Immunotherapy with chimeric antigen receptor (CAR)-expressing T cells that target the disialoganglioside GD2 expressed on tumor cells may be a therapeutic option for patients with high-risk neuroblastoma. In an academic, phase 1-2 clinical trial, we enrolled patients (1 to 25 years of age) with relapsed or refractory, high-risk neuroblastoma in order to test autologous, third-generation GD2-CAR T cells expressing the inducible caspase 9 suicide gene (GD2-CART01). A total of 27 children with heavily pretreated neuroblastoma (12 with refractory disease, 14 with relapsed disease, and 1 with a complete response at the end of first-line therapy) were enrolled and received GD2-CART01. No failure to generate GD2-CART01 was observed. Three dose levels were tested (3-, 6-, and 10×10⁶ CAR-positive T cells per kilogram of body weight) in the phase 1 portion of the trial, and no dose-limiting toxic effects were recorded; the recommended dose for the phase 2 portion of the trial was 10×10⁶ CAR-positive T cells per kilogram. Cytokine release syndrome occurred in 20 of 27 patients (74%) and was mild in 19 of 20 (95%). In 1 patient, the suicide gene was activated, with rapid elimination of GD2-CART01. GD2-targeted CAR T cells expanded in vivo and were detectable in peripheral blood in 26 of 27 patients up to 30 months after infusion (median persistence, 3 months; range, 1 to 30). Seventeen children had a response to the treatment (overall response, 63%); 9 patients had a complete response, and 8 had a partial response. Among the patients who received the recommended dose, the 3-year overall survival and event-free survival were 60% and 36%, respectively. The use of GD2-CART01 was feasible and safe in treating high-risk neuroblastoma. Treatment-related toxic effects developed, and the activation of the suicide gene controlled side effects. GD2-CART01 may have a sustained antitumor effect. (Funded by the Italian Medicines Agency and others; ClinicalTrials.gov number, NCT03373097.).

Purpose: Patients with cardiovascular malformations (CVMs) and deletion 22q11 from our series were studied in order to (1) analyze the association with dysmorphic features and noncardiac anomalies, (2) identify specific cardiac patterns and the distinctive association with additional CVMs. Methods: From 1993 to 2000, 931 patients with CVM (95 with a clinical diagnosis of DiGeorge/velocardiofacial syndrome (DG/VCFS), 208 with different genetic syndromes, 628 without dysmorphic features) underwent accurate cardiac assessment, clinical and phenotypical examination, and screening for deletion 22q11 by fluorescence in situ hybridization (FISH). Results: Deletion 22q11 was detected in 88 of the total patients, and in 87 of the 95 patients with a clinical diagnosis of DG/VCFS. Only one patient among the 628 without dysmorphic features had deletion 22q11. Conotruncal heart defects were the most common CVMs, often presenting in association with additional anomalies in four areas of the cardiovascular system: (1) the aortic arch can be right sided, cervical, double, and the subclavian artery can be aberrant, (2) the pulmonary arteries can present discontinuity, diffuse hypoplasia, discrete stenosis, defect of arborization and major aortopulmonary collateral arteries (MAPCA), (3) the infundibular septum can be malaligned, hypoplastic, or absent, (4) the semilunar valves can be bicuspid, severely dysplastic, insufficient, or stenotic. Conclusion: In subjects with deletion 22q11 CVM is virtually always associated with one or more noncardiac anomalies. Deletion 22q11 is exceptionally rare in children with nonsyndromic CVMs. Specific patterns of CVMs are observed in patients with deletion 22q11, including (1) anomalies of the aortic arch, (2) anomalies of the pulmonary arteries and of the pulmonary blood supply, (3) defects of the infundibular septum, (4) malformations of the semilunar valves. These additional CVMs may influence the surgical treatment of these patients.

MMSET (WHSC1/NSD2) is a SET domain–containing histone lysine methyltransferase the expression of which is deregulated in a subgroup of multiple myelomas with the t(4;14)(p16;q32) translocation associated with poor prognosis. Recent studies have shown that MMSET mRNA levels are increased in other tumor types as well. We have carried out immunohistochemical staining of tissue microarrays and found that MMSET protein is frequently and highly expressed in neuroblastoma (MMSET positive in 75% of neuroblastomas, n = 164). The expression level of MMSET in neuroblastomas was significantly associated with poor survival, negative prognostic factors, and metastatic disease. Moreover, a subset of neuroblastomas for which pre- and postchemotherapy biopsies were available displayed a strong decrease in MMSET protein levels after chemotherapy. In agreement with neuroblastomas becoming more differentiated after treatment, we show that retinoic acid–induced differentiation of human neuroblastoma cells in vitro also leads to a strong decrease in MMSET levels. Furthermore, we show that the high levels of MMSET in normal neural progenitor cells are strongly downregulated during differentiation. Importantly, we show that MMSET is required for proliferation of neuroblastoma cells and brain-derived neural stem cells. Taken together, our results suggest that MMSET is implicated in neuroblastomagenesis possibly by supporting proliferation of progenitor cells and negatively regulating their differentiation. In this respect, MMSET might be a strong candidate therapeutic target in a subset of neuroblastomas with unfavorable prognosis. Cancer Res; 71(12); 4226–35. ©2011 AACR.

We evaluated severe acute respiratory syndrome coronavirus 2 RNA clearance in 22 children. The estimation of positivity at day 14 was 52% for nasopharyngeal swab and 31% for stool samples. These data underline the significance of nasopharyngeal and stoolsample for detecting infected children. Additional studies are needed for transmissibility.