Adoptive cell therapy in paediatric extracranial solid tumours: current approaches and future challenges

Immunotherapy has ignited hope to cure paediatric solid tumours that resist traditional therapies. Among the most promising methods is adoptive cell therapy (ACT). Particularly, ACT using T cells equipped with chimeric antigen receptors (CARs) has moved into the spotlight in clinical studies. However, the efficacy of ACT is challenged by ACT-intrinsic factors, like lack of activation or T cell exhaustion, as well as immune evasion strategies of paediatric solid tumours, such as their highly immunosuppressive microenvironment. Novel strategies, including ACT using innate-like lymphocytes, innovative cell engineering techniques, and ACT combination therapies, are being developed and will be crucial to overcome these challenges. Here, we discuss the main classes of ACT for the treatment of paediatric extracranial solid tumours, reflect on the available preclinical and clinical evidence supporting promising strategies, and address the challenges that ACT is still facing. Ultimately, we highlight state-of-the-art developments and opportunities for new therapeutic options, which hold great potential for improving outcomes in this challenging patient population.