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in Response to Bacillus Calmette-Guérin1
*
Division of Urology, Beth Israel Deaconess Medical Center, Boston, MA 02215;
Genetics Institute, Inc., Cambridge, MA 02140; and
Division Hematology and Oncology, Arthur G. James Cancer Hospital, Columbus, OH 43210
Although Mycobacterium bovis bacillus
Calmette-Guérin (BCG) has been accepted as the most effective
agent in clinical use against superficial bladder cancer, its mechanism
of action remains incompletely understood. A kinetic analysis in
assessing the potential role of cytokines from BCG-stimulated murine
splenocytes showed that IL-12 expression preceded that of other
cytokines. Experiments subtracting endogenous BCG-driven IL-12 using
neutralizing Ab or augmenting its activity with supplemental rIL-12
revealed not only that IL-12 plays a dominant role in IFN-
induction
but also that it is normally dose limiting. A striking increase in
IFN- production could be generated in both mouse and human
immunocompetent cell culture by the addition of even a small amount of
rIL-12. Moreover, this same synergistic effect could be replicated
during in vivo administration of BCG plus rIL-12 into the mouse bladder
and was observed in a patient receiving intravesical combination
therapy. In costimulation cultures, this synergy appeared to partially
rely on IL-18 and IL-2 and could be down-regulated by IL-10. This
suggests that a dynamic interplay between Th1 and Th2 cytokines is
responsible for net IFN- production. The ability of supplemental
exogenous IL-12 to strongly shift this balance toward Th1 provides an
immunological basis for using it in conjunction with intravesical BCG
for bladder cancer immunotherapy.
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