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PMID: 17295916 Published · epublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Toll like receptor-3 ligand poly-ICLC promotes the efficacy of peripheral vaccinations with tumor antigen-derived peptide epitopes in murine CNS tumor models.

Journal of translational medicine ·Vol. 5 ·2007-02-12 ·Pages 10

Zhu X, Nishimura F, Sasaki K, Fujita M, Dusak JE, Eguchi J, Fellows-Mayle W, Storkus WJ, Walker PR, Salazar AM, Okada H

Abstract

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. 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. 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. 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.

MeSH Terms
Animals Antigens, Neoplasm/immunology Cancer Vaccines/immunology Carboxymethylcellulose Sodium/administration & dosage,analogs & derivatives,pharmacology Cell Line, Tumor Combined Modality Therapy Disease Models, Animal Encephalomyelitis, Autoimmune, Experimental/immunology Ephrin-A2/immunology Epitopes/immunology Glioma/immunology,prevention & control,therapy Humans Injections, Intramuscular Integrin alpha4beta1/immunology Ligands Lymphocytes, Tumor-Infiltrating/drug effects,immunology Mice Mice, Inbred C57BL Ovalbumin/immunology Peptides/immunology Poly I-C/administration & dosage,pharmacology Polylysine/administration & dosage,analogs & derivatives,pharmacology Staining and Labeling T-Lymphocytes, Cytotoxic/immunology Toll-Like Receptor 3/immunology Treatment Outcome Up-Regulation/drug effects Vaccination
Chemicals
Antigens, Neoplasm Cancer Vaccines Ephrin-A2 Epitopes Integrin alpha4beta1 Ligands Peptides Toll-Like Receptor 3 Polylysine poly ICLC Ovalbumin Carboxymethylcellulose Sodium Poly I-C
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Zhu Xinmei
Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, USA. [email protected]
Nishimura Fumihiko
Sasaki Kotaro
Fujita Mitsugu
Dusak Jill E
Eguchi Junichi
Fellows-Mayle Wendy
Storkus Walter J
Walker Paul R
Salazar Andres M
Okada Hideho
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Article Info
Journal
Journal of translational medicine
Abbr.
J Transl Med
ISSN
1479-5876
DOI
10.1186/1479-5876-5-10
Email
[email protected]
Published
2007-02-12
Epub
2007-00-12
Pages
10
Language
English
Region
England
NLM ID
101190741
PMCID
PMC1802742
Subset
IM
Grants
NCI NIH HHS · P01 CA100327 · United States
NINDS NIH HHS · P01 NS040923 · United States
NCATS NIH HHS · UL1 TR000005 · United States
NINDS NIH HHS · P01 NS40923 · United States
External Links
PubMed source DOI: 10.1186/1479-5876-5-10 PMC Full Text View journal details
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