© 1997 by Oxford University Press
Journal Of The National Cancer Institute, Vol 89, 428-436, Copyright © 1997 by Oxford University Press
M Kawakita, GS Rao, JK Ritchey, DK Ornstein, MA Hudson, J Tartaglia, E Paoletti, PA Humphrey, TJ Harmon and TL Ratliff
BACKGROUND: Canarypox virus, ALVAC, does not replicate in infected
mammalian cells and has potential as a vector for gene therapy in the
treatment of cancer. PURPOSE: Recombinant viruses carrying DNA sequences
encoding interleukin 2 (ALVAC-IL-2), interferon gamma (ALVAC- IFN gamma),
tumor necrosis factor-alpha (ALVAC-TNF-alpha), or the co- stimulatory
molecule B7-1 (ALVAC-B7-1) were investigated as agents for the treatment of
a newly defined mouse prostate tumor model. METHODS: RM-1 mouse prostate
cancer cells, which are syngeneic (i.e., same genetic background) to
C57BL/6 mice, were used. The expression of foreign gene products in vitro
in infected RM-1 cells was measured by immunoprecipitation, bioassay, or
flow cytometry. The effects of foreign gene product expression on RM-1
tumor cell growth in C57BL/6 mice were measured after subcutaneous
injection (in the back) of 5 x 10(5) uninfected or infected cells;
measurements included determinations of time to a measurable tumor size,
tumor size as a function of time, and survival. The induction of protective
immunity by uninfected and infected RM-1 cells was tested by injection of
lethally irradiated (70 Gy) cells and subsequent challenge with uninfected
cells. The generation of cytotoxic T cells was monitored by use of a 51Cr
release assay. Severe combined immunodeficient (SCID) mice were used to
determine whether T or B lymphocytes were involved in ALVAC vector-mediated
antitumor responses. Data were analyzed by use of Pearson's modification of
the chi-squared test and Kaplan-Meier survival methods. Reported P values
are two-sided. RESULTS: The level of foreign gene product expression in
ALVAC-infected RM-1 cells was dependent on the multiplicity of virus
infection used; a multiplicity of five viruses per infected cell was chosen
for subsequent experiments. RM-1 tumor growth in C57BL/6 mice was not
affected by tumor cell expression of IL-2 alone, IFN gamma alone, or B7-1
alone; however, expression of TNF-alpha alone significantly delayed tumor
growth at early time points (compared with parental ALVAC-infected tumors,
P = .0001 at day 21 and P = .037 at day 28). Tumor cell expression of both
TNF-alpha and IL-2 completely inhibited tumor growth in 60%-100% of treated
mice. No protection against subsequent tumor challenge was detected in mice
previously exposed to RM-1 cells expressing both TNF-alpha and IL-2.
Cytotoxic T-lymphocyte activity toward RM-1 cells was not observed in
C57BL/6 mice that rejected tumors. Tumor cell expression of TNF-alpha and
IL-2 also resulted in tumor growth inhibition in SCID mice. CONCLUSIONS:
RM-1 mouse prostate cancer cells are readily infected by ALVAC vectors, and
foreign gene products are efficiently expressed. Inhibition of RM-1 tumor
growth by tumor cell expression of TNF-alpha and IL-2 appears to involve
nonspecific antitumor activity.
ARTICLES
Effect of canarypox virus (ALVAC)-mediated cytokine expression on murine prostate tumor growth
Division of Urologic Surgery, Washington University School of Medicine, St. Louis, MO, USA.
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