Children have a developing immune system which is different from adults 1-4. However, this distinction is often overlooked in preclinical cancer research where adult mouse models are predominantly used, even in studies of paediatric cancers 5-7. This practice may overlook crucial developmental influences on pediatric cancer cell biology, particularly when identifying and testing treatments that target the tumour immune microenvironment rather than cancer cell-intrinsic vulnerabilities. Clinical trials have shown that certain immunotherapies effective in adults demonstrate limited efficacy in children. A notable example is immune checkpoint inhibitors, which show response rates of less than 6% in paediatric solid tumours, compared to 13-60% in adult cancers 8.
Recognizing these gaps, our interdisciplinary team has pioneered a groundbreaking initiative—developing "juvenile cancer mouse models" that mirror cancer conditions in children aged 0 to 4 years, the age range where 50% of childhood cancers manifest. In fact, many of these cancers have prenatal origins resulting from dysregulated developmental pathways 9. Our research using juvenile mouse models and patient datasets have revealed a distinctive "age-dependent immune suppressive signatures" in paediatric cancers, characterized by altered T cell responses and a dominance of tumour-promoting myeloid cells within tumour tissues.
We unravelled an age-dependent response to T cell targeting immunotherapies such as immune checkpoint inhibitors and bispecific T cell engagers. Consequently, we have devised a combination of immunotherapies that enhance response rates by modifying paediatric immune cells to resemble their adult counterparts. Given that this combination targets an age-dependent signature rather than specific cancer types, we anticipate its potential to benefit multiple paediatric cancers, particularly those diagnosed at a younger age.