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Novel Kidney Cancer Immunotherapy Based on the Granulocyte- Macrophage Colony-stimulating Factor and Carbonic Anhydrase IX Fusion Gene

Departments of Urology [J. M. H., M. H. T. B., K-r. H., H. M., D. G. F., D. N., R. C., S. H. P., C-L. T., A. S. B.], Medicine [R. A. F.], and Pathology [P. I. S.], University of California, Los Angeles, California

Purpose: We investigated the ability of the fusion protein granulocyte-macrophage colony-stimulating factor and carbonic anhydrase IX (GMCA-9)¹ to induce an immune response in vitro and in vivo for the development of a GMCA-9-based kidney cancer vaccine.

Experimental design: Human dendritic cells (DCs) were transduced with a recombinant adenovirus containing the GMCA-9 gene and tested for their capacity to induce CA9-specific cytotoxic T lymphocytes in vitro. Tumor growth was studied in severe compromised immunodeficiency disease (SCID) mice s.c. injected with R11-GMCA-9, a human renal cell carcinoma cell line stably transfected with the GMCA-9 gene. Involvement of natural killer (NK) cells in the antitumor activity of GMCA-9 was determined in SCID mice treated with the NK-blocking agent anti-asialoGM-1.

Results: DC and R11 cells transduced with GMCA-9 produced a GMCA-9 protein that is targeted to the cell membrane and partially processed to granulocyte macrophage colony-stimulating factor- and CA9-like products. Furthermore, GMCA-9 was capable of inducing DC maturation, as well as CA9-specific cytotoxic lymphocytes in vitro. Tumor growth of R11 cells in SCID mice was significantly inhibited after transfection with the GMCA-9 fusion gene (P < 0.01). In mice treated with anti-asialoGM-1, R11-GMCA-9 tumors grew significantly faster than those of control mice (P < 0.05), suggesting an involvement of NK cells.

Conclusions: Our results suggest that the fusion protein GMCA-9 is capable of generating an immune response both in vitro and in vivo. Additional studies will confirm the utility of ex vivo GMCA-9-transduced DCs as a kidney cancer vaccine.

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