TY - JOUR
T1 - Checkpoint proteins in pediatric brain and extracranial solid tumors
T2 - Opportunities for immunotherapy
AU - Ring, Eric K.
AU - Markert, James M.
AU - Gillespie, G. Yancey
AU - Friedman, Gregory K.
N1 - Funding Information:
This work was supported by St. Baldrick's Foundation, the Rally Foundation for Childhood Cancer Research, The Truth 365, Department of Defense (W81XWH-15-1-0108), Kaul Pediatric Research Institute (to G.K. Friedman), and the NIH (P01CA071933, to J.M. Markert; and P20CA151129, to G.Y. Gillespie).
Publisher Copyright:
© 2016 AACR.
PY - 2017/1/15
Y1 - 2017/1/15
N2 - 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 longterm 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.
AB - 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 longterm 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.
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U2 - 10.1158/1078-0432.CCR-16-1829
DO - 10.1158/1078-0432.CCR-16-1829
M3 - Review article
C2 - 27836863
AN - SCOPUS:85011024300
SN - 1078-0432
VL - 23
SP - 342
EP - 350
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 2
ER -