IL-12 is an effective adjuvant to recombinant vaccinia virus-based tumor vaccines: enhancement by simultaneous B7-1 expression.
A number of cytokines and costimulatory molecules involved in immune activation have recently been identified including IL-12, a heterodimeric cytokine that supports the development of cell-mediated immunity, and B7-1, a costimulatory molecule involved in the activation of T lymphocytes. We explored the use of these immunomodulants as molecularly defined adjuvants in the function of recombinant anticancer vaccines using a murine model adenocarcinoma, CT26, transduced with a model Ag, beta-galactosidase (beta-gal). Although IL-12 given alone to mice bearing tumors established for 3 days did not have consistent antitumor activity, a profound therapeutic effect was observed when IL-12 administration was combined with a recombinant vaccinia virus (rVV) encoding beta-gal called VJS6. On the basis of the reported synergistic effects of IL-12 and the costimulatory molecule B7-1 (CD80) in vitro, we immunized mice with a double recombinant vaccinia encoding both the model tumor Ag and the costimulatory molecule B7-1, designated B7-1 beta-gal rVV. The adjuvant administration of IL-12 after immunization with this virus significantly enhanced survival in tumor-bearing animals. T cell subset depletions demonstrated that the in vivo activity of IL-12 was largely independent of CD4+ T lymphocytes, whereas the in vivo activity of a B7-1 rVV required both CD4+ and CD8+ T cells to elicit maximal therapeutic effect. To our knowledge, this is the first description of B7-1 and IL-12 cooperation in vivo and represents a novel strategy to enhance the efficacy of recombinant anticancer vaccines.
Rao
J B
JB
Howard Hughes Medical Institute-National Institutes of Health Research Scholars Program, Surgery Branch, National Cancer Institute, Bethesda, MD 20892, USA.
Chamberlain
R S
RS
Bronte
V
V
Carroll
M W
MW
Irvine
K R
KR
Moss
B
B
Rosenberg
S A
SA
Restifo
N P
NP
D000276:Adjuvants, Immunologic / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D018122:B7-1 Antigen / Q000096:biosynthesis* / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003110:Colonic Neoplasms / Q000276:immunology / Q000401:mortality / Q000517:prevention & control*; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000276:immunology / Q000517:prevention & control / Q000556:secondary; D008212:Lymphocyte Depletion; D051379:Mice; D008807:Mice, Inbred BALB C; D013154:Spleen / Q000637:transplantation; D014407:Tumor Cells, Cultured; D014614:Vaccines, Synthetic / Q000276:immunology* / Q000627:therapeutic use; D014616:Vaccinia virus / Q000276:immunology*
D000276:Adjuvants, Immunologic; D000951:Antigens, Neoplasm; D018122:B7-1 Antigen; D014614:Vaccines, Synthetic; D018664:Interleukin-12