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Information on the clinical relevance of minor histocompatibility antigen allo-immune responses in solid organ allografting is still scarce. The possible implications of the minor histocompatibility allo-immune responses for future clinical practice in solid organ transplantation are discussed in relation to their possible detrimental or beneficial effects on the host.

Long-term trends in neuroblastoma incidence and survival in unscreened populations are unknown. We explored trends in incidence, stage at diagnosis, treatment and survival of neuroblastoma in the Netherlands from 1990 to 2014. Methods: The Netherlands Cancer Registry provided data on all patients aged <18 years diagnosed with a neuroblastoma. Trends in incidence and stage were evaluated by calculating the average annual percentage change (AAPC). Univariate and multivariable survival analyses were performed for stage 4 disease to test whether changes in treatment are associated with survival. Results: Of the 593 newly diagnosed neuroblastoma cases, 45% was <18 months of age at diagnosis and 52% had stage 4 disease. The age-standardized incidence rate for stage 4 disease increased at all ages from 3.2 to 5.3 per million children per year (AAPC þ 2.9%, p < .01).

BackgroundCurrent immunotherapy for patients with high-risk neuroblastoma involves the therapeutic antibody dinutuximab that targets GD2, a ganglioside expressed on the majority of neuroblastoma tumors. Opsonized tumor cells are killed through antibody-dependent cellular cytotoxicity (ADCC), a process mediated by various immune cells, including neutrophils. The capacity of neutrophils to kill dinutuximab-opsonized tumor cells can be further enhanced by granulocyte-macrophage colony-stimulating factor (GM-CSF), which has been shown in the past to improve responses to anti-GD2 immunotherapy. However, access to GM-CSF (sargramostim) is limited outside of Northern America, creating a high clinical need for an alternative method to stimulate dinutuximab responsiveness in the treatment of neuroblastoma. In this in vitro study, we have investigated whether clinically well-established granulocyte colony-stimulating factor (G-CSF) can be a potentially suitable alternative for GM-CSF in the dinutuximab immunotherapy regimen of patients with neuroblastoma.MethodsWe compared the capacity of neutrophils stimulated either in vitro or in vivo with GM-CSF or G-CSF to kill dinutuximab-opsonized GD2-positive neuroblastoma cell lines and primary patient tumor material. Blocking experiments with antibodies inhibiting either respective Fc gamma receptors (FcγR) or neutrophil integrin CD11b/CD18 demonstrated the involvement of these receptors in the process of ADCC. Flow cytometry and live cell microscopy were used to quantify and visualize neutrophil-neuroblastoma interactions.ResultsWe found that G-CSF was as potent as GM-CSF in enhancing the killing capacity of neutrophils towards neuroblastoma cells. This was observed with in vitro stimulated neutrophils, and with in vivo stimulated neutrophils from both patients with neuroblastoma and healthy donors. Enhanced killing due to GM-CSF or G-CSF stimulation was consistent regardless of dinutuximab concentration, tumor-to-neutrophil ratio and concentration of the stimulating cytokine. Both GM-CSF and G-CSF stimulated neutrophils required FcγRIIa and CD11b/CD18 integrin to perform ADCC, and this was accompanied by trogocytosis of tumor material by neutrophils and tumor cell death in both stimulation conditions.ConclusionsOur preclinical data support the use of G-CSF as an alternative stimulating cytokine to GM-CSF in the treatment of high-risk neuroblastoma with dinutuximab, warranting further testing of G-CSF in a clinical setting.

BackgroundSex difference is an established risk factor for hematopoietic stem cell transplantation (HSCT)-related complications like graft versus host disease (GVHD). CD8pos cytotoxic T cells specific for Y chromosome-encoded minor Histocompatibility antigens (HY) play an important role therein. Prior to HSC donation, female donors may encounter HY antigens through fetomaternal or transmaternal cell flow, potentially leading to the induction of HY-specific cytotoxic or regulatory immune responses. Whether HY priming occurs independent of parity, and whether HY priming is dependent on the presence of male microchimerism, is as yet unknown.MethodsWe investigated the presence of HY-specific regulatory T cells (Treg) and male microchimerism in 45 healthy women with a fully documented pregnancy and family history. HY peptide-induced linked suppression, a commonly reported functional feature of CD4pos and CD8pos Treg, was measured by trans vivo Delayed Type Hypersensitivity testing. As source of HY antigens, male microchimerism was analyzed by real-time PCR and defined by the presence of male DNA in at least one purified leukocyte cell type.ResultsHLA class I or class II restricted HY-specific Treg were detected in 26/42 (62%) women eligible for analysis. The prevalence of HY-specific Treg was significantly higher in women who had never given birth to sons than in women with male offspring (p = 0.004). Male microchimerism could be detected in 24 out of 45 (53%) women but did not correlate with the presence of HY specific Treg.ConclusionsHY-specific Treg in women with male offspring have been described previously. Here we show for the first time that, in fact, HY specific Treg are more common in nulliparous women and in parous women with female offspring. Their presence is independent of the presence of male microchimerism. Whether HY-specific Treg presence in female stem cell grafts might decrease the GVHD incidence in male HSCT recipients needs to be investigated.

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The introduction of immunotherapy using an anti-GD2 antibody (dinutuximab, ch14.18) has significantly improved survival rates for high-risk neuroblastoma patients. However, this improvement in survival is accompanied by a substantial immunotherapy-related toxicity burden. The primary objective of this study was to describe treatment-related toxicities during immunotherapy with dinutuximab, IL-2, GM-CSF, and isotretinoin. A retrospective, single center analysis of immunotherapy-related toxicities was performed in twenty-six consecutive high-risk neuroblastoma patients who received immunotherapy as maintenance therapy in the Princess Máxima Center (Utrecht, Netherlands). Toxicities were recorded and graded according to the CTCAE. Particular attention was drawn to pain and fever management and toxicities leading to dose modifications of dinutuximab and IL-2. Twenty-three patients (88%) completed all six courses of immunotherapy. Disease progression, isotretinoin-associated liver toxicity, and catheter-related infection in combination with peripheral neuropathy were reasons for immunotherapy discontinuation. The most common grade ≥3 toxicities for courses 1–5, respectively, were pain, catheter-related infections, and fever. In total, 310 grade ≥3 toxicities were recorded in 124 courses. Thirty-three grade 4 toxicities in 19/26 patients and no grade 5 toxicities (death) were seen. Fifty-nine percent of grade ≥3 toxicities were recorded in the two courses with IL-2. Catheter-related bloodstream infections were identified in 81% of patients. Four of these episodes led to intensive care admission followed by full recovery (grade 4).