The combination of ionizing radiation and peripheral vaccination produces long-term survival of mice bearing established invasive GL261 gliomas.
OBJECTIVE
High-grade glioma treatment includes ionizing radiation therapy. The high invasiveness of glioma cells precludes their eradication and is responsible for the dismal prognosis. Recently, we reported the down-regulation of MHC class I (MHC-I) products in invading tumor cells in human and mouse GL261 gliomas. Here, we tested the hypothesis that whole-brain radiotherapy (WBRT) up-regulates MHC-I expression on GL261 tumors and enhances the effectiveness of immunotherapy.


METHODS
MHC-I molecule expression on GL261 cells was analyzed in vitro and in vivo by flow cytometry and immunohistochemistry, respectively. To test the response of established GL261 gliomas to treatment, mice with measurable (at CT imaging) brain tumors were randomly assigned to four groups receiving (a) no treatment, (b) WBRT in two fractions of 4 Gy, (c) vaccination with irradiated GL261 cells secreting granulocyte-macrophage colony-stimulating factor, or (d) WBRT and vaccination. Endpoints were tumor response and survival.


RESULTS
An ionizing radiation dose of 4 Gy maximally up-regulated MHC-I molecules on GL261 cells in vitro. In vivo, WBRT induced the expression of the beta2-microglobulin light chain subunit of the MHC class I complex on glioma cells invading normal brain and increased CD4+ and CD8+ T cell infiltration. However, the survival advantage obtained with WBRT or vaccination alone was minimal. In contrast, WBRT in combination with vaccination increased long-term survival to 40% to 80%, compared with 0% to 10% in the other groups (P < 0.002). Surviving animals showed antitumor immunity by rejecting challenge tumors.


CONCLUSIONS
Ionizing radiation can be successfully combined with peripheral vaccination for the treatment of established high-grade gliomas.
Newcomb
Elizabeth W
EW
Department of Pathology, New York University School of Medicine, New York, New York 10016, USA. newcoe01@med.nyu.edu
Demaria
Sandra
S
Lukyanov
Yevgeniy
Y
Shao
Yongzhao
Y
Schnee
Tona
T
Kawashima
Noriko
N
Lan
Li
L
Dewyngaert
J Keith
JK
Zagzag
David
D
McBride
William H
WH
Formenti
Silvia C
SC
D000818:Animals; D001932:Brain Neoplasms / Q000175:diagnosis / Q000276:immunology / Q000628:therapy*; D019496:Cancer Vaccines / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D018572:Disease-Free Survival; D004307:Dose-Response Relationship, Radiation; D005260:Female; D005434:Flow Cytometry; D005910:Glioma / Q000175:diagnosis / Q000276:immunology / Q000628:therapy*; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000528:radiation effects; D006801:Humans; D007147:Immunoglobulin Light Chains / Q000096:biosynthesis / Q000528:radiation effects; D007150:Immunohistochemistry; D007167:Immunotherapy; D051379:Mice; D011839:Radiation, Ionizing; D014057:Tomography, X-Ray Computed; D014183:Transplantation, Heterologous; D015854:Up-Regulation / Q000528:radiation effects; D023041:Xenograft Model Antitumor Assays; D001613:beta 2-Microglobulin / Q000096:biosynthesis / Q000528:radiation effects
D019496:Cancer Vaccines; D015395:Histocompatibility Antigens Class I; D007147:Immunoglobulin Light Chains; D001613:beta 2-Microglobulin