ADENOVIRUS-MEDIATED EXPRESSION OF MELANOMA ANTIGEN GP75 AS IMMUNOTHERAPY FOR METASTATIC MELANOMA

Citation
Ea. Hirschowitz et al., ADENOVIRUS-MEDIATED EXPRESSION OF MELANOMA ANTIGEN GP75 AS IMMUNOTHERAPY FOR METASTATIC MELANOMA, Gene therapy, 5(7), 1998, pp. 975-983
Citations number
82
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Biothechnology & Applied Migrobiology","Genetics & Heredity",Biology,"Medicine, Research & Experimental","Pharmacology & Pharmacy
Journal title
ISSN journal
0969-7128
Volume
5
Issue
7
Year of publication
1998
Pages
975 - 983
Database
ISI
SICI code
0969-7128(1998)5:7<975:AEOMAG>2.0.ZU;2-Y
Abstract
Melanocyte differentiation antigens, such as the brown locus protein g p75, are potential biological targets for immunotherapy. We investigat ed whether expression of the murine gp75 cDNA mediated by an adenoviru s (Ad) vector could induce melanoma rejection using this model self an tigen that usually induces tolerance, and whether Ad vector-directed p roduction of interleukin-2 (IL-2) might augment this response. To eval uate this approach, Ad vectors were constructed containing the murine gp75 cDNA (Ad.gp75) and the human IL2 cDNA (Ad.IL2). Efficacy was eval uated in C57BI/6 mice challenged i.v. with 10(5) B16 cells, using the number of lung metastases as the efficacy parameters. Naive control mi ce developed 175 +/- 12 metastases by day 14. Controls receiving intra nasal Ad.IL2 1 day after B16 cell injection, intraperitoneal (i.p.) mi tocycin-C-treated B16 cells +/- i.p. Ad.IL2 before B16 cell challenge and Ad.beta gal-treated mice had similar number of metastases as contr ols (P > 0.1). In marked contrast, preimmunization with intradermal Ad .gp75 provided dramatic. reduction in the number of lung metastases (5 2 +/- 7, 29% : of control). Addition of regional (intranasal delivery to the lung) Ad.IL2 to intradermal Ad.gp75 preimmunization 1 day follo wing tumor challenge provided further protection (18 +/- 6, 10% of con trol). Depletion of CD4(+) and CD8(+) T- cell subsets:effectively bloc ked the protective effect seen following immunization. Adoptive transf er;:of macrophage-depleted splenocytes from Ad.gp75-immunized mice sim ilarly afforded significant protection against B16 tumor cell challeng e. Further serum, obtained 21 days following Ad.gp75 immunization show ed no detectable: anti-gp75 antibody by immunoprecipitation. These-res ults suggest that immunization with Ad.gp75 induces cellular immune re sponses that are capable of reflecting B16 melanoma in a host that is usually tolerant to gp75 antigen.