Darren Hargrave

Central nervous system (CNS) tumours are the deadliest cancer for children and currently present limited treatment options. Chimeric antigen receptor (CAR)-T cell therapies have emerged as an innovative approach supported by encouraging clinical results. Current clinical trials using CAR-T cells in the treatment of paediatric CNS cancers differ in a number of variables, including the CAR-T cell route of delivery, presence of lymphodepletion, identified target antigen, and CAR engineering features. Considering early learnings across these areas is an essential step to developing more effective treatment options, especially given the challenges of immunosuppressive tumour microenvironments, various toxicities, CAR-T cell exhaustion, and tumour antigen heterogeneity. In sum, while there is a need for continued innovation, CAR-T cells represent a promising treatment approach for this devastating category of diseases.

Rare paediatric central nervous system (CNS) tumours comprise a biologically-heterogeneous group of low-incidence diseases that present significant challenges to both therapeutic development and clinical research, limiting the availability of high-quality evidence to guide clinical care. The UK3CR Children’s Cancer Research Group (CRG) CNS Tumours Subgroup convened a multidisciplinary workshop to identify research priorities and establish a strategic framework for advancing clinical trials in this setting. Four high-priority tumour groups—craniopharyngioma, choroid plexus carcinoma (CPC), very high-risk medulloblastoma (VHR-MB), and rare embryonal and sarcomatous tumours (REST), including embryonal tumour with multilayered rosettes (ETMR)—were evaluated. Key outcomes included the feasibility of a UK-led craniopharyngioma trial, the need for enhanced national CPC data collection, and support for European early-phase platform trials in VHR-MB. REST highlighted transnational regulatory complexity requiring coordinated registries and parallel trial models. Cross-cutting barriers included regulatory discordance, contracting delays, fragmented funding, pharmacovigilance differences, data-sharing constraints, and interoperable infrastructures. The workshop emphasised innovative methodologies, including Bayesian/adaptive designs, platform trials, and external control arms, to maximise efficiency in small populations, alongside strengthened patient involvement and international collaboration. Collectively, these findings define a collaborative and internationally-aligned strategic roadmap to accelerate clinical research and improve outcomes in rare paediatric CNS tumours.

Disease-specific cfDNA vs. tissue sequence variants.

Paediatric cancer specific cfDNA panel (ctPC Panel).

Disease-specific diagnostic vs. relapse sequence variants.

Relapse vs. primary somatic variants.

Similarity matrix for TFBS sets.

Top relapse-specific copy number events.