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Clinical Trial
. 2003 Aug 1;9(8):2973-80.

Recombinant fowlpox viruses encoding the anchor-modified gp100 melanoma antigen can generate antitumor immune responses in patients with metastatic melanoma

Steven A Rosenberg  1 , James C Yang, Douglas J Schwartzentruber, Patrick Hwu, Suzanne L Topalian, Richard M Sherry, Nicholas P Restifo, John R Wunderlich, Claudia A Seipp, Linda Rogers-Freezer, Kathleen E Morton, Sharon A Mavroukakis, Linda Gritz, Dennis L Panicali, Donald E White
Affiliations
Clinical Trial

Recombinant fowlpox viruses encoding the anchor-modified gp100 melanoma antigen can generate antitumor immune responses in patients with metastatic melanoma

Steven A Rosenberg et al. Clin Cancer Res. .

Abstract

Purpose: The purpose of this study was to evaluate the immunological responses and therapeutic effectiveness of immunization with fowlpox vaccines encoding the gp100 melanoma antigen in patients with metastatic melanoma.

Experimental design: In three consecutive clinical trials, patients were immunized with recombinant fowlpox viruses encoding three different forms of the melanoma/melanocyte-associated antigen gp100: (a) the native, full-length gp100 molecule; (b) the gp100 molecule with two amino acids modified to increase binding to HLA-A*0201 molecules; and (c) a "minigene" construct encoding a single, modified epitope gp100:209-217(210M) targeted to the endoplasmic reticulum. The immunogenicity of these constructs was studied using peripheral blood mononuclear cells to measure epitope-specific release of IFN-gamma.

Results: Reactivity against gp100 was not seen in any patient before receiving fowlpox immunization. Whereas just one of seven patients developed reactivity after receiving fowlpox encoding native gp100, 10 of 14 patients who received fowlpox encoding the anchor modified full-length gp100 exhibited reactivity against the native gp100 molecule, and 12 of 16 patients were successfully immunized after inoculation with the modified minigene construct (p2 = 0.02). There was no difference in the latter group between those randomized to vaccination by i.v. or i.m. routes. There was one partial cancer regression in the group of 46 patients receiving virus in the absence of interleukin (IL)-2. Once patients showed evidence of progressive disease, they were eligible for "cross-over" treatment to IL-2 alone or with the fowlpox virus. None of the 13 patients receiving the full-length or modified full-length forms of gp100 responded when receiving IL-2, whereas 6 of 12 patients who received the fowlpox containing the minigene construct and then received IL-2 showed objective cancer regressions, including three patients with complete regression.

Conclusions: These data underscore the importance of modifying anchor residues of nonmutated self-antigen peptides to generate cellular immune responses after immunization and support the further investigation of recombinant fowlpox viruses encoding modified epitopes administered in combination with IL-2.

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Figures

Fig. 1
Fig. 1
Antifowlpox antibody titers in patients receiving immunization with recombinant fowlpox virus encoding gp100.
See this image and copyright information in PMC

References

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    1. Rosenberg SA, editor. Principles and Practice of the Biologic Therapy of Cancer. Philadelphia: Lippincott Williams & Wilkins; 2000.
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    1. Rosenberg SA, Yang JC, Schwartzentruber DJ, Hwu P, Marincola FM, Topalian SL, Restifo NP, Dudley ME, Schwarz SL, Spiess PJ, Wunderlich JR, Parkhurst MR, Kawakami Y, Seipp CA, Einhorn JH, White DE. Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma. Nat. Med. 1998;4:321–327. - PMC - PubMed

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