Checkpoint Proteins in Pediatric Brain and Extracranial Solid Tumors: Opportunities for Immunotherapy.
Pediatric brain and extracranial solid tumors are a diverse group of malignancies that represent almost half of all pediatric cancers. Standard therapy includes various combinations of surgery, cytotoxic chemotherapy, and radiation, which can be very harmful to a developing child, and survivors carry a substantial burden of long-term morbidities. Although these therapies have improved survival rates for children with solid tumors, outcomes still remain extremely poor for subsets of patients. Recently, immunosuppressive checkpoint molecules that negatively regulate immune cell function have been described. When found on malignant cells or in the tumor microenvironment, they contribute to immune evasion and tumor escape. Agents designed to inhibit these proteins have demonstrated significant efficacy in human adult solid tumor studies. However, there is limited research focusing on immune checkpoint molecules and inhibitors in pediatric solid tumors. In this review, we examine the current knowledge on immune checkpoint proteins with an emphasis on cytotoxic T lymphocyte antigen-4 (CTLA-4); programmed cell death protein-1 (PD-1) and programmed death-ligand 1 (PD-L1); OX-2 membrane glycoprotein (CD200); and indoleamine 2,3-dioxygenase (IDO). We review T-cell signaling, the mechanisms of action of these checkpoint molecules, pediatric preclinical studies on checkpoint proteins and checkpoint blockade, pediatric checkpoint inhibitor clinical trials conducted to date, and future immunotherapy opportunities for childhood cancers. Clin Cancer Res; 23(2); 342-50. ©2016 AACR.
Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama.
Eric K
EK
Ring
Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama.
James M
JM
Markert
Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama.
G Yancey
GY
Gillespie
Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama. GFriedman@peds.uab.edu.
Gregory K
GK
Friedman
D015703:Antigens, CD / Q000235:genetics; D060890:B7-H1 Antigen / Q000235:genetics; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D060908:CTLA-4 Antigen / Q000235:genetics; D002648:Child; D018816:Genes, cdc / Q000235:genetics*; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics; D010372:Pediatrics; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics; D013601:T-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D059016:Tumor Microenvironment / Q000235:genetics*
D015703:Antigens, CD; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D060908:CTLA-4 Antigen; C576710:IDO1 protein, human; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; C042739:antigens, CD200