A novel immunotherapeutic approach to melanoma-bearing hosts with protein-transduction domain-containing immunogenic foreign antigens.
BACKGROUND
Active immunotherapy is accomplished by two critical factors; (1) induction of strong antigen-specific immune responses, and (2) abundant expression of antigen-epitopes on target cells. Previously, we have shown that the nona-arginine protein-transduction domain (R9-PTD) induced efficient protein-antigen transduction to a variety of cell types in vitro and in vivo. We have also demonstrated that intradermal (i.d.) injections of R9-PTD-containing immunogenic foreign antigens (rR9-OVA) induced dual immunological effects: the induction of OVA-specific Tc1- and Th1-dominant immune responses, and the induction of CTL-mediated immune responses at the injection area by expressing OVA-epitopes.


OBJECTIVE
We investigated and compared the antitumor effects by intratumoral (i.t.) injections of rR9-containing natural tumor-associated autoantigen (TAA) and other rR9-containing proteins, including rR9-OVA, into B16 melanoma.


RESULTS
Our results clearly demonstrate that multiple i.t. injections of rR9-OVA, but not rR9-containing TAA, elicited strong antitumor effects in B16-bearing mice, and resulted in complete tumor regression in some (50%) animals. These antitumor effects were abrogated by depletion of CD8(+) T cells, and SIINFEKL-specific CTL lysed rR9-OVA-treated B16 cells in vitro. I.t. injections with rR9-OVA altered the proportion of CD4(+) T cell subsets in B16-bearing mice. Interestingly, B16-tumor growth at the untreated site was also reduced following multiple injections of rR9-OVA at the other B16 tumor site. Finally, we confirmed that mice that had rejected B16 tumors by i.t. injections of rR9-OVA subsequently acquired CTL activities to Trp2-epitope/B16 cells.


CONCLUSIONS
Multiple i.t. injections of rR9-PTD-containing immunogenic foreign Ags elicit strong antitumor effects, and thereby may provide important clinical benefits to melanoma patients.
Kanzaki
Mirei
M
Department of Dermatology, University of Yamanashi, Faculty of Medicine, 1110 Shimokato, Chuo-shi, Yamanashi 409-3898, Japan.
Okamoto
Takashi
T
Mitsui
Hiroshi
H
Shibagaki
Naotaka
N
Shimada
Shinji
S
D000704:Analysis of Variance; D000818:Animals; D000941:Antigens / Q000276:immunology / Q000627:therapeutic use*; D000951:Antigens, Neoplasm / Q000276:immunology / Q000627:therapeutic use*; D005260:Female; D016233:Immunotherapy, Active / Q000379:methods*; D015552:Injections, Intralesional; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009363:Neoplasm Proteins / Q000276:immunology / Q000627:therapeutic use*; D009842:Oligopeptides / Q000276:immunology; D010047:Ovalbumin / Q000276:immunology; D011994:Recombinant Proteins / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D000941:Antigens; D000951:Antigens, Neoplasm; D009363:Neoplasm Proteins; D009842:Oligopeptides; D011994:Recombinant Proteins; C491427:nonaarginine; D010047:Ovalbumin