Targeted immunotherapies for anaplastic lymphoma kinase-positive pediatric tumors: current advances and future...

Next-Generation Treatment for Pediatric Cancer: Advancing Immunotherapy through Combinations. Cancer remains one of the leading causes of disease-related mortality among children and adolescents. Despite advances in treatments, outcomes for many pediatric tumors remain limited, particularly in patients with high-risk, relapsed, or refractory disease. Standard therapies, including surgery, chemotherapy, radiotherapy, and stem cell transplantation, are frequently associated with severe long-term toxicities and secondary malignancies. Resistance and relapse remain major clinical challenges. Recent progress in cancer immunotherapy has revolutionized adult oncology, and remarkable clinical advances have been observed in several pediatric cancers. However, comparable benefits in most solid tumors remain limited. Among molecular targets, anaplastic lymphoma kinase (ALK) has emerged as a critical driver of tumorigenesis in several pediatric malignancies, including anaplastic large cell lymphoma (ALCL), neuroblastoma and inflammatory myofibroblastic tumor. While ALK tyrosine kinase inhibitors have demonstrated clinical benefit, the emergence of resistance highlights the need for alternative or complementary strategies. ALK can act as an oncoantigen, as shown by spontaneous ALK-specific humoral and T-cell responses in patients with ALK-positive ALCL, and ALK-directed immunotherapies have been developed and have shown efficacy in preclinical models of ALK-positive tumors, including ALCL and neuroblastoma. Therefore, ALK-directed immunotherapies represent biologically rational and promising approaches that may, if proven safe and effective in clinical trials, address resistance and improve long-term disease control. In this review, we will discuss ALK-specific immunotherapies, including ALK vaccines, ALK CAR-T and other cellular therapies, as well as ALK-targeting antibodies with a particular focus on pediatric ALK-positive tumors.