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 language | English |
|---|---|
| Pages (from-to) | 975-983 |
| Number of pages | 9 |
| Journal | Gene Therapy |
| Volume | 5 |
| Issue number | 7 |
| DOIs | |
| State | Published - 1998 |
Bibliographical note
Funding Information:We would like to thank Hassan Naama and Carlo Russo for their helpful discussions, and N Mohamed for help in preparation of the manuscript. These studies were supported, in part, by the National Cancer Institute 1R01CA75192–01; by the Will Rogers Memorial Fund, White Plains, NY; GenVec, Inc., Rockville, MD; and NIH grant CA56821, Swim Across America, The Louis and Anne Abrons Foundation, and the Milstein Family Fund by the National Cancer Institute 1R01CA75192–01.
Funding
We would like to thank Hassan Naama and Carlo Russo for their helpful discussions, and N Mohamed for help in preparation of the manuscript. These studies were supported, in part, by the National Cancer Institute 1R01CA75192–01; by the Will Rogers Memorial Fund, White Plains, NY; GenVec, Inc., Rockville, MD; and NIH grant CA56821, Swim Across America, The Louis and Anne Abrons Foundation, and the Milstein Family Fund by the National Cancer Institute 1R01CA75192–01.
| Funders | Funder number |
|---|---|
| GenVec, Inc. | |
| Milstein Family Fund | |
| GIST Cancer Research Fund and Swim Across America | |
| Will Rogers Memorial Fund | |
| National Institutes of Health (NIH) | |
| National Childhood Cancer Registry – National Cancer Institute | R01CA056821, 1R01CA75192–01 |
| Louis and Anne Abrons Foundation |
Keywords
- Adenovirus
- Antigen
- IL2
- Melanoma
- Vaccine
- gp75
ASJC Scopus subject areas
- Molecular Medicine
- Molecular Biology
- Genetics
