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Simple Summary
Neurotoxicity is an on-target side effect of GD2-directed immunotherapy due to the expression of GD2 on healthy cells. Patients with high-risk neuroblastoma who receive treatment with anti-GD2 immunotherapy, therefore, require close observation and supportive management to improve treatment tolerance and avoid the persistence of neurological symptoms. This study reports on the incidence, clinical course and management of patients who experienced neurotoxicity due to treatment with the anti-GD2 antibody dinutuximab beta, given with or without interleukin-2, in two clinical trials. The majority of severe neurotoxic events were observed in patients treated with dinutuximab beta combined with interleukin-2, with most patients recovering following supportive management. Given the increased risk of neurotoxic events and the lack of clinical benefit reported for the combination treatment in clinical trials, adding interleukin-2 to dinutuximab beta therapy is not recommended. The clinical experiences described here may aid clinicians in managing neurotoxicity associated with dinutuximab beta more effectively.
Abstract
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.
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.
GMP-Compliant Manufacturing of TRUCKs: CAR T Cells targeting GD2 and Releasing Inducible IL-18
(2022)
Chimeric antigen receptor (CAR)-engineered T cells can be highly effective in the treatment of hematological malignancies, but mostly fail in the treatment of solid tumors. Thus, approaches using 4th advanced CAR T cells secreting immunomodulatory cytokines upon CAR signaling, known as TRUCKs (“T cells redirected for universal cytokine-mediated killing”), are currently under investigation. Based on our previous development and validation of automated and closed processing for GMP-compliant manufacturing of CAR T cells, we here present the proof of feasibility for translation of this method to TRUCKs. We generated IL-18-secreting TRUCKs targeting the tumor antigen GD2 using the CliniMACS Prodigy® system using a recently described “all-in-one” lentiviral vector combining constitutive anti-GD2 CAR expression and inducible IL-18. Starting with 0.84 x 108 and 0.91 x 108 T cells after enrichment of CD4+ and CD8+ we reached 68.3-fold and 71.4-fold T cell expansion rates, respectively, in two independent runs. Transduction efficiencies of 77.7% and 55.1% was obtained, and yields of 4.5 x 109 and 3.6 x 109 engineered T cells from the two donors, respectively, within 12 days. Preclinical characterization demonstrated antigen-specific GD2-CAR mediated activation after co-cultivation with GD2-expressing target cells. The functional capacities of the clinical-scale manufactured TRUCKs were similar to TRUCKs generated in laboratory-scale and were not impeded by cryopreservation. IL-18 TRUCKs were activated in an antigen-specific manner by co-cultivation with GD2-expressing target cells indicated by an increased expression of activation markers (e.g. CD25, CD69) on both CD4+ and CD8+ T cells and an enhanced release of pro-inflammatory cytokines and cytolytic mediators (e.g. IL-2, granzyme B, IFN-γ, perforin, TNF-α). Manufactured TRUCKs showed a specific cytotoxicity towards GD2-expressing target cells indicated by lactate dehydrogenase (LDH) release, a decrease of target cell numbers, microscopic detection of cytotoxic clusters and detachment of target cells in real-time impedance measurements (xCELLigence). Following antigen-specific CAR activation of TRUCKs, CAR-triggered release IL-18 was induced, and the cytokine was biologically active, as demonstrated in migration assays revealing specific attraction of monocytes and NK cells by supernatants of TRUCKs co-cultured with GD2-expressing target cells. In conclusion, GMP-compliant manufacturing of TRUCKs is feasible and delivers high quality T cell products.
Simple Summary
The treatment of high-risk neuroblastoma patients with anti-GD2 antibodies has improved survival, and it is an established treatment strategy; however, many patients still experience a late relapse. One disadvantage of passive immunotherapy is the absence of a memory response. Therefore, developing an active immunotherapy leading to a sustained immune response may provide a solution and prevent the occurrence of late relapses following anti-GD2 antibody therapy. Here, we describe the first-in-man compassionate use of the ganglidiomab vaccine following passive immunotherapy with an anti-GD2 antibody (dinutuximab beta) in seven neuroblastoma patients. The vaccine was well-tolerated, and all patients not pre-treated by haploidentical transplantation developed vaccine-specific immune responses.
Abstract
(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.
Haploidentical stem cell transplantation (haplo SCT) in Stage IV neuroblastoma relapsed patients has been proven efficacious, while immunotherapy utilizing the anti-GD2 antibody dinutuximab beta has become a standard treatment for neuroblastoma. The combinatorial therapy of haplo SCT and dinutuximab may potentiate the efficacy of the immunotherapy. To gain further understanding of the synergistic effects, functional immunomonitoring was assessed during the clinical trial CH14.18 1021 Antibody and IL2 After haplo SCT in Children with Relapsed Neuroblastoma (NCT02258815). Rapid immune reconstitution of the lymphoid compartment was confirmed, with clinically relevant dinutuximab serum levels found in all patients over the course of treatment. Only one patient developed human anti-chimeric antibodies (HACAs). In-patient monitoring revealed highly functional NK cell posttransplant capable of antibody-dependent cellular cytotoxicity (ADCC). Degranulation of NK cell subsets revealed a significant response increased by dinutuximab. This was irrespective of the KIR receptor–ligand constellation within the NK subsets, defined by the major KIR receptors CD158a, CD158b, and CD158e. Moreover, complement-dependent cytotoxicity (CDC) was shown to be an extremely potent effector-cell independent mechanism of tumor cell lysis, with a clear positive correlation to GD2 expression on the cancer cells as well as to the dinutuximab concentrations. The ex vivo testing of patient-derived effector cells and the sera collected during dinutuximab therapy demonstrated both high functionality of the newly established lymphoid immune compartment and provided confidence that the antibody dosing regimen was sufficient over the duration of the dinutuximab therapy (up to nine cycles in a 9-month period). During the course of the dinutuximab therapy, proinflammatory cytokines and markers (sIL2R, TNFa, IL6, and C reactive protein) were significantly elevated indicating a strong anti-GD2 immune response. No impact of FcGR polymorphism on event-free and overall survival was found. Collectively, this study has shown that in-patient functional immunomonitoring is feasible and valuable in contributing to the understanding of anti-cancer combinatorial treatments such as haplo SCT and antibody immunotherapy.
Patients with high-risk neuroblastoma treated with continuous long-term infusion of anti-GD2 antibody dinutuximab beta (DB) in combination with IL-2 show an acceptable safety profile. Here, we compared treatment tolerance with and without IL-2. Ninety-nine patients with high-risk neuroblastoma received up to five cycles of DB given as long-term infusion (10 mg/m2/d, 100 mg/m2; per cycle) with IL-2 (53 patients; regimen A; 6 × 106 IU/m2/d; 60 × 106 IU/m2/cycle) and without IL-2 (46 patients; regimen B) in a single-center compassionate use program. Clinical parameters (body temperature, vital signs, Lansky performance score), laboratory values [C-reactive protein, IFN-γ, IL-6, and IL-18 (cycle 1)], and requirement of i.v. co-medication (e.g., morphine, metamizole) were systematically assessed. Patients with stable clinical parameters and that did not require co-medication were defined as potential “outpatient candidates.” Patients showed higher levels of body temperature and CRP in regimen A compared to B. However, IL-6 serum concentrations were similar in pts of both cohorts in the first cycle. Patients receiving regimen B showed a shorter time to achieve normal vital parameters and required less co-medication compared to patients in regimen A that resulted in a shorter median time period to discharge and to achieve a potential outpatient status (6d regimen A and 3–5d regimen B after start of antibody infusion, respectively). This study shows that omitting IL-2 from immunotherapy with DB allows reduced co-medication and hospitalization time and therefore results in improved quality of life in patients with high-risk neuroblastoma.
Background
Short-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.
Methods
In 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.
Results
Of 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.
Conclusion
Long-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 registration
The study is registered with ClinicalTrials.gov (NCT02743429) and EudraCT (2014-000588-42).
This article reports on the development, implementation and management of a German–Polish telemedicine network in the field of pediatric oncology and hematology in the Euroregion Pomerania. The achievements and challenges of joint medical case reviews involving patients and their care givers, as well as cross-border education activities for physicians, students and nursing staff, are presented. In addition to a progress report, the results of an evaluation of the participants and teachers, likewise the measurement of knowledge growth, are given.