An aggressive childhood cancer case opens new avenues for advanced cell therapies

Although relatively rare, many childhood cancers remain life-threatening and lack effective personalised treatments. Rhabdoid tumours are among these fatal cancers and can develop in various tissues and organs. Approximately 12 new cases of this extremely aggressive cancer that typically appears before the age of two are diagnosed in Spain each year. The case featured in this study is that of a little girl who was only five months old when she was diagnosed with a malignant rhabdoid tumour of the kidney. The clinical team at Sant Joan de Déu Hospital in Barcelona surgically resected the tumour and began treatment with chemotherapy and radiotherapy, followed by immunotherapy. It was at this point that researchers from IRB Barcelona and CNAG began an in-depth, cell-by-cell study of the patient’s immune response, aiming to identify the key factors behind the successful outcome reported in Annals of Oncology.

The research team carried out a comprehensive analysis of the patient’s immune response, studying immune cells extracted from both the tumour mass and blood samples taken at different stages of treatment over 12 months. Using advanced genomic technologies, around 37,000 T cells — a type of immune cell that detects and attacks cancer cells — were sequenced at CNAG, and cell subtypes with the strongest anti-cancer activity were identified. In parallel, advanced immune profiling technologies (OS-T, Omniscope) were leveraged for large-scale sequencing of T cell receptors (TCRs), molecules on the cell surface that recognise tumour antigens. These analyses led to the identification of a set of cells and receptors that were later tested in vitro to assess their ability to fight the patient’s cancer cells.

The results were promising. The patient showed clear signs of recovery: her T cells expanded, remained active over time, recognised the tumour and held it in check. The same process was observed in laboratory tests. This dual confirmation — in the patient and in vitro — not only validated immunotherapy as an effective treatment for this tumour, but also provided valuable insights for developing future personalised cell therapies.

According to Dr. Inés Sentís, first author of the study, formerly at CNAG and now a postdoctoral researcher at IRB Barcelona: “Our study highlights the enormous potential of sequencing technologies to track changes in immune cell profiles during treatment. By comparing blood samples before and after treatment, we were able to identify T cells and receptors strengthened by immunotherapy — potential candidates with greater anti-cancer activity.” The authors also emphasise the importance of detecting these cells in blood, since liquid biopsies represent a much less invasive approach for patients.

“Our findings highlight that studying each individual patient case in great depth can yield valuable insights that directly impact patient outcomes — even more so in cancers as rare and aggressive as rhabdoid tumours. Our focus was to identify what determines the response to ICI therapy in children, and our findings offer a real foundation for developing personalised immunotherapies for young patients who currently have very limited options", said Dr. Alexandra Avgustinova, Group Leader at IRB Barcelona and IRSJD, and co-corresponding author of the study.

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Cellular immunotherapy: towards personalised treatments for more children

The patient received immunotherapy through compassionate use —an approach that is explored in cases where there is no other option to tackle the disease, even though it has not been previously approved for the condition. In adults, this type of immunotherapy is already more common — for instance, in colorectal or skin cancers — and tends to work better in part because adult tumours carry more mutations, making them easier for the immune system to detect.
This immunotherapy, known as immune checkpoint inhibition (ICI), helps the body’s defences — particularly T cells — recognise and attack tumour cells more effectively. It works by blocking the PD-L1 protein, which many tumours use to evade immune detection. By disabling this shield, cancer cells become exposed and vulnerable to T cell-mediated killing.

Based on their detailed analyses, the authors believe that this immunotherapy strategy contributed to the child’s recovery and provided a unique opportunity to design the “ingredients” for a potential advanced therapy: cellular immunotherapy. These therapies, which also aim to enhance the patient’s immune system, use cellular engineering to improve the cancer-fighting capacity of immune cells. Specifically, CNAG and IRB Barcelona researchers designed a strategy known as TCR-T, in which T cells are extracted from the patient and genetically modified to produce T cell receptors (TCRs) that more precisely recognise the tumour’s unique proteins.

According to one of the authors of the study, Single-Cell Genomics Group Leader at CNAG, Dr. Holger Heyn: “This study highlights the power of T cell profiling to monitor and predict the response to immuno-therapies. Moreover, it paves the way towards personalized cell therapies, engineering the patient´s own T cells with tumor-reactive TCR sequences. Today, this can be achieved with mRNA technologies in vitro. However, we foresee its application directly in the patients in vivo, making such therapies more scalable and accessible”.

The patient is in complete remission two years after being diagnosed with a rhabdoid tumour of the kidney. Her case marks a step forward towards more personalized medicine, capable of tailoring treatments to the unique characteristics of each patient. It also demonstrates how new genomic techniques enable the development of therapeutic strategies— in this case, in the field of cell therapy— that may help other children in the future.

This research was led by the Centro Nacional de Análisis Genómico (CNAG), the Institute for Research in Biomedicine of Barcelona (IRB Barcelona), and the Institut de Recerca Sant Joan de Déu (IRSJD), in collaboration with Omniscope. The first author is Dr. Inés Sentís, with Dr. Holger Heyn (CNAG) and Dr. Alexandra Avgustinova (IRB Barcelona / IRSJD) as corresponding authors.
 

Reference article:
Spatiotemporal T-cell tracking for personalized T-cell receptor T-cell therapy designs in childhood cancer
I. Sentís, J.L. Melero, A. Cebria-Xart, M. Grzelak, M. Soto, A. Michel, Q. Rovira, C.J. Rodriguez-Hernandez, G. Caratù, A. Urpi, C. Sauvage, A. Mendizabal-Sasieta, D. Maspero, C.E. Lavarino, A. Pascual-Reguant, A. Castañeda Heredia, J.P. Muñoz Perez, J. Mora, A. Harari, J.C. Nieto, A. Avgustinova & H. Heyn
Annals of Oncology (2025) DOI: 10.1016/j.annonc.2025.05.530