Adenovirus-mediated expression of melanoma antigen gp75 as immunotherapy for metastatic melanoma

E. A. Hirschowitz, S. Leonard, W. Song, B. Ferris, P. L. Leopold, J. J. Lewis, W. B. Bowne, S. Wang, A. N. Houghton, Ronald Crystal

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Melanocyte differentiation antigens, such as the brown locus protein gp75, are potential biological targets for immunotherapy. We investigated whether expression of the murine gp75 cDNA mediated by an adenovirus (Ad) vector could induce melanoma rejection using this model self antigen that usually induces tolerance, and whether Ad vector-directed production of interleukin-2 (IL2) might augment this response. To evaluate this approach, Ad vectors were constructed containing the murine gp75 cDNA (Ad.gp75) and the human IL2 cDNA (Ad.IL2). Efficacy was evaluated in C57Bl/6 mice challenged i.v. with 105 B16 cells, using the number of lung metastases as the efficacy parameter. Naive control mice developed 175 ± 12 metastases by day 14. Controls receiving intranasal Ad.IL2 1 day after B16 cell injection, intraperitoneal (i.p.) mitomycin-C-treated B16 cells ± i.p. Ad.IL2 before B16 cell challenge and Ad.βgal-treated mice had similar numbers of metastases as controls (P > 0.1). In marked contrast, preimmunization with intradermal Ad.gp75 provided dramatic reduction in the number of lung metastases (52 ± 7, 29% of control). Addition of regional (intranasal delivery to the lung) Ad.IL2 to intradermal Ad.gp75 preiminunization 1 day following tumor challenge provided further protection (18 ± 6, 10% of control). Depletion of CD4+ and CD8+ T-cell subsets effectively blocked the protective effect seen following immunization. Adoptive transfer of macrophage-depleted splenocytes from Ad.gp75-immunized mice similarly afforded significant protection against B16 tumor cell challenge. Further, serum obtained 21 days following Ad.gp75 immunization showed no detectable anti-gp75 antibody by immunoprecipitation. These results suggest that immunization with Ad.gp75 induces cellular immune responses that are capable of rejecting B16 melanoma in a host that is usually tolerant to gp75 antigen.

Original languageEnglish
Pages (from-to)975-983
Number of pages9
JournalGene Therapy
Volume5
Issue number7
Publication statusPublished - 24 Aug 1998
Externally publishedYes

Fingerprint

Melanoma-Specific Antigens
Adenoviridae
Immunotherapy
Melanoma
Interleukin-2
Neoplasm Metastasis
Immunization
Complementary DNA
Lung
Human Adenoviruses
Experimental Melanomas
Adoptive Transfer
Melanocytes
Differentiation Antigens
Autoantigens
T-Lymphocyte Subsets
Mitomycin
Intraperitoneal Injections
Interleukin-1
Immunoprecipitation

Keywords

  • Adenovirus
  • Antigen
  • gp75
  • IL2
  • Melanoma
  • Vaccine

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

Hirschowitz, E. A., Leonard, S., Song, W., Ferris, B., Leopold, P. L., Lewis, J. J., ... Crystal, R. (1998). Adenovirus-mediated expression of melanoma antigen gp75 as immunotherapy for metastatic melanoma. Gene Therapy, 5(7), 975-983.

Adenovirus-mediated expression of melanoma antigen gp75 as immunotherapy for metastatic melanoma. / Hirschowitz, E. A.; Leonard, S.; Song, W.; Ferris, B.; Leopold, P. L.; Lewis, J. J.; Bowne, W. B.; Wang, S.; Houghton, A. N.; Crystal, Ronald.

In: Gene Therapy, Vol. 5, No. 7, 24.08.1998, p. 975-983.

Research output: Contribution to journalArticle

Hirschowitz, EA, Leonard, S, Song, W, Ferris, B, Leopold, PL, Lewis, JJ, Bowne, WB, Wang, S, Houghton, AN & Crystal, R 1998, 'Adenovirus-mediated expression of melanoma antigen gp75 as immunotherapy for metastatic melanoma', Gene Therapy, vol. 5, no. 7, pp. 975-983.
Hirschowitz EA, Leonard S, Song W, Ferris B, Leopold PL, Lewis JJ et al. Adenovirus-mediated expression of melanoma antigen gp75 as immunotherapy for metastatic melanoma. Gene Therapy. 1998 Aug 24;5(7):975-983.
Hirschowitz, E. A. ; Leonard, S. ; Song, W. ; Ferris, B. ; Leopold, P. L. ; Lewis, J. J. ; Bowne, W. B. ; Wang, S. ; Houghton, A. N. ; Crystal, Ronald. / Adenovirus-mediated expression of melanoma antigen gp75 as immunotherapy for metastatic melanoma. In: Gene Therapy. 1998 ; Vol. 5, No. 7. pp. 975-983.
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abstract = "Melanocyte differentiation antigens, such as the brown locus protein gp75, are potential biological targets for immunotherapy. We investigated whether expression of the murine gp75 cDNA mediated by an adenovirus (Ad) vector could induce melanoma rejection using this model self antigen that usually induces tolerance, and whether Ad vector-directed production of interleukin-2 (IL2) might augment this response. To evaluate this approach, Ad vectors were constructed containing the murine gp75 cDNA (Ad.gp75) and the human IL2 cDNA (Ad.IL2). Efficacy was evaluated in C57Bl/6 mice challenged i.v. with 105 B16 cells, using the number of lung metastases as the efficacy parameter. Naive control mice developed 175 ± 12 metastases by day 14. Controls receiving intranasal Ad.IL2 1 day after B16 cell injection, intraperitoneal (i.p.) mitomycin-C-treated B16 cells ± i.p. Ad.IL2 before B16 cell challenge and Ad.βgal-treated mice had similar numbers of metastases as controls (P > 0.1). In marked contrast, preimmunization with intradermal Ad.gp75 provided dramatic reduction in the number of lung metastases (52 ± 7, 29{\%} of control). Addition of regional (intranasal delivery to the lung) Ad.IL2 to intradermal Ad.gp75 preiminunization 1 day following tumor challenge provided further protection (18 ± 6, 10{\%} of control). Depletion of CD4+ and CD8+ T-cell subsets effectively blocked the protective effect seen following immunization. Adoptive transfer of macrophage-depleted splenocytes from Ad.gp75-immunized mice similarly afforded significant protection against B16 tumor cell challenge. Further, serum obtained 21 days following Ad.gp75 immunization showed no detectable anti-gp75 antibody by immunoprecipitation. These results suggest that immunization with Ad.gp75 induces cellular immune responses that are capable of rejecting B16 melanoma in a host that is usually tolerant to gp75 antigen.",
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