Regression of experimental medulloblastoma following transfer of HER2-specific T cells.
Medulloblastoma is a common malignant brain tumor of childhood. Human epidermal growth factor receptor 2 (HER2) is expressed by 40% of medulloblastomas and is a risk factor for poor outcome with current aggressive multimodal therapy. In contrast to breast cancer, HER2 is expressed only at low levels in medulloblastomas, rendering monoclonal antibodies ineffective. We determined if T cells grafted with a HER2-specific chimeric antigen receptor (CAR; HER2-specific T cells) recognized and killed HER2-positive medulloblastomas. Ex vivo, stimulation of HER2-specific T cells with HER2-positive medulloblastomas resulted in T-cell proliferation and secretion of IFN-gamma and interleukin 2 (IL-2) in a HER2-dependent manner. HER2-specific T cells killed autologous HER2-positive primary medulloblastoma cells and medulloblastoma cell lines in cytotoxicity assays, whereas HER2-negative tumor cells were not killed. No functional difference was observed between HER2-specific T cells generated from medulloblastoma patients and healthy donors. In vivo, the adoptive transfer of HER2-specific T cells resulted in sustained regression of established medulloblastomas in an orthotopic, xenogenic severe combined immunodeficiency model. In contrast, delivery of nontransduced T cells did not change the tumor growth pattern. Adoptive transfer of HER2-specific T cells may represent a promising immunotherapeutic approach for medulloblastoma.
Ahmed
Nabil
N
Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, The Methodist Hospital, Houston, Texas 77030, USA.
Ratnayake
Maheshika
M
Savoldo
Barbara
B
Perlaky
Laszlo
L
Dotti
Gianpietro
G
Wels
Winfried S
WS
Bhattacharjee
Meenakshi B
MB
Gilbertson
Richard J
RJ
Shine
H David
HD
Weiss
Heidi L
HL
Rooney
Cliona M
CM
Heslop
Helen E
HE
Gottschalk
Stephen
S
D019264:Adoptive Transfer; D000818:Animals; D001932:Brain Neoplasms / Q000276:immunology / Q000628:therapy*; D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008213:Lymphocyte Activation / Q000276:immunology; D008527:Medulloblastoma / Q000276:immunology / Q000628:therapy*; D051379:Mice; D009374:Neoplasms, Experimental / Q000276:immunology / Q000628:therapy; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D016511:Severe Combined Immunodeficiency; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation*
D016207:Cytokines; D018719:Erb-b2 Receptor Tyrosine Kinases