The Journal of Experimental Medicine
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J. Exp. Med., Volume 190, Number 3, August 2, 1999 355-366
Copyright © 1999 by The Rockefeller University Press.

Combination Immunotherapy of B16 Melanoma Using Anti–Cytotoxic T Lymphocyte–associated Antigen 4 (CTLA-4) and Granulocyte/Macrophage Colony-Stimulating Factor (GM-CSF)-producing Vaccines Induces Rejection of Subcutaneous and Metastatic Tumors Accompanied by Autoimmune Depigmentation

Andrea van Elsasa, Arthur A. Hurwitza, and James P. Allisona
a From the Howard Hughes Medical Institute, Cancer Research Laboratory and Department of Molecular and Cellular Biology, University of California, Berkeley, California 94720-3200

Correspondence to: James P. Allison, 401 LSA, University of California, Berkeley, CA 94720-3200., jallison{at}uclink4.berkeley.edu (E-mail), 510-643-6012 (phone), 510-643-5692 (fax)

We examined the effectiveness of cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) blockade, alone or in combination with a granulocyte/macrophage colony-stimulating factor (GM-CSF)–expressing tumor cell vaccine, on rejection of the highly tumorigenic, poorly immunogenic murine melanoma B16-BL6. Recently established tumors could be eradicated in 80% (68/85) of the cases using combination treatment, whereas each treatment by itself showed little or no effect. Tumor rejection was dependent on CD8+ and NK1.1+ cells but occurred irrespective of the presence of CD4+ T cells. Mice surviving a primary challenge rejected a secondary challenge with B16-BL6 or the parental B16-F0 line. The same treatment regimen was found to be therapeutically effective against outgrowth of preestablished B16-F10 lung metastases, inducing long-term survival. Of all mice surviving B16-BL6 or B16-F10 tumors after combination treatment, 56% (38/68) developed depigmentation, starting at the site of vaccination or challenge and in most cases progressing to distant locations. Depigmentation was found to occur in CD4-depleted mice, strongly suggesting that the effect was mediated by CTLs. This study shows that CTLA-4 blockade provides a powerful tool to enhance T cell activation and memory against a poorly immunogenic spontaneous murine tumor and that this may involve recruitment of autoreactive T cells.

Key Words: CTLA-4, immunotherapy, autoimmunity, vitiligo, melanoma


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