1. ¹Department of Medical Biophysics, University of Toronto, Toronto,Ontario,Canada
2. ²Division of Stem Cell and Developmental Biology, Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada
3. ³Center for Cancer Research, Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Rockville, Maryland, USA
4. ⁴Centre for Gene Therapeutics, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
5. ⁵Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada

Correspondence: Jeffrey A. Medin, University Health Network, 67 College Street, Room 406, Toronto, Ontario M5G 2M1, Canada. E-mail: jmedin@uhnres.utoronto.ca

Received 8 May 2007; Accepted 26 November 2007; Published online 8 January 2008.

Abstract

Gene therapy strategies may accelerate the development of prophylactic immunotherapy against cancer. We synthesized a lentiviral (LV) vector encoding a kinase-deficient form of erbB2 (erbB2tr) to transduce murine dendritic cells (DCs) efficiently. Murine erbB2 models a clinically relevant tumor-associated self-antigen; its human homolog (HER-2/neu) is overexpressed in breast cancer and in 80% of metastatic prostate cancers. Following one infection, 47% of DCs overexpressed erbB2tr. To determine whether low doses of transduced DCs could protect mice from prostate cancer cells, we performed prime/boost vaccinations with 2 10³ or 2 10⁵ erbB2tr-transduced DCs. Six weeks after vaccination, mice were simultaneously bilaterally challenged with the aggressive RM-1 prostate cancer cell line and an erbB2tr-expressing variant (RM-1-erbB2tr). Whereas control mice developed both tumors, all recipients of 2 10⁵ erbB2tr-transduced DCs developed only wild-type RM-1 tumors. One-third of mice vaccinated with just 2 10³ erbB2tr-transduced DCs also demonstrated erbB2tr-specific tumor protection. Protection against RM-1-erbB2tr tumors was associated with sustained levels of anti-erbB2tr antibody production and also correlated with erbB2tr-specific Th1 cytokine secretion. Depletion of CD4⁺, CD8⁺, or natural killer (NK) cells prior to tumor challenge underscored their role in mediating tumor protection. We conclude that administration of DCs expressing a self-antigen through efficient LV-based gene transfer activates cellular and humoral immunity, protecting host animals against specific tumor challenge.