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

Xinmei Zhu¹^,4 , Fumihiko Nishimura¹^,4 , Kotaro Sasaki³ , Mitsugu Fujita¹^,4 , Jill E Dusak¹^,4 , Junichi Eguchi¹^,4 , Wendy Fellows-Mayle¹ , Walter J Storkus³ , Paul R Walker⁵ , Andres M Salazar⁶ and Hideho Okada¹^,2^,4

¹Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, USA

²Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, USA

³Departments of Dermatology and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, USA

⁴Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, USA

⁵Division of Oncology, Geneva University Hospital, Geneva, Switzerland

⁶Oncovir Inc., Washington D.C., USA

author email corresponding author email

Journal of Translational Medicine 2007, 5:10doi:10.1186/1479-5876-5-10


Published:	12 February 2007

Abstract

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-γ by CNS tumor-infiltrating CTLs, and improved the survival of tumor bearing mice in the absence of detectable autoimmunity.

Conclusion

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.