Enhanced interleukin-2 gene transfer immunotherapy of breast cancer by coexpression of B7-1 and B7-2.
The capability of B7-1 to augment the antitumor activity of some cytokines has been shown primarily for such cytokines as interleukin-12 (IL-12), IL-7, and to a lesser extent IL-2. In this study, we investigate the ability of B7-1 and B7-2 to augment the antitumor activity of IL-2. Considering the affinity of both molecules for CD28 (T cell receptor for B7-1 and B7-2), we postulated that their potential to augment IL-2 antitumor activity would be similar. Two murine transgenic adenocarcinoma models were chosen to investigate the activity of adenoviral vectors constructed to express either B7-1 and IL-2 or B7-2 and IL-2. Before administering the vector intratumorally to tumor-bearing mice, we determined the expression of B7-1, B7-2, MHC I, and MHC II on these tumor cells and demonstrated positive expression of only MHC I. Intratumoral injection of the vector expressing B7-1 and IL-2 resulted in complete regression of all tumors treated. In contrast, the vector expressing B7-2 and IL-2 was significantly less effective at regressing PyMT tumors, whereas both double recombinant vectors demonstrated similar levels of complete regression in the Neu (NDL 8142) model. Regressed mice were all protected for rechallenge in both models and demonstrated antigen-specific cytotoxic T lymphocytes (CTL) in the PyMT model. These findings indicate that the combination of IL-2 with B7-1 or B7-2 significantly enhances the antitumor activity of IL-2.
Emtage
P C
PC
Department of Pathology, McMaster University, Hamilton, Ontario, Canada.
Wan
Y
Y
Muller
W
W
Graham
F L
FL
Gauldie
J
J
D000230:Adenocarcinoma / Q000276:immunology / Q000628:therapy*; D000256:Adenoviridae / Q000235:genetics; D000276:Adjuvants, Immunologic / Q000235:genetics*; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D018122:B7-1 Antigen / Q000096:biosynthesis; D051940:B7-2 Antigen; D002461:Cell Line, Transformed; D004274:DNA, Recombinant / Q000235:genetics; D005260:Female; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D007167:Immunotherapy / Q000379:methods*; D007376:Interleukin-2 / Q000235:genetics*; D008175:Lung Neoplasms / Q000276:immunology / Q000556:secondary / Q000628:therapy; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000628:therapy*; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D008822:Mice, Transgenic
D000276:Adjuvants, Immunologic; D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; D004274:DNA, Recombinant; D007376:Interleukin-2; D008562:Membrane Glycoproteins