Immune checkpoint therapy in pediatric and adolescent lymphomas

Immune checkpoint therapy (ICT) is designed to unleash the anti-tumor activity of T-lymphocytes. Cytotoxic T-lymphocyte- associated antigen 4 (CTLA-4) inhibition and programmed death 1 (PD-1) inhibition are the most commonly utilized ICT in clinical cancer therapy, and they enhance anti-tumor immunity by interrupting the inhibitory signals CTLA-4 and programmed death ligand 1 (PD-L1), respectively. In pediatric Hodgkin lymphoma, ICT has demonstrated remarkable efficacy in both high-risk and relapsed disease, with investigation into the efficacy in low-risk disease ongoing. Pediatric mature B-cell lymphomas have variable expression of PD-L1 and there is very limited experience of incorporating ICT in their treatment. Primary mediastinal B-cell lymphoma (PMBCL), anaplastic large cell lymphoma, aggressive natural killer-cell lymphoma, and peripheral T-cell lymphoma, not otherwise specified all consistently express PD-L1, which provides a strong biological rationale for the use of ICT in these diseases. In PMBCL, the Children's Oncology Group and the National Cancer Institute's National Clinical Trials Network recently completed a randomized phase III trial of nivolumab in combination with chemo-immunotherapy in children and adults with newly diagnosed PMBCL. Results of this trial are expected in 2027. In anaplastic large cell lymphoma and aggressive natural killer-cell lymphoma, ongoing clinical trials are evaluating the efficacy of ICT. Given the transformational role of ICT in pediatric Hodgkin lymphoma, there is significant promise for the use of ICT in multiple subtypes of pediatric non-Hodgkin lymphoma with increased expression of PD-L1.