International clinical trial programme launched to harness the immune system against childhood solid tumours

Cancer remains one of the leading causes of disease-related death in children globally. While survival rates have improved for certain paediatric cancers, especially haematological malignancies, progress for many solid tumours has been limited and current treatments carry substantial long-term toxicity. Existing treatments are often adapted from adult therapies and offer limited success due to distinct biological differences and an immunosuppressive tumour microenvironment (TME). 

The solid tumours in children challenge was first set by Cancer Grand Challenges in 2020 to develop much-needed effective targeted therapeutics for paediatric solid tumours. After over three years of intensive research and collaboration, the NexTGen team launched three complementary early-phase studies, testing engineered CAR T-cell therapies designed specifically for children and young people with solid tumours. Co-funded by Cancer Research UK, the National Cancer Institute, and the Mark Foundation for Cancer Research, these studies build on extensive preclinical and translational work across the team.

“Cancer Grand Challenges is setting the bar for international team science in cancer research,” says Ryan Schoenfeld, CEO of The Mark Foundation. “We decided to support the NexTGen team because of its bench-to-bedside approach that aims to not only unlock new understanding of paediatric solid tumours, but also to use those findings to develop and test potential treatments.”

These studies are evaluating next generation CAR T-cells and tumour-associated antigen T cells (TAA-T) engineered to resist TGFβ-mediated immunosuppression, building on extensive preclinical and translational work across the team. The team’s coordinated approach places clinical learning loops at the heart of the clinical trial programme, with correlative science informing iterative vector and product design. 

“We urgently need new treatments that kill cancer cells without harming healthy ones,” emphasizes Karin Straathof, MIGHTY lead. “T-cell immunotherapy has the potential to do just that - not only improve survival but also protect their long-term quality of life. We’re looking forward to seeing the results of this important study.”

Engineering therapies for the solid tumour landscape

The trials build on extensive preclinical work conducted by researchers who are now part of the NexTGen team, identifying B7-H3 as a broadly and often homogeneously expressed target across paediatric sarcomas and brain tumours, and on rational engineering modules to contend with the hostile tumour microenvironment.

Key innovations that the team has undertaken include designing CAR T-cells for locoregional delivery, where the therapy is administered directly into or close to the central nervous system to improve therapeutic access to brain and spinal cord tumours, while managing inflammatory risks such as tumour inflammation-associated neurotoxicity and hydrocephalus.

One vision, two countries, three trials

This international multi-centre clinical trial programme is the first of its kind, and is now open at three leading centres, each targeting different tumour types with tailored cell therapy approaches.

University College London (UCL) site:
The MIGHTY trial focuses on paediatric sarcomas, including relapsed/refractory rhabdomyosarcoma and Ewing sarcoma. Under the leadership of Karin Straathof, the UK arm of the trial is treating patients at University College London Hospital (UCLH) and Great Ormond Street Hospital (GOSH). Patients with relapsed or refractory disease will receive B7-H3-targeting CAR T-cells, designed to recognise and attack tumour cells while sparing healthy tissue. 

Children’s National Hospital (CNH) site:
The SABRE trial is taking place in Washington, DC, under the direction of Holly Meany and Catherine Bollard. This trial is focused on children and young people with relapsed or refractory embryonal tumours, including rhabdomyosarcoma, Ewing sarcoma, neuroblastoma and Wilms tumour. Patients will receive a combination of B7-H3-targeting CAR T-cells and PRAME-specific T cells. This dual approach aims to tackle both antigen loss and the suppressive tumour microenvironment.

Dana-Farber Cancer Institute (DFCI) site:
A parallel trial at the Dana-Farber Institute in Boston is being run to target central nervous system tumours, including diffuse midline gliomas and other high-risk paediatric brain tumours. Led by Robbie Majzner, this study uses the same B7-H3 CAR T-cell backbone and will explore intracranial delivery routes to enhance uptake to the tumour.

Learning from every patient

Each trial includes a learning loop process, with comprehensive correlative studies to track CAR T-cell behaviour, persistence, and interactions with the TME. This unique and iterative design approach enables cross-trial comparisons and adaptive modifications to trial protocols in real-time.

“We’re not just testing therapies, we’re learning from every patient,” says Catherine Bollard, NexTGen co-lead. “Our correlative studies will help us understand why therapies work and how to make them better.”

Patient advocates at the heart of the programme

From the outset, team NexTGen has worked closely with patient advocates to shape its research and clinical strategy. Advocacy team members have contributed to trial design, communications and ethics protocols, and have played a key role in ensuring that the patient voice remains central.

One of the most impactful contributions has been the tailoring of the patient information booklet for the MIGHTY trial to make it accessible for parents and two different ages of children. Created in collaboration with the team’s patient advocates, these materials are now considered the gold standard for paediatric trial communications in the UK by the Gene Therapy Advisory Committee (GTAC) regulatory body, and are being adopted more widely.

“Key roles included comprehensive review of the wording, branding, key messages, style, tone and tailoring of three versions for parents, teens and younger children ,” says Sara Wakeling, NexTGen patient advocate. “The patient information sheets are a key touchpoint for families considering enrolling and it is so important to clearly explain the trial goals, how it works and what it might be like for the patient on trial.”

Looking ahead

The first patient receiving investigational treatment in this international multi-centre clinical trial programme marks a major milestone not only for the NexTGen team, but for the wider Cancer Grand Challenges initiative as NexTGen is the first team to take its discovery research into the clinic. These trials will generate critical data on safety, feasibility and early signs of efficacy, while informing future iterations of cell therapy design.
As the trials progress, NexTGen remains committed to integrating perspectives from patients and their families, data transparency and scientific excellence, with the ultimate goal of transforming outcomes for children and young people with solid tumours.

The Cancer Grand Challenges NexTGen team is co-funded by Cancer Research UK, the National Cancer Institute, and the Mark Foundation for Cancer Research.

Article written by Louise Stack, with thanks to Rebecca Eccles and Gabriela Carreno.