Updates on Paediatric Brain tumor Treatment

Written by Shang Yuxin Catherine

Introduction

In Hong Kong, 20 – 30 children are diagnosed with paediatric brain tumors per year (Children Cancer's Foundation, n.d.). The cause of paediatric brain tumor is still unclear, but it is widely accepted that genetic predisposition contributes to its occurrence, for example, TP53 and NF2 genes are found to be defective in the incidence of two of the most common paediatric brain tumors, medulloblastoma and ependymal tumor (Paediatric Brain tumor Foundation, n.d.). Conventional cancer treatments include chemotherapy and surgery. Craniospinal irradiation is also a proposed solution, however, its application is much more limited due to the risk of secondary cancer and neurocognitive defects such as loss of speech and cognitive development. In this newsletter, the progress in novel paediatric tumor treatment, specifically target therapy and immunotherapy, will be introduced.

Targeted Therapy - Dabrafenib and trametinib combined therapy

Figure 1. Mechanism of Action of Dabrafenib and Trametinib (Rissmann et al., 2015)

In 2022, the Food and Drug Administration (FDA) approved the combined use of dabrafenib and trametinib to treat solid or metastasized brain tumors. This therapy targets cancer cells containing BRAF V600E mutation, where ‘V’ refers to the valine, which is replaced by ‘E’ glutamic acid as a result of this mutation, and ‘600’ refers to the amino acid number at which this mutation occurs (Loo et al., 2018). The BRAF V600E gene plays an important role in regulating cell division, hence because of its mutation, cells undergo uncontrolled proliferation. Dabrafenib works by inhibiting the mutated BRAF serine/threonine kinase in the third step of MAPK/ERK pathway signalling (Khunger et al., 2018), whereas Trametinib inhibits MEK1/2 allosterically in the fourth step of this pathway, inhibiting MEK phosphorylation, hence regulating cell division and survival (Kumar, 2022). In April 2024, the UK National Health Service (NHS) offers this combined targeted therapy to children with glioma as their studies have shown that it has been shown to halt growth of tumors for more than three times than chemotherapy, with less side effects. The progression-free survival of patients under dabrafenib treatment alone is much lower than that of this combined treatment (median survival 9.4 months and 5.8 months respectively), as many patients develop resistance to dabrafenib months after treatment, whereas the combined therapy is able to mitigate the potential resistance and offer a higher response rate (Rissmann et al., 2015). 

Immunotherapy

Unlike the conventional approaches of ‘cut, burn, and poison’ that require an external intervention, immunotherapy leverages the body’s own immune system and destroys cancerous cells which escaped the patrolling white blood cells. Its application is also seen in treating paediatric brain tumors.

Chimeric Antigen Receptor T-Cell (CAR-T) Therapy 

CAR-T therapy employs genetically modified T lymphocytes that express chimeric antigen receptor, and, upon binding to specific antigens expressed by tumor cells, unlocks T cell cytotoxicity against cancer cells. It has been shown successful in treating paediatric leukemia with manageable toxicity (Seng et al., 2023). In a clinical trial conducted by Stanford Medicine between 2022 and 2024, CAR-T therapy is applied to paediatric patients (median age 15) who were diagnosed diffuse intrinsic pontine glioma (DIPG) and other H3K27M-mutated diffuse midline gliomas.

Figure 2. Mechanism of action of CAR-T cells targeting H3K27M-mutant DMG cells (Ramaswamy & Taylor, 2018)

Nine out of eleven patients have shown benefits, with one showing complete elimination of tumor. In this study, the targeted antigen is a surfaceome known as GD2 - a disaloganglioside that is widely expressed in DIPG and many other diffuse midline glioma cells . CAR-T cells that target GD2 are manufactured for each patient, followed by injection into cerebrospinal fluid (CSF) directly. With the treatment delivered every one to three months, many patients have shown shrunken tumor size and regained neurological functions which were previously lost, such as walking and speech (Monje et al., 2024).

At the same time, Shaw et al. found multiple novel immunotherapy targets. In the study, 1532 RNA-seq datasets from 16 types of paediatric solid and brain tumors were analysed (Shaw et al., 2024). Researchers then found cancer-specific exons which produce proteins of cell membrane and extracellular fluid that are absent from healthy tissues, but are essential in performing cellular functions such as cell adhesion and proliferation in cancer cells. Out of all exons found, CAR-T therapy is developed for the exon produced by COL11A1 gene, whose mutation is found in over 50% of paediatric brain and solid tumors. COL11A1 is responsible for encoding type XI collagen, and mutations in COL11A1 results in the production of cancer associated fibroblasts, and stimulates cancer cell migration and metastasis (National Library of Medicine, 2025). COL11A1 CAR-T cells’ potency were tested in mice with induced tumor, and it gave rise to an increase in median survival by over 100 days than infusing NT T cells which had no antitumor activity. With clinical trials taking place, COL11A1 CAR-T therapy has a potential to mediate paediatric brain tumors such as glioblastoma.

Vaccine ✅

Notably, vaccine is another branch of immunotherapy that has been put under the spotlight in recent decades. Cancer vaccines require several factors to work: first, the tumor antigen must be highly expressed; second, the antigen must interact closely with the major histocompatibility complex for immune cell recognition and killing. In 2024, SurVaxM was shown to be a leading candidate in paediatric tumor vaccine. It contains modified survivin peptide, which is a protein that is usually expressed only in foetal development but present in all glioblastoma and suppresses immune response (Fenstermaker et al., 2016). SurVaxM triggers adaptive immunity that targets survivin, hence shutting down the growth and proliferation in tumor cells. Response from the adult population is satisfactory, with median overall survival increasing from 16 months to 28 months (Ahluwalia et al., 2023). Hence, SurVaxM vaccine is another potential candidate for clinical trial in paediatric brain tumor patients.

Conclusion

Progress is seen in multiple realms of cancer treatment. Target therapy evolves as the emergence of more possible combined therapy targets more specific steps of cancer growth, hence minimizing chance of relapse. This would ensure growth and repair of cognitive abilities in children. Immunotherapy is the realm that has seen most breakthroughs in recent decades, in particular, vaccines have grasped most attention after the COVID-19 pandemic because of the pervasion of mRNA vaccine. Because immunotherapy requires antigen-specific targeting, it has been shown to induce less cognitive impairment and toxicity compared to chemotherapy and radiotherapy. However, several factors still restrict the use of immunotherapy, such as the heterogeneity of tumor population and antigen, restricted T cell invasion into solid tumors, and antigen escape that is particularly common in paediatric high grade gliomas (Gupta & Shukla, 2022). It is still optimistic that with the availability of novel technology such as AlphaFold and molecular mapping, more specific target therapies and immunotherapies can be found to ensure maximum curability of paediatric brain tumors with minimum toxicity.

References

Ahluwalia, M., Reardon, D., Abad, A., & Curry, W. (2023). Phase IIa Study of SurVaxM Plus Adjuvant Temozolomide for Newly Diagnosed Glioblastoma. J Clin Oncol. https://pubmed.ncbi.nlm.nih.gov/36521103/ 

Children Cancer's Foundation. (n.d.). https://www.ccf.org.hk/en/information/diagnosis_and_treatment/?id=10

Fenstermaker, R., Ciesielski, M., Qiu, J., & Yang, N. (2016). Clinical study of a survivin long peptide vaccine (SurVaxM) in patients with recurrent malignant glioma. Cancer Immunol Immunother. https://pubmed.ncbi.nlm.nih.gov/27576783/

Gupta, S., & Shukla, S. (2022). Limitations of Immunotherapy in Cancer. Cureus. https://pmc.ncbi.nlm.nih.gov/articles/PMC9708058/

Khunger, A., Khunger, M., & Velcheti, V. (2018). Dabrafenib in combination with trametinib in the treatment of patients with BRAF V600-positive advanced or metastatic non-small cell lung cancer: clinical evidence and experience. Ther Adv Respir Dis. https://pmc.ncbi.nlm.nih.gov/articles/PMC5941661/

Kumar, R. (Ed.). (2022). Fused Pyrimidine-Based Drug Discovery. Elsevier Science.

Loo, E., Hill, P., Beuhler, K., Siddiqu, I., & Vasef, M. A. (2018). BRAF V600E Mutation Across Multiple Tumor Types: Correlation Between DNA-based Sequencing and Mutation-specific Immunohistochemistry. Appl Immunohistochem Mol Morphol. https://pubmed.ncbi.nlm.nih.gov/29271794/

Majzner, R.G., Ramakrishna, S., & Yeom, K.W. (2022). GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas. Nature, 603. https://www.nature.com/articles/s41586-022-04489-4

Monje, M., Mahdi, J., & Majzner, R. (2024). Intravenous and intracranial GD2-CAR T cells for H3K27M+ diffuse midline gliomas. Nature, 637. https://www.nature.com/articles/s41586-024-08171-9

National Library of Medicine. (2025). COL11A1 collagen type XI alpha 1 chain [ Homo sapiens (human) ]. https://www.ncbi.nlm.nih.gov/gene/1301

Paediatric Brain Tumour Foundation. (n.d.). FACT SHEET for PEDIATRIC BRAIN TUMORS.

Ramaswamy, V., & Taylor, M. D. (2018). CAR T cells for childhood diffuse midline gliomas. nature medicine. https://www.nature.com/articles/s41591-018-0031-9

Rissmann, R., Hessel, M. H. M., & Cohen, A. F. (2015). Vemurafenib/dabrafenib and trametinib. https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bcp.12651

Seng, M., Meierhofer, A., Lim, F., Soh, S., & Hwang, W. (2023). A Review of CAR-T Therapy in Pediatric and Young Adult B-Lineage Acute Leukemia: Clinical Perspectives in Singapore. Onco Targets Ther. https://pmc.ncbi.nlm.nih.gov/articles/PMC10024535/

Shaw, T.I., Wagner, J., & Tian, L. (2024). Discovery of immunotherapy targets for pediatric solid and brain tumors by exon-level expression. https://www.nature.com/articles/s41467-024-47649-y