An in vivo immunotherapy screen of costimulatory molecules identifies Fc-OX40L as a potent reagent for the treatment of established murine gliomas.
OBJECTIVE
We tested the combination of a tumor lysate vaccine with a panel of costimulatory molecules to identify an immunotherapeutic approach capable of curing established murine gliomas.


METHODS
Glioma-bearing mice were primed with a tumor lysate vaccine, followed by systemic administration of the following costimulatory ligands: OX40L, CD80, 4-1BBL, and GITRL, which were fused to the Fc portion of human immunoglobulin. Lymphocytes and mRNA were purified from the brain tumor site for immune monitoring studies. Numerous variations of the vaccine and Fc-OX40L regimen were tested alone or in combination with temozolomide.


RESULTS
Lysate vaccinations combined with Fc-OX40L led to the best overall survival, yielding cure rates of 50% to 100% depending on the timing, regimen, and combination with temozolomide. Cured mice that were rechallenged with glioma cells rejected the challenge, showing immunologic memory. Lymphocytes isolated from the draining lymph nodes of vaccine/Fc-OX40L-treated mice had superior tumoricidal function relative to all other groups. Vaccine/Fc-OX40L-treated mice exhibited a significant increase in proliferation of brain-infiltrating CD4 and CD8 T cells, as indicated by Ki67 staining. Fc-OX40L had single-agent activity in transplanted and spontaneous glioma models, and the pattern of inflammatory gene expression in the tumor predicted the degree of therapeutic response.


CONCLUSIONS
These data show that Fc-OX40L has unique and potent activity against experimental gliomas and warrants further testing.
Departments of Pediatrics and Neurosurgery, University of Minnesota, Minneapolis, MN 55455, USA.
Katherine A
KA
Murphy
Melissa G
MG
Lechner
Flavia E
FE
Popescu
Jessica
J
Bedi
Stacy A
SA
Decker
Peisheng
P
Hu
Jami R
JR
Erickson
M Gerard
MG
O'Sullivan
Lauryn
L
Swier
Andres M
AM
Salazar
Michael R
MR
Olin
Alan L
AL
Epstein
John R
JR
Ohlfest
D053330:4-1BB Ligand / Q000235:genetics / Q000276:immunology; D000818:Animals; D018122:B7-1 Antigen / Q000235:genetics / Q000276:immunology; D001932:Brain Neoplasms / Q000276:immunology / Q000628:therapy; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005910:Glioma / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D007156:Immunologic Memory; D007167:Immunotherapy; D008024:Ligands; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000628:therapy; D051379:Mice; D053278:OX40 Ligand / Q000235:genetics / Q000276:immunology; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000276:immunology
D053330:4-1BB Ligand; D018122:B7-1 Antigen; D019496:Cancer Vaccines; D007141:Immunoglobulin Fc Fragments; D008024:Ligands; D053278:OX40 Ligand; C478967:TNFSF18 protein, human; C089251:TNFSF4 protein, human; D048069:Tumor Necrosis Factors