Combination immunotherapy of B16 melanoma using anti–cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) and granulocyte/macrophage colony-stimulating …

A Van Elsas, AA Hurwitz, JP Allison - The Journal of experimental …, 1999 - rupress.org
A Van Elsas, AA Hurwitz, JP Allison
The Journal of experimental medicine, 1999rupress.org
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 …
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.
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