Glypican 3 (GPC3) is a
heparan sulfate proteoglycan and cell surface oncofetal
protein which is highly expressed on a variety of pediatric solid embryonal
tumors including the majority of
hepatoblastomas, Wilms
tumors, rhabdoid tumors, certain
germ cell tumor subtypes, and a minority of
rhabdomyosarcomas. Via both its core
protein and
heparan sulfate side chains, GPC3 activates the canonical Wnt/β-
catenin pathway, which is frequently overexpressed in these
malignancies. Loss of function mutations in GPC3 lead to
Simpson-Golabi-Behmel Syndrome, an X-linked overgrowth condition with a predisposition to GPC3-expressing
cancers including
hepatoblastoma and
Wilms tumor. There are several immunotherapeutic approaches to targeting GPC3, including
vaccines,
monoclonal antibodies,
antibody-drug conjugates,
bispecific antibodies, cytolytic T lymphocytes, and CAR T cells. These
therapies offer a potentially novel means to target these pediatric solid embryonal
tumors. A key pediatric-specific consideration of GPC3-targeted immunotherapeutics is that GPC3 can be physiologically expressed in normal tissues during the first year of life, particularly in the liver and kidney. In summary, this article reviews the current evidence for targeting childhood
cancers with GPC3-directed
immunotherapies.