Toll like receptor-3 ligand poly-ICLC promotes the efficacy of peripheral vaccinations with tumor antigen-derived peptide epitopes in murine CNS tumor models.
BACKGROUND
Toll-like receptor (TLR)3 ligands serve as natural inducers of pro-inflammatory cytokines capable of promoting Type-1 adaptive immunity, and TLR3 is abundantly expressed by cells within the central nervous system (CNS). To improve the efficacy of vaccine strategies directed against CNS tumors, we evaluated whether administration of a TLR3 ligand, polyinosinic-polycytidylic (poly-IC) stabilized with poly-lysine and carboxymethylcellulose (poly-ICLC) would enhance the anti-CNS tumor effectiveness of tumor peptide-based vaccinations.


METHODS
C57BL/6 mice bearing syngeneic CNS GL261 glioma or M05 melanoma received subcutaneous (s.c.) vaccinations with synthetic peptides encoding CTL epitopes--mEphA2 (671-679), hgp100 (25-33) and mTRP-2 (180-188) for GL261, or ovalbumin (OVA: 257-264) for M05. The mice also received intramuscular (i.m.) injections with poly-ICLC.


RESULTS
The combination of subcutaneous (s.c.) peptide-based vaccination and i.m. poly-ICLC administration promoted systemic induction of antigen (Ag)-specific Type-1 CTLs expressing very late activation antigen (VLA)-4, which confers efficient CNS-tumor homing of vaccine-induced CTLs based on experiments with monoclonal antibody (mAb)-mediated blockade of VLA-4. In addition, the combination treatment allowed expression of IFN-gamma by CNS tumor-infiltrating CTLs, and improved the survival of tumor bearing mice in the absence of detectable autoimmunity.


CONCLUSIONS
These data suggest that poly-ICLC, which has been previously evaluated in clinical trials, can be effectively combined with tumor Ag-specific vaccine strategies, thereby providing a greater index of therapeutic efficacy.
Zhu
Xinmei
X
Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, USA. zhux3@upmc.edu
Nishimura
Fumihiko
F
Sasaki
Kotaro
K
Fujita
Mitsugu
M
Dusak
Jill E
JE
Eguchi
Junichi
J
Fellows-Mayle
Wendy
W
Storkus
Walter J
WJ
Walker
Paul R
PR
Salazar
Andres M
AM
Okada
Hideho
H
D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology; D002266:Carboxymethylcellulose Sodium / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology; D036383:Ephrin-A2 / Q000276:immunology; D000939:Epitopes / Q000276:immunology*; D005910:Glioma / Q000276:immunology / Q000517:prevention & control* / Q000628:therapy; D006801:Humans; D007273:Injections, Intramuscular; D039041:Integrin alpha4beta1 / Q000276:immunology; D008024:Ligands; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000276:immunology; D010455:Peptides / Q000276:immunology*; D011070:Poly I-C / Q000008:administration & dosage / Q000494:pharmacology*; D011107:Polylysine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D013194:Staining and Labeling; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D051196:Toll-Like Receptor 3 / Q000276:immunology*; D016896:Treatment Outcome; D015854:Up-Regulation / Q000187:drug effects; D014611:Vaccination
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D036383:Ephrin-A2; D000939:Epitopes; D039041:Integrin alpha4beta1; D008024:Ligands; D010455:Peptides; D051196:Toll-Like Receptor 3; D011107:Polylysine; C019531:poly ICLC; D010047:Ovalbumin; D002266:Carboxymethylcellulose Sodium; D011070:Poly I-C