Ea. Hirschowitz et al., ADENOVIRUS-MEDIATED EXPRESSION OF MELANOMA ANTIGEN GP75 AS IMMUNOTHERAPY FOR METASTATIC MELANOMA, Gene therapy, 5(7), 1998, pp. 975-983
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.