Adenoviral vectors expressing lymphotactin and interleukin 2 or lymphotactin and interleukin 12 synergize to facilitate tumor regression in murine breast cancer models.
We have previously demonstrated that intratumoral injection with Ad vectors expressing IL-2 or IL-12 can induce regression in a murine breast cancer model. These IL-2- or IL-12-induced antitumor responses were mainly mediated by Ag-specific T cells. Lymphotactin is a novel lymphocyte chemokine that can cause local accumulation of CD4+, CD8+, and NK cells. We hypothesized that addition of lymphotactin may enhance the antitumor immune responses induced by locally produced IL-2 and IL-12 as we have previously shown. To this end we constructed two double-recombinant adenoviral vectors expressing lymphotactin along with either IL-2 (Ad5 Lym/IL-2) or IL-12 (Ad5 Lym/IL-12). Subcutaneous injection of polyoma middle T (PyMT) or Neu (8142) transgenically derived breast adenocarcinoma cells, in the hind flank of FVB/n mice, results in the formation of tumor nodules in 14-21 days. We show that these constructs elicit potent antitumor responses when administered intratumorally. The antitumor responses are long lasting as determined by rechallenge experiments and hence demonstrate a protective immunity. These observations indicate that by augmenting the antitumor response with adenoviral vectors expressing lymphotactin in combination with IL-2 or IL-12 is a novel way to enhance immunotherapeutic approaches.
Emtage
P C
PC
Department of Pathology, McMaster University, Hamilton, Ontario, Canada.
Wan
Y
Y
Hitt
M
M
Graham
F L
FL
Muller
W J
WJ
Zlotnik
A
A
Gauldie
J
J
D000256:Adenoviridae / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D017252:CD3 Complex / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002460:Cell Line; D019744:Chemokines, C; D003601:Cytotoxicity Tests, Immunologic; D004359:Drug Therapy, Combination; D015316:Genetic Therapy; D005822:Genetic Vectors; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000235:genetics* / Q000627:therapeutic use; D007376:Interleukin-2 / Q000235:genetics* / Q000627:therapeutic use; D015847:Interleukin-4 / Q000378:metabolism; D008222:Lymphokines / Q000235:genetics* / Q000627:therapeutic use; D008325:Mammary Neoplasms, Experimental / Q000628:therapy*; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D012795:Sialoglycoproteins / Q000235:genetics* / Q000627:therapeutic use; D013997:Time Factors
D017252:CD3 Complex; D019744:Chemokines, C; D007376:Interleukin-2; D008222:Lymphokines; D012795:Sialoglycoproteins; C486249:Xcl1 protein, mouse; C018997:lymphotactin; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma