Targeted interleukin 2 therapy enhances protective immunity induced by an autologous oral DNA vaccine against murine melanoma.
We demonstrate that a mouse-human chimeric anti-ganglioside GD2-interleukin (IL)-2 fusion protein (ch14.18-IL2) substantially amplifies tumor-protective immunity against murine melanoma induced by an autologous oral DNA vaccine containing the murine ubiquitin gene fused to murine melanoma peptide epitopes gp100(25-35) and TRP-2(181-188). This combination therapy led to the complete rejection of a lethal challenge with B78D14 murine melanoma cells in six of eight mice and a marked suppression of s.c. tumor growth in the two remaining animals. The tumor-protective immunity was mediated by MHC class I antigen- restricted CD8(+) T cells together with CD4(+) T cell help, which was required only for tumor cell killing in the effector phase of the immune response. A single oral vaccination with the DNA vaccine, which was carried by attenuated Salmonella typhimurium, was equally as effective as three such vaccinations applied at 2-week intervals. The immunological mechanisms involved in this antitumor effect were suggested by a decisively increased secretion of tumor necrosis factor alpha TNFTnTNa and IFN-gamma from CD4(+) and CD8(+) T cells and a markedly up-regulated expression on CD8(+) T cells of high-affinity IL-2 receptor alpha chain (CD25), costimulatory molecule CD28, and adhesion molecule lymphocyte function-associated antigen-2 (LFA-2/CD2). Additionally, the combination therapy induced increased expression of costimulatory molecules B7.1 and CD48 on murine antigen-presenting cells. Taken together, our results suggest that IL-2 targeted to the tumor microenvironment by a specific antibody-IL-2 fusion protein is a potent enhancer of tumor-protective immunity induced by an oral DNA vaccine that may ultimately enhance the chances of success in its clinical application.
Niethammer
A G
AG
Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, USA.
Xiang
R
R
Ruehlmann
J M
JM
Lode
H N
HN
Dolman
C S
CS
Gillies
S D
SD
Reisfeld
R A
RA
D000284:Administration, Oral; D000818:Animals; D018122:B7-1 Antigen / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D004357:Drug Synergism; D000939:Epitopes / Q000276:immunology; D005260:Female; D005732:Gangliosides / Q000276:immunology; D006801:Humans; D000922:Immunotoxins / Q000008:administration & dosage / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000008:administration & dosage / Q000276:immunology*; D019746:Intramolecular Oxidoreductases / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008546:Melanoma, Experimental / Q000276:immunology* / Q000517:prevention & control*; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000276:immunology*; D058951:gp100 Melanoma Antigen
D018122:B7-1 Antigen; D000939:Epitopes; D005732:Gangliosides; D000922:Immunotoxins; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; C548637:PMEL protein, human; D010446:Peptide Fragments; C548642:Pmel protein, mouse; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D019444:Vaccines, DNA; D058951:gp100 Melanoma Antigen; C019403:ganglioside, GD2; D007371:Interferon-gamma; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase