Efficacy of systemic adoptive transfer immunotherapy targeting NY-ESO-1 for glioblastoma.
BACKGROUND
Immunotherapy is an ideal treatment modality to specifically target the diffusely infiltrative tumor cells of malignant gliomas while sparing the normal brain parenchyma. However, progress in the development of these therapies for glioblastoma has been slow due to the lack of immunogenic antigen targets that are expressed uniformly and selectively by gliomas.


METHODS
We utilized human glioblastoma cell cultures to induce expression of New York-esophageal squamous cell carcinoma (NY-ESO-1) following in vitro treatment with the demethylating agent decitabine. We then investigated the phenotype of lymphocytes specific for NY-ESO-1 using flow cytometry analysis and cytotoxicity against cells treated with decitabine using the xCelligence real-time cytotoxicity assay. Finally, we examined the in vivo application of this immune therapy using an intracranially implanted xenograft model for in situ T cell trafficking, survival, and tissue studies.


RESULTS
Our studies showed that treatment of intracranial glioma-bearing mice with decitabine reliably and consistently induced the expression of an immunogenic tumor-rejection antigen, NY-ESO-1, specifically in glioma cells and not in normal brain tissue. The upregulation of NY-ESO-1 by intracranial gliomas was associated with the migration of adoptively transferred NY-ESO-1-specific lymphocytes along white matter tracts to these tumors in the brain. Similarly, NY-ESO-1-specific adoptive T cell therapy demonstrated antitumor activity after decitabine treatment and conferred a highly significant survival benefit to mice bearing established intracranial human glioma xenografts. Transfer of NY-ESO-1-specific T cells systemically was superior to intracranial administration and resulted in significantly extended and long-term survival of animals.


CONCLUSIONS
These results reveal an innovative, clinically feasible strategy for the treatment of glioblastoma.
Department of Neurosurgery, University of California Los Angeles, Los Angeles, California (R.G.E., J.P.A., D.N.L., H.S., R.S., M.C.G., C.A.K., L.M.L., R.M.P.); Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California (D.N.L., R.M.P.); Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California (W.H.Y.); Department of Biostatistics, University of California Los Angeles, Los Angeles, California (N.L., G.L.); Brain Research Institute, University of California Los Angeles, Los Angeles, California (C.A.K., L.M.L., R.M.P.); Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, California (C.A.K., L.M.L., R.M.P.).
Richard G
RG
Everson
Department of Neurosurgery, University of California Los Angeles, Los Angeles, California (R.G.E., J.P.A., D.N.L., H.S., R.S., M.C.G., C.A.K., L.M.L., R.M.P.); Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California (D.N.L., R.M.P.); Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California (W.H.Y.); Department of Biostatistics, University of California Los Angeles, Los Angeles, California (N.L., G.L.); Brain Research Institute, University of California Los Angeles, Los Angeles, California (C.A.K., L.M.L., R.M.P.); Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, California (C.A.K., L.M.L., R.M.P.).
Joseph P
JP
Antonios
Department of Neurosurgery, University of California Los Angeles, Los Angeles, California (R.G.E., J.P.A., D.N.L., H.S., R.S., M.C.G., C.A.K., L.M.L., R.M.P.); Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California (D.N.L., R.M.P.); Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California (W.H.Y.); Department of Biostatistics, University of California Los Angeles, Los Angeles, California (N.L., G.L.); Brain Research Institute, University of California Los Angeles, Los Angeles, California (C.A.K., L.M.L., R.M.P.); Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, California (C.A.K., L.M.L., R.M.P.).
Dominique N
DN
Lisiero
Department of Neurosurgery, University of California Los Angeles, Los Angeles, California (R.G.E., J.P.A., D.N.L., H.S., R.S., M.C.G., C.A.K., L.M.L., R.M.P.); Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California (D.N.L., R.M.P.); Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California (W.H.Y.); Department of Biostatistics, University of California Los Angeles, Los Angeles, California (N.L., G.L.); Brain Research Institute, University of California Los Angeles, Los Angeles, California (C.A.K., L.M.L., R.M.P.); Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, California (C.A.K., L.M.L., R.M.P.).
Horacio
H
Soto
Department of Neurosurgery, University of California Los Angeles, Los Angeles, California (R.G.E., J.P.A., D.N.L., H.S., R.S., M.C.G., C.A.K., L.M.L., R.M.P.); Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California (D.N.L., R.M.P.); Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California (W.H.Y.); Department of Biostatistics, University of California Los Angeles, Los Angeles, California (N.L., G.L.); Brain Research Institute, University of California Los Angeles, Los Angeles, California (C.A.K., L.M.L., R.M.P.); Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, California (C.A.K., L.M.L., R.M.P.).
Rudi
R
Scharnweber
Department of Neurosurgery, University of California Los Angeles, Los Angeles, California (R.G.E., J.P.A., D.N.L., H.S., R.S., M.C.G., C.A.K., L.M.L., R.M.P.); Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California (D.N.L., R.M.P.); Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California (W.H.Y.); Department of Biostatistics, University of California Los Angeles, Los Angeles, California (N.L., G.L.); Brain Research Institute, University of California Los Angeles, Los Angeles, California (C.A.K., L.M.L., R.M.P.); Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, California (C.A.K., L.M.L., R.M.P.).
Matthew C
MC
Garrett
Department of Neurosurgery, University of California Los Angeles, Los Angeles, California (R.G.E., J.P.A., D.N.L., H.S., R.S., M.C.G., C.A.K., L.M.L., R.M.P.); Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California (D.N.L., R.M.P.); Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California (W.H.Y.); Department of Biostatistics, University of California Los Angeles, Los Angeles, California (N.L., G.L.); Brain Research Institute, University of California Los Angeles, Los Angeles, California (C.A.K., L.M.L., R.M.P.); Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, California (C.A.K., L.M.L., R.M.P.).
William H
WH
Yong
Department of Neurosurgery, University of California Los Angeles, Los Angeles, California (R.G.E., J.P.A., D.N.L., H.S., R.S., M.C.G., C.A.K., L.M.L., R.M.P.); Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California (D.N.L., R.M.P.); Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California (W.H.Y.); Department of Biostatistics, University of California Los Angeles, Los Angeles, California (N.L., G.L.); Brain Research Institute, University of California Los Angeles, Los Angeles, California (C.A.K., L.M.L., R.M.P.); Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, California (C.A.K., L.M.L., R.M.P.).
Ning
N
Li
Department of Neurosurgery, University of California Los Angeles, Los Angeles, California (R.G.E., J.P.A., D.N.L., H.S., R.S., M.C.G., C.A.K., L.M.L., R.M.P.); Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California (D.N.L., R.M.P.); Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California (W.H.Y.); Department of Biostatistics, University of California Los Angeles, Los Angeles, California (N.L., G.L.); Brain Research Institute, University of California Los Angeles, Los Angeles, California (C.A.K., L.M.L., R.M.P.); Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, California (C.A.K., L.M.L., R.M.P.).
Gang
G
Li
Department of Neurosurgery, University of California Los Angeles, Los Angeles, California (R.G.E., J.P.A., D.N.L., H.S., R.S., M.C.G., C.A.K., L.M.L., R.M.P.); Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California (D.N.L., R.M.P.); Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California (W.H.Y.); Department of Biostatistics, University of California Los Angeles, Los Angeles, California (N.L., G.L.); Brain Research Institute, University of California Los Angeles, Los Angeles, California (C.A.K., L.M.L., R.M.P.); Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, California (C.A.K., L.M.L., R.M.P.).
Carol A
CA
Kruse
Department of Neurosurgery, University of California Los Angeles, Los Angeles, California (R.G.E., J.P.A., D.N.L., H.S., R.S., M.C.G., C.A.K., L.M.L., R.M.P.); Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California (D.N.L., R.M.P.); Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California (W.H.Y.); Department of Biostatistics, University of California Los Angeles, Los Angeles, California (N.L., G.L.); Brain Research Institute, University of California Los Angeles, Los Angeles, California (C.A.K., L.M.L., R.M.P.); Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, California (C.A.K., L.M.L., R.M.P.).
Linda M
LM
Liau
Department of Neurosurgery, University of California Los Angeles, Los Angeles, California (R.G.E., J.P.A., D.N.L., H.S., R.S., M.C.G., C.A.K., L.M.L., R.M.P.); Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California (D.N.L., R.M.P.); Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California (W.H.Y.); Department of Biostatistics, University of California Los Angeles, Los Angeles, California (N.L., G.L.); Brain Research Institute, University of California Los Angeles, Los Angeles, California (C.A.K., L.M.L., R.M.P.); Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, California (C.A.K., L.M.L., R.M.P.).
Robert M
RM
Prins
D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology* / Q000378:metabolism; D001374:Azacitidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D045744:Cell Line, Tumor; D000077209:Decitabine; D004195:Disease Models, Animal; D005909:Glioblastoma / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D006801:Humans; D016219:Immunotherapy, Adoptive; D051379:Mice; D013601:T-Lymphocytes / Q000187:drug effects*
D000951:Antigens, Neoplasm; D000077209:Decitabine; D001374:Azacitidine
cancer; decitabine; engineered T cells; glioblastoma; immunotherapy