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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.
Neuroblastoma is the most common extracranial, malignant, solid tumor found in children. In more than one-third of cases, the tumor is in an advanced stage, with limited resectability. The treatment options include resection, with or without (neo-/) adjuvant therapy, and conservative therapy, the latter even with curative intent. Contrast-enhanced MRI is used for staging and therapy monitoring. Diffusion-weighted imaging (DWI) is often included. DWI allows for a calculation of the apparent diffusion coefficient (ADC) for quantitative assessment. Histological tumor characteristics can be derived from ADC maps. Monitoring the response to treatment is possible using ADC maps, with an increase in ADC values in cases of a response to therapy. Changes in the ADC value precede volume reduction. The usual criteria for determining the response to therapy can therefore be supplemented by ADC values. While these changes have been observed in neuroblastoma, early changes in the ADC value in response to therapy are less well described. In this study, we evaluated whether there is an early change in the ADC values in neuroblastoma under therapy; if this change depends on the form of therapy; and whether this change may serve as a prognostic marker. We retrospectively evaluated neuroblastoma cases treated in our institution between June 2007 and August 2014. The examinations were grouped as ‘prestaging’; ‘intermediate staging’; ‘final staging’; and ‘follow-up’. A classification of “progress”, “stable disease”, or “regress” was made. For the determination of ADC values, regions of interest were drawn along the borders of all tumor manifestations. To calculate ADC changes (∆ADC), the respective MRI of the prestaging was used as a reference point or, in the case of therapies that took place directly after previous therapies, the associated previous staging. In the follow-up examinations, the previous examination was used as a reference point. The ∆ADC were grouped into ∆ADCregress for regressive disease, ∆ADCstable for stable disease, and ∆ADC for progressive disease. In addition, examinations at 60 to 120 days from the baseline were grouped as er∆ADCregress, er∆ADCstable, and er∆ADCprogress. Any differences were tested for significance using the Mann–Whitney test (level of significance: p < 0.05). In total, 34 patients with 40 evaluable tumor manifestations and 121 diffusion-weighted MRI examinations were finally included. Twenty-seven patients had INSS stage IV neuroblastoma, and seven had INSS stage III neuroblastoma. A positive N-Myc expression was found in 11 tumor diseases, and 17 patients tested negative for N-Myc (with six cases having no information). 26 patients were assigned to the high-risk group according to INRG and eight patients to the intermediate-risk group. There was a significant difference in mean ADC values from the high-risk group compared to those from the intermediate-risk group, according to INRG. The differences between the mean ∆ADC values (absolute and percentage) according to the course of the disease were significant: between ∆ADCregress and ∆ADCstable, between ∆ADCprogress and ∆ADCstable, as well as between ∆ADCregress and ∆ADCprogress. The differences between the mean er∆ADC values (absolute and percentage) according to the course of the disease were significant: between er∆ADCregress and er∆ADCstable, as well as between er∆ADCregress and er∆ADCprogress. Forms of therapy, N-Myc status, and risk groups showed no further significant differences in mean ADC values and ∆ADC/er∆ADC. A clear connection between the ADC changes and the response to therapy could be demonstrated. This held true even within the first 120 days after the start of therapy: an increase in the ADC value corresponds to a probable response to therapy, while a decrease predicts progression. Minimal or no changes were seen in cases of stable disease.
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.
Treatment of high-risk neuroblastoma (NB) patients with the anti-GD2 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.
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.
BACKGROUND
Eosinophilic granuloma (EG) belongs to the family of Langerhans cell histiocytosis (LCH) and is considered to be a benign disease typically found in children younger than 15 years of age. Here, the authors describe an EG of unusual localization and clinical presentation.
OBSERVATIONS
The authors report a 9-year-old girl with an EG presenting as an osteolytic lesion of the clivus. After transsphenoidal resection and histological confirmation, adjuvant chemotherapy was initiated. Presenting signs and symptoms were weight loss, episodic grimacing, and moderate ballism-like movements. After a follow-up-period of 32 months, the patient presented with a total resolution of initial symptoms and no further tumor growth.
LESSONS
Although these lesions are rare, one should consider EG as a differential diagnosis when confronted with osteolytic lesions of the clivus.
Background
Invasive mold infections are a well-known and life-threatening condition after allogeneic hematopoietic stem cell transplantation (HSCT). While Aspergillus species are recognized as predominant pathogens, Fusarium species should also be considered due to their broad environmental distribution and the expected poor outcome of invasive fusariosis. Particularly, splenic rupture as a complication of disseminated disease has not been reported yet.
Case presentation
Two weeks after allogeneic HSCT for severe aplastic anemia, a 16-year-old boy presented with painful, erythematous skin nodules affecting the entire integument. As disseminated mycosis was considered, treatment with liposomal amphotericin B and voriconazole (VCZ) was initiated. Invasive fusariosis was diagnosed after histological and previously unpublished polymerase chain reaction-based examination of skin biopsies. Microbiological tests revealed Fusarium solani species. Despite stable neutrophil engraftment and uninterrupted treatment with VCZ, he developed mold disease-associated splenic rupture with hypovolemic shock and fungal endocarditis. The latter induced a cardiac thrombus and subsequent embolic cerebral infarctions with unilateral hemiparesis. Following cardiac surgery, the patient did not regain consciousness because of diffuse cerebral ischemia, and he died on day +92 after HSCT.
Conclusion
Invasive fusariosis in immunocompromised patients is a life-threatening condition. Despite antimycotic treatment adapted to antifungal susceptibility testing, the patient reported here developed uncommon manifestations such as splenic rupture and fungal endocarditis.
BCL11B, an essential transcription factor for thymopoiesis, regulates also vital processes in post-thymic lymphocytes. Increased expression of BCL11B was recently correlated with the maturation of NK cells, whereas reduced BCL11B levels were observed in native and induced T cell subsets displaying NK cell features. We show that BCL11B-depleted CD8+ T cells stimulated with IL-15 acquired remarkable innate characteristics. These induced innate CD8+ (iiT8) cells expressed multiple innate receptors like NKp30, CD161, and CD16 as well as factors regulating migration and tissue homing while maintaining their T cell phenotype. The iiT8 cells effectively killed leukemic cells spontaneously and neuroblastoma spheroids in the presence of a tumor-specific monoclonal antibody mediated by CD16 receptor activation. These iiT8 cells integrate the innate natural killer cell activity with adaptive T cell longevity, promising an interesting therapeutic potential. Our study demonstrates that innate T cells, albeit of limited clinical applicability given their low frequency, can be efficiently generated from peripheral blood and applied for adoptive transfer, CAR therapy, or combined with therapeutic antibodies.
Aim
Periprosthetic joint infections are a devastating complication after arthroplasty, leading to rejection of the prosthesis. The prevention of septic loosening may be possible by an antimicrobial coating of the implant surface. Poly (hexamethylene) biguanide hydrochloride [PHMB] seems to be a suitable antiseptic agent for this purpose since previous studies revealed a low cytotoxicity and a long-lasting microbicidal effect of Ti6Al4V alloy coated with PHMB. To preclude an excessive activation of the immune system, possible inflammatory effects on macrophages upon contact with PHMB-coated surfaces alone and after killing of S. epidermidis and P. aeruginosa are analyzed.
Methods
THP-1 monocytes were differentiated to M0 macrophages by phorbol 12-myristate 13-acetate and seeded onto Ti6Al4V surfaces coated with various amounts of PHMB. Next to microscopic immunofluorescence analysis of labeled macrophages after adhesion on the coated surface, measurement of intracellular reactive oxygen species and analysis of cytokine secretion at different time points without and with previous bacterial contamination were conducted.
Results
No influence on morphology of macrophages and only slight increases in iROS generation were detected. The cytokine secretion pattern depends on the surface treatment procedure and the amount of adsorbed PHMB. The PHMB coating resulted in a high reduction of viable bacteria, resulting in no significant differences in cytokine secretion as reaction to coated surfaces with and without bacterial burden.
Conclusion
Ti6Al4V specimens after alkaline treatment followed by coating with 5–7 μg PHMB and specimens treated with H2O2 before PHMB-coating (4 μg) had the smallest influence on the macrophage phienotype and thus are considered as the surface with the best cytocompatibility to macrophages tested in the present study.