The reprogramming of a patient’s immune system through genetic modification of the T cell compartment with chimeric antigen receptors (CARs) has led to durable remissions in chemotherapy-refractory B cell cancers. Targeting of solid cancers by CAR-T cells is dependent on their infiltration and expansion within the tumor microenvironment, and thus far, fewer clinical responses have been reported. Here, we report a phase 1 study (NCT02761915) in which we treated 12 children with relapsed/refractory neuroblastoma with escalating doses of second-generation GD2-directed CAR-T cells and increasing intensity of preparative lymphodepletion. Overall, no patients had objective clinical response at the evaluation point +28 days after CAR-T cell infusion using standard radiological response criteria. However, of the six patients receiving ≥108/meter2 CAR-T cells after fludarabine/cyclophosphamide conditioning, two experienced grade 2 to 3 cytokine release syndrome, and three demonstrated regression of soft tissue and bone marrow disease. This clinical activity was achieved without on-target off-tumor toxicity. Targeting neuroblastoma with GD2 CAR-T cells appears to be a valid and safe strategy but requires further modification to promote CAR-T cell longevity.

Hereditary leiomyomatosis and renal cell cancer is a hereditary cancer syndrome in which affected individuals are at risk for cutaneous and uterine leiomyomas, and renal cancer. Previous reports have stressed the aggressiveness of the renal tumours, often with early metastasis, despite small primary tumour size. Almost all the previously reported patients were adults, and different studies showed variability in penetrance for the renal tumours. We report a patient in whom renal cancer was detected at the age of 11 years at his first routine screening imaging after he was found to carry a fumarate hydratase gene mutation (c.1189G > A) transmitted from his mother. This report serves to emphasize the need to improve guidelines for screening of at risk individuals, including the necessity for predictive genetic testing and early institution of tumour surveillance in childhood.

BackgroundFor children with cancer, the clinical integration of precision medicine to enable predictive biomarker–based therapeutic stratification is urgently needed.MethodsWe have developed a hybrid-capture next-generation sequencing (NGS) panel, specifically designed to detect genetic alterations in paediatric solid tumours, which gives reliable results from as little as 50 ng of DNA extracted from formalin-fixed paraffin-embedded (FFPE) tissue. In this study, we offered an NGS panel, with clinical reporting via a molecular tumour board for children with solid tumours. Furthermore, for a cohort of 12 patients, we used a circulating tumour DNA (ctDNA)–specific panel to sequence ctDNA from matched plasma samples and compared plasma and tumour findings.ResultsA total of 255 samples were submitted from 223 patients for the NGS panel. Using FFPE tissue, 82% of all submitted samples passed quality control for clinical reporting. At least one genetic alteration was detected in 70% of sequenced samples. The overall detection rate of clinically actionable alterations, defined by modified OncoKB criteria, for all sequenced samples was 51%. A total of 8 patients were sequenced at different stages of treatment. In 6 of these, there were differences in the genetic alterations detected between time points. Sequencing of matched ctDNA in a cohort of extracranial paediatric solid tumours also identified a high detection rate of somatic alterations in plasma.ConclusionWe demonstrate that tailored clinical molecular profiling of both tumour DNA and plasma-derived ctDNA is feasible for children with solid tumours. Furthermore, we show that a targeted NGS panel–based approach can identify actionable genetic alterations in a high proportion of patients.

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BackgroundThis study reports how parents and young people who had an experience offebrile neutropenia (FN) improved the design of a trial to inform the management of this condition. Five parents, a young person who had completed treatment and three clinician-researchers contributed.MethodsThe group was formed after an invitation on social media and met via video conference. Many participants were from an existing childhood-cancer parent-involvement group. The initial questions asked during discussion were about the importance of the topic, the views on the need for a trial, which important outcomes should be measured and the practical aspects which would make it easier or more difficult for people to take part in it. The conversation occurred for an entire afternoon, was audio and video recorded, transcribed, analysed and checked by those involved. The fifth parent added to this via email.ResultsThe group altered the trial structure by proposing randomising of each child to one of the two management methods through the whole of their anti-cancer treatment, rather than randomising the study sites or the child at each visit. They felt that even if people declined taking part in the study in the first weeks of diagnosis, their views might change and they should be allowed to consent later. They also proposed methods of collecting important patient and family data, enriching the medical information gained in the study. Active follow-up, negotiated for each individual family, was also suggested.ConclusionTrials for improving the management of FN in children and young people who are undergoing anti-cancer treatments should consider individual-patient randomisation, collection of ‘quality of life’ and ‘experience of care’ aspects using digital and paper-based methods, engage families in shared decision-making about management options and ensure adequate supportive information is available and accessible to all patients regardless of background, geographical location or age.