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Amplification of Virus-Induced Antimelanoma T-Cell Reactivity by High-Dose Interferon-2b

Implications for Cancer Vaccines

Division of Molecular and Cellular Biology, Research Institute, [I. A., C. H., D. E. S.] and Department of Radiology [P. H.], Sunnybrook and Women’s College Health Sciences Center; Cancer Vaccine Program, Aventis-Pasteur [E. U. B., M. d. B., R. U., N. B., I. E.]; Toronto-Sunnybrook Regional Cancer Center [T. P., G. L., N. B., N. I., D. E. S.]; and Department of Medicine, University of Toronto [T. P., N. B., N. I., D. E. S.], Toronto, Quebec, M4N 3M5 Canada

Purpose: The therapeutic effectiveness of cancer vaccines, composed of tumor antigens that are also self-antigens, may be limited by the normal mechanisms that preserve immunological tolerance. Consistent with this notion, we found that vaccination of melanoma patients with recombinant viral vaccines expressing gp100 (a melanoma antigen also expressed by normal melanocytes) produced only transient increases in noncytotoxic T cells specific for immunodominant gp100 epitopes. To improve the therapeutic effects of these vaccines, IFN-2b (IFN-) was administered to some high-risk patients.

Experimental Design: 7 HLA-A*0201⁺ patients were injected with high doses of IFN- (20 MU/m² x 20 doses) at various times after completing the vaccination protocol. Clinical toxicity and responses were documented, and the effects on gp100-reactive T cells were measured by IFN- enzyme-linked immunospot assays, tetramers of HLA-A*0201 and gp100 epitopes, and cellular cytotoxicity assays.

Results: In patients who had previously responded to vaccination, high doses of IFN- recalled gp100-reactive T cells with the ability to kill gp100-expressing tumor targets in vitro. Concomitant with the reappearance of these cytotoxic T cells, tumor regression was observed in the two patients with clinically evident metastatic disease.

Conclusions: The finding that high-dose IFN recalls previously activated tumor-reactive T cells with potent killing ability suggests a strategy to maintain antitumor responses initiated by cancer vaccines.

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