Checkpoint Immunotherapy in Pediatrics: Here, Gone, and Back Again

Abstract

The role of immune checkpoint inhibitors (ICIs) in the treatment of pediatric cancers continues to evolve. Such therapies function by augmenting existing antitumor T-cell responses that have been rendered ineffective by inhibitory pathways. Although ICIs have proven highly effective for adult cancers, initial phase I/II clinical trials using single-agent ICIs against unselected pediatric cancers have been overall disappointing. With the exception of pediatric classic Hodgkin lymphoma, responses to ICIs have been infrequent, likely stemming from an inherent difference in the immunogenicity of childhood cancers, which, on average, have far fewer neoantigens than adult cancers. Recently, however, hope has reemerged that certain subsets of children with cancer may benefit from ICI therapies. In preliminary studies, patients with both pediatric hypermutated and SMARCB1-deficient cancers have had impressive responses to ICI therapies, likely as a result of underlying biologies that enhance neoantigen expression and tumoral inflammation. Dedicated trials are ongoing to fully evaluate the efficacy of ICIs for patients with these subsets of pediatric cancer.

Multi‐institution analysis of tumor mutational burden and outcomes in pediatric central nervous system tumor patients

“…These responses have been demonstrated in non‐small cell lung cancer, malignant melanoma, cervical cancer, breast cancer, gastric, esophageal, and head and neck cancers 19,20,23–25 . In pediatrics, however, responses have been inconsistent, possibly because of the relatively low TMB of pediatric cancers 26,27 …”

“…19,20,[23][24][25] In pediatrics, however, responses have been inconsistent, possibly because of the relatively low TMB of pediatric cancers. 26,27 There are over 2000 clinical trials investigating ICI in patients of all ages and with all tumor types (accessed June 2022). Of the 141 trials investigating ICI in pediatric patients, five of which have or are currently investigating ICI in pediatric CNS tumor patients.…”

Multi-institution analysis of tumor mutational burden and outcomes in pediatric CNS tumor patients

“…18,19,[22][23][24] In pediatrics, however, responses have been inconsistent, possibly because of the relatively low TMB of pediatric cancers. 25,26 There are over 2,000 clinical trials investigating ICI in patients of all ages and with all tumor types (accessed June 2022). Of the 141 trials investigating ICI in pediatric patients, five of which have or are currently investigating ICI in pediatric CNS tumor patients.…”

STINGing the immune system: lessons learned through a model of G34-mutant pediatric high-grade glioma

“…However, an improved understanding of the immune consequences of precision therapies like PARP inhibitors suggest that there may be untapped synergies in combining these categories of therapies to improve outcomes. Checkpoint inhibitors effectively treat many cancers by combating cancer-driven immunosuppression and T cell exhaustion of the immune system, however the efficacy of checkpoint inhibitors has been limited in the treatment of pediatric cancers ( 16 , 17 ). The results reported in the study by Haase and colleagues hint that immune stimulation from radiation and PARP inhibitors in G34-mutant pHGG could lead to potential synergies in combination with checkpoint inhibitors to further amplify the immune response against these cancers and improve survival ( 7 ).…”