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[Cancer Research 60, 2444-2448, May 1, 2000]
© 2000 American Association for Cancer Research

Immunology

Combination Immunotherapy of Primary Prostate Cancer in a Transgenic Mouse Model Using CTLA-4 Blockade1

Arthur A. Hurwitz2, Barbara A. Foster, Eugene D. Kwon, Tan Truong, Eugene M. Choi, Norman M. Greenberg, Maurice B. Burg and James P. Allison3

Cancer Research Laboratory [A. A. H., T. T., E. M. C., J. P. A.] and Howard Hughes Medical Institute [T. T., E. M. C., J. P. A.], University of California, Berkeley, California 94720; Department of Cell Biology, Baylor College of Medicine, Houston, Texas 77027 [B. A. F., N. M. G.]; Department of Urology and Cardinal Bernardin Cancer Center, Loyola University School of Medicine, Maywood, Illinois 60153 [E. D. K.]; and Laboratory of Kidney and Electrolyte Metabolism, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892 [E. D. K., M. B. B.]

We have previously shown that antibodies to CTLA-4, an inhibitory receptor on T cells, can be effective at inducing regression of transplantable murine tumors. In this study, we demonstrate that an effective immune response against primary prostate tumors in transgenic (TRAMP) mice can be elicited using a strategy that combines CTLA-4 blockade and an irradiated tumor cell vaccine. Treatment of TRAMP mice at 14 weeks of age resulted in a significant reduction in tumor incidence (15% versus control, 75%), as assessed 2 months after treatment. Histopathological analysis revealed that treated mice had a lower tumor grade with significant accumulation of inflammatory cells in interductal spaces when treated with anti-CTLA-4 and a granulocyte-macrophage colony-stimulating factor-expressing vaccine. Vaccination of nontransgenic mice with this regimen resulted in marked prostatitis accompanied by destruction of epithelium, indicating that the immune response was, at least in part, directed against normal prostate antigens. These findings demonstrate that this combinatorial treatment can elicit a potent antiprostate response and suggest potential of this approach for treatment of prostate cancer.




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