Tackling solid tumours in children

Cancer is a leading cause of death by disease in children worldwide. Many barriers exist to developing specific, effective treatments for children with solid tumours – for example, because adult cancers are very different to childhood ones, therapies developed to exploit cancer’s vulnerabilities in adults have limited efficacy in children. Despite this, developing specific treatments for children has also not been prioritised by biopharma.

Cancer Grand Challenges set the solid tumours in children challenge first in 2020, then again in 2023, in the hopes that addressing this challenge would lead to the development of effective targeted therapies that will not only improve survival for children diagnosed with cancer, but will diminish the lifelong toxicities experienced by those that do survive.

While the major genetic drivers of many childhood cancers have been identified, the oncoproteins encoded by these genes have previously been considered ‘undruggable’ using conventional small molecule inhibitors. Furthermore, attempts to target the activity of these oncoproteins indirectly have shown limited, if any, success. Teams PROTECT and KOODAC are working to turn these critical oncoproteins into druggable targets. Unlike traditional small molecule inhibitors that aim to inhibit target protein activity, the teams are developing a new generation of compounds – targeted protein degraders – which induce the degradation of the target protein instead. 

While immunotherapy approaches have been a game-changer in haematological malignancies, they are yet to make real impact in the majority of solid tumours. Team NexTGen are trying to overcome the immunosuppressive effects of the microenvironment, a major barrier in the treatment of solid tumours, by developing next generation CAR-T cell therapies specifically for children, with a focus on sarcomas and brain tumours. 

Co-led by clinician scientists Catherine Bollard in the US and Martin Pule in the UK, the NexTGen team comprises leading experts in oncology, immunology, glycobiology (Nobel Prize winner Carolyn Bertozzi), proteomics and mathematics across the UK, US and France. 

Team NexTGen will soon be starting three parallel clinical trials using bespoke CAR T-cell therapies specifically for children with sarcomas and brain tumours. These trials will be carried out in a centralised manner across the US and UK. This unique approach will allow a larger number of children to be included and enable the team to learn from and adapt the trials’ efficiency in real time. 

The team’s patient advocates have been involved throughout. At the University College London clinical trial site, the patient information pack, which was co-developed with the team’s patient advocates, has been tailored to make it accessible for parents and two different ages of children. It has received excellent feedback from the UK Gene Therapy Advisory Committee (GTAC) and will be used as best practice for all new clinical trials in the UK. 

Back in the lab, in work led by John Maris (University of Pennsylvania), NexTGen extensively compared tumour and normal tissue by using an integrative proteogenomic approach to identify promising immunotherapy targets in neuroblastoma. The team followed up on Delta-like canonical notch ligand 1 (DLK1), identifying how it becomes upregulated in neuroblastoma cells and that it plays a critical role in maintaining the cancerous state. The team went on to show the promise of a DLK1 antibody-drug conjugate as a treatment option in mouse models. 

In work led by Andrew Sewell (Cardiff University), NexTGen identified a novel subset of T cells, MHC-related protein 1 (MR1)-restricted T cells, which are capable of recognising and targeting cancer cells while avoiding healthy cells. These T cells detect metabolites specific to cancer cells that arise from altered metabolic pathways, such as changes in amino acid metabolism, increased glycolysis or shifts in lipid utilisation. This paper lays the groundwork for therapies targeting MR1, including novel vaccines to stimulate these T cells against cancer. 

In a study led by Nikolaos Sgourakis’ lab (The Children’s Hospital of Philadelphia), NexTGen revealed the molecular mechanism of antigen proofreading by MHC-I molecules by capturing the dynamic intermediate state of MHC-I during peptide selection, together with the molecular chaperone TAP binding protein-related (TAPBPR). The innovative approach the team used allows for rapid in vitro validation of potential antigens, with these findings holding promise for advancing cancer vaccines and immunotherapies. 

KOODAC is co-led by Yaël Mossé, Children’s Hospital of Philadelphia, US, and Martin Eilers, University of Würzburg, Germany and brings together leading scientists and clinicians with industry partners and patient advocates. The team encompasses expertise in structural and chemical biology, paediatric oncology and medicinal chemistry from ten institutions across five countries. 

For KOODAC, the involvement of Nurix Therapeutics and its cutting-edge DNA-encoded library screening platforms has been integral to the team’s progress. This has led to the identification of promising degrader candidates across the five childhood solid tumour types that KOODAC is focusing on. 

The team has also made strides in understanding the structures and mechanisms of key molecular targets. 

Team PROTECT is led by Stefan Pfister of the Hopp Children’s Cancer Center in Heidelberg, Germany. Across nine research institutions and five countries, PROTECT brings together paediatric oncologists, immunologists, cancer biologists and chemists, with patient advocates.  

In its first year, PROTECT has developed protein degraders for key ‘undruggable’ targets and engineered systems to model small molecule-induced degradation for further targets lacking existing degraders. 

PROTECT’s patient advocates will play a crucial role in translating the team’s research and building a sustainable business model for paediatric cancer drug development. The team has currently identified priority disease areas, ensuring that its work addresses high unmet medical needs and benefits diverse stakeholders, including scientists, investors and patients.

In their first year, KOODAC and PROTECT have hit the ground running, with their efforts to use “Protein-slayer drugs” to take on deadly cancers highlighted by Nature. At the heart of the story is Evan Lindberg, who lost his life to neuroblastoma at just seven years old. His parents, Gavin and Wendy, are now part of KOODAC’s mission to find better and more accessible treatments for children around the world. All three teams have dedicated patient advocates, many of whom have lost children to these devastating diseases.

With NexTGen poised to begin clinical trials and KOODAC and PROTECT also aiming to carry out clinical trials within their funding period, all three teams are bringing hope for a better future.

A proteogenomic surfaceome study identifies DLK1 as an immunotherapeutic target in neuroblastoma, Cancer Cell

MHC-related protein 1–restricted recognition of cancer via a semi-invariant TCR-α chain, The Journal of Clinical Investigation

CryoEM structure of an MHC-I/TAPBPR peptide-bound intermediate reveals the mechanism of antigen proofreading, PNAS

How protein-slayer drugs could beat some of the cruellest cancers, Nature

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

Through Cancer Grand Challenges team KOODAC is funded by Cancer Research UK, the French National Cancer Institute (INCa) and KiKa (Children Cancer Free Foundation).    

Through Cancer Grand Challenges team PROTECT is funded by Cancer Research UK, the National Cancer Institute, the Scientific Foundation of the Spanish Association Against Cancer and KiKa (Children Cancer Free Foundation)