor), INS1, and INS2 expression levels were analyzed with q-RT-PCR.ResultsThe cell cytotoxicity was induced by Streptozotocin. The cells proliferated with the administration of Dinutuximab beta alone. The result of Dinutuximab beta administered following Streptozotocin administration resulted in more cell death, increased ROS levels, GLUT2, Ins1, and Ins2 mRNA expression levels, and decreased IR mRNA expression levels. Furthermore, the cells predominantly died via apoptosis showing cytoplasmic condensation and DNA fragmentation.ConclusionsThe lethal effect of Dinutuximab beta without a natural killer was provided by Streptozotocin in Beta cell tumors of the pancreas.

Dinutuximab beta combined with chemotherapy in patients with relapsed or refractory neuroblastoma.

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.