Nonspecific immunotherapy with intratumoral lipopolysaccharide and zymosan A but not GM-CSF leads to an effective anti-tumor response in subcutaneous RG-2 gliomas.
OBJECTIVE
Nonspecific stimulation of cells of the immune system may be useful in generating an anti-tumor response for a variety of cancers and may work synergistically with currently available cytotoxic therapies. In this study we examined the response of syngeneic rat gliomas to treatment with several nonspecific stimulators of dendritic cells and macrophages alone or in combination with radiation therapy.


METHODS
RG-2 gliomas were implanted subcutaneously and treated with intratumoral (IT) injections of the toll-like receptor (TLR) ligands lipopolysaccharide (LPS) and zymosan A (ZymA) and the cytokine granulocyte-macrophage colony stimulating factor (GM-CSF). Combination treatment with IT LPS and single-fraction external beam radiotherapy (EBRT) was also evaluated.


RESULTS
Treatment with IT LPS and ZymA delayed tumor growth compared to saline controls. Multiple doses of both substances were superior to single doses, and led to complete tumor regression in 71% (LPS) and 50% (ZymA) of animals. GM-CSF showed no anti-tumor effects in this study. Combinations of IT LPS and EBRT appeared to have a synergistic effect in delaying tumor growth. Rechallenge studies and IT LPS treatment of RG-2 tumors in nude rats suggested the importance of T cells in this treatment paradigm.


CONCLUSIONS
Direct IT treatment with the TLR ligands LPS and ZymA are effective in generating an anti-tumor response. These treatments may synergize with cytotoxic therapies such as EBRT, and appear to require T cells for a successful outcome.
Mariani
Christopher L
CL
Department of Neuroscience, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL, USA. clmarian@ncsu.edu
Rajon
Didier
D
Bova
Francis J
FJ
Streit
Wolfgang J
WJ
D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D001932:Brain Neoplasms / Q000276:immunology / Q000401:mortality / Q000532:radiotherapy / Q000628:therapy*; D003131:Combined Modality Therapy; D003713:Dendritic Cells / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005910:Glioma / Q000276:immunology / Q000401:mortality / Q000532:radiotherapy / Q000628:therapy*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage* / Q000276:immunology; D007167:Immunotherapy / Q000379:methods*; D015552:Injections, Intralesional; D007279:Injections, Subcutaneous; D008070:Lipopolysaccharides / Q000008:administration & dosage* / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D008297:Male; D009374:Neoplasms, Experimental; D051381:Rats; D011916:Rats, Inbred F344; D011923:Rats, Nude; D040521:Subcutaneous Tissue / Q000473:pathology; D016019:Survival Analysis; D016896:Treatment Outcome; D015054:Zymosan / Q000008:administration & dosage* / Q000276:immunology
D000276:Adjuvants, Immunologic; D008070:Lipopolysaccharides; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D015054:Zymosan