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2B Enhances Th1 Cytokine Responses in Bladder Cancer Patients Receiving Mycobacterium bovis Bacillus Calmette-Guérin Immunotherapy1
Division of Urology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215
Combination therapy with intravesical bacillus
Calmette-Guérin (BCG) plus IFN-
for superficial bladder cancer
has been demonstrated to be more effective than either single agent
alone in animal studies and of suggested greater efficacy in clinical
studies. However, the mechanism by which IFN- enhances BCG-mediated
antitumor activity is poorly understood. Using PBMCs from bladder
cancer patients, IFN- was found to substantially enhance the
efficacy of BCG to induce IFN-
production. Among 34 patients tested,
80% showed >4-fold increase. This effect of IFN- was observed in
both initial and memory responses to BCG. In addition, IFN-
up-regulated BCG-induced IL-12 and TNF- and down-regulated
BCG-induced IL-10. Neutralizing endogenous IL-10 or adding exogenous
IL-12 provided further synergy for IFN- production. In clinical
practice, intravesical IFN- 2B (50 million units (MU)/dose) was
observed to accelerate urinary IFN- production to low-dose BCG
(one-tenth or one-third of a full dose) in patients treated with
combination therapy compared with BCG alone. These results suggest that
IFN- is a potent BCG enhancer that polarizes the BCG-induced immune
response toward the cellular immune pathway by promoting Th1 cytokine
expression and reducing Th2 cytokine expression. This study provides an
immunological basis for future rational use of IFN- in conjunction
with intravesical BCG for bladder cancer
immunotherapy.
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