Active immunotherapy for advanced intracranial murine tumors by using dendritic cell-tumor cell fusion vaccines.
OBJECTIVE
Immunotherapy for malignant brain tumors by active immunization or adoptive transfer of tumor antigen-specific T lymphocytes has the potential to make up for some of the limitations of current clinical therapy. In this study, the authors tested whether active immunotherapy is curative in mice bearing advanced, rapidly progressive intracranial tumors.


METHODS
Tumor vaccines were created through electrofusion of dendritic cells (DCs) and irradiated tumor cells to form multinucleated heterokaryons that retained the potent antigen processing and costimulatory function of DCs as well as the entire complement of tumor antigens. Murine hosts bearing intracranial GL261 glioma or MCA 205 fibrosarcoma were treated with a combination of local cranial radiotherapy, intrasplenic vaccination with DC/tumor fusion cells, and anti-OX40R (CD134) monoclonal antibody (mAb) 7 days after tumor inoculation. Whereas control mice had a median survival of approximately 20 days, the treated mice underwent complete tumor regression that was immunologically specific. Seven days after vaccination treated mice demonstrated robust infiltration of CD4+ and CD8+ T cells, which was exclusively confined to the tumor without apparent neurological toxicity. Cured mice survived longer than 120 days with no evidence of tumor recurrence and resisted intracranial tumor challenge.


CONCLUSIONS
These data indicate a strategy to achieve an antitumor response against tumors in the central nervous system that is highly focused from both immunological and anatomical perspectives.
Kjaergaard
Jorgen
J
Center for Surgery Research, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
Wang
Li-Xin
LX
Kuriyama
Hideyuki
H
Shu
Suyu
S
Plautz
Gregory E
GE
D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy; D019496:Cancer Vaccines / Q000627:therapeutic use*; D002459:Cell Fusion; D017024:Chemotherapy, Adjuvant; D003713:Dendritic Cells / Q000502:physiology*; D004195:Disease Models, Animal; D005260:Female; D005354:Fibrosarcoma / Q000188:drug therapy* / Q000532:radiotherapy; D005910:Glioma / Q000188:drug therapy* / Q000532:radiotherapy; D016233:Immunotherapy, Active / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D018714:Radiotherapy, Adjuvant; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors / Q000627:therapeutic use
D019496:Cancer Vaccines; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; C505717:Tnfrsf4 protein, mouse