Intratumoral injection of dendritic cells transduced by an SV40-based vector expressing interleukin-15 induces curative immunity mediated by CD8+ T lymphocytes and NK cells.
Cancer immunotherapy has been extensively attempted by gene transfer of cytokines with viral vectors. In this work, we compared the therapeutic effects of interleukin 12 and 15 (IL-12 and IL-15) genes transferred to tumor cells or to dendritic cells (DCs), which were subsequently injected into established tumors. For this purpose, we used viral vectors based on simian virus 40 (rSV40). Importantly, we observed that nonmatured DCs infected with rSV40 vectors remained phenotypically immature. Infection of CT-26 tumor cells with rSV40 expressing IL-12 (rSVIL-12) or IL-15 (rSVIL-15) failed to inhibit tumor development. In contrast, the intratumoral administration of syngeneic DCs transduced with rSVIL-12 or rSVIL-15 was associated with a strong antitumor response; up to 40% tumor remissions were achieved with DCs transduced by rSVIL-12 and 73% with DCs expressing IL-15. This antitumor effect correlated with the in vivo priming of tumor-specific CD8+ T lymphocytes. Depletion studies showed that rSVIL-15-mediated antitumor efficacy was mediated mainly by CD8+ T lymphocytes and NK cells. We conclude that (i) SV40-derived vectors are an advantageous alternative to transduce genes into DCs and (ii) DCs transferred with IL-15 have an enhanced capability to induce curative antitumor immunity when injected into malignant lesions.
Vera
Maria
M
Division of Hepatology and Gene Therapy, CIMA, School of Medicine, University of Navarra, Pio XII 55, 31008 Pamplona, Spain.
Razquin
Nerea
N
Prieto
Jesús
J
Melero
Ignacio
I
Fortes
Puri
P
González-Aseguinolaza
Gloria
G
D000230:Adenocarcinoma / Q000235:genetics / Q000628:therapy*; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000628:therapy*; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors; D007167:Immunotherapy; D018664:Interleukin-12 / Q000235:genetics; D019409:Interleukin-15 / Q000235:genetics; D007694:Killer Cells, Natural / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D013539:Simian virus 40 / Q000235:genetics*; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured
D019409:Interleukin-15; D018664:Interleukin-12