Faculty Collaboration Database

Tumor protection following vaccination with low doses of lentivirally transduced DCs expressing the self-antigen erbB2. Mol Ther 2008 Mar;16(3):607-17

Date

01/09/2008

Pubmed ID

18180774

DOI

10.1038/sj.mt.6300390

Scopus ID

2-s2.0-39849098133 (requires institutional sign-in at Scopus site)   22 Citations

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, approximately 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 x 10(3) or 2 x 10(5) 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 x 10(5) erbB2tr-transduced DCs developed only wild-type RM-1 tumors. One-third of mice vaccinated with just 2 x 10(3) 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.

Author List

Mossoba ME, Walia JS, Rasaiah VI, Buxhoeveden N, Head R, Ying C, Foley JE, Bramson JL, Fowler DH, Medin JA

Author

Jeffrey A. Medin PhD Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
CD4-Positive T-Lymphocytes
CD8-Positive T-Lymphocytes
Cancer Vaccines
Cell Line, Tumor
Cytokines
Dendritic Cells
Female
Flow Cytometry
Genetic Therapy
Green Fluorescent Proteins
Immunotherapy, Adoptive
Killer Cells, Natural
Lentivirus
Male
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Prostatic Neoplasms
Receptor, ErbB-2
Recombinant Fusion Proteins
Spleen
Transduction, Genetic
Vaccination