Canarypox virus-mediated interleukin 12 gene transfer into murine mammary adenocarcinoma induces tumor suppression and long-term antitumoral immunity.
The antitumoral activity of recombinant canarypox virus vectors (ALVAC) expressing murine interleukin 12 (IL-12) was evaluated in the syngeneic, nonimmunogenic murine mammary adenocarcinoma model (TS/A). Seven-day preestablished subcutaneous tumors (5- to 6-mm mean diameters) were injected on days 7, 10, 14, 17, 21, and 24 with the vector ALVAC-IL12 at 2.5 x 10(5) TCID50 (50% tissue culture infective dose). Total tumor regression occurred in 40 to 50% of the treated mice. Furthermore, 100% of the cured mice were protected against a contralateral subsequent challenge with the TS/A parental cells on day 28. The ALVAC-IL12 treatment is not effective in nude mice, suggesting the critical role of T cells. CD4 and CD8 T cells infiltrated the tumors treated with ALVAC-IL12 in the BALB/c model. Furthermore, in vivo depletion of CD4+ T cells totally abrogated the induction of the long-term antitumoral immune response by ALVAC-IL12. Interestingly, some tumor growth inhibition was also observed with ALVAC-betaGal treatment and a vaccinal effect was found in 33% of the treated animals, suggesting an adjuvant effect of the vector itself. Other ALVAC vectors expressing murine cytokines (IL-2, GM-CSF, IFN-gamma) were evaluated in the same model. Major antitumoral activity was observed with ALVAC-GM-CSF. However, a combination of ALVAC-GM-CSF and ALVAC-IL12 had no synergistic effect. These results suggest that in vivo gene transfer with canarypox virus expressing IL-12 may provide an effective and safe strategy for the treatment of human cancers.
Puisieux
I
I
Department of Tumor Biology, Centre Léon Bérard, Lyon, France.
Odin
L
L
Poujol
D
D
Moingeon
P
P
Tartaglia
J
J
Cox
W
W
Favrot
M
M
D000230:Adenocarcinoma / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D000818:Animals; D018150:Avipoxvirus / Q000235:genetics*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002455:Cell Division; D002522:Chlorocebus aethiops; D005260:Female; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D015552:Injections, Intralesional; D018664:Interleukin-12 / Q000235:genetics*; D008156:Luciferases / Q000235:genetics; D008212:Lymphocyte Depletion; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D014709:Vero Cells
D018664:Interleukin-12; D008156:Luciferases