Cytokine gene therapy using adenovirally transduced, tumor-seeking activated natural killer cells.
We previously demonstrated that adoptively transferred, interleukin (IL)-2-activated natural killer (A-NK) cells are effective in reducing B16 lung tumors in tumor-bearing animals. This effect depends on high and often toxic doses of IL-2 to support the survival and antitumor functions of the transferred A-NK cells. We hypothesized that A-NK cells transduced to express pro-NK cell cytokines would become less dependent on high and potentially toxic amounts of IL-2. Here, we demonstrate that A-NK cells adenovirally transduced to express mIL-12 survive well and function efficiently in mice bearing B16 lung tumors when supported with low, nontoxic doses of IL-2. The intratumoral survival of nontransduced "bystander'' A-NK cells also increased when they were coinjected with IL-12 gene-transduced A-NK cells. The enhanced survival of exogenously delivered, IL-12 gene-transduced A-NK cells resulted in greater antitumor responsiveness. This led to a 7- to 10-day increase in median survival time compared with tumor-bearing mice receiving mock-transduced A-NK cells. These data show that the presence of IL-12 around tumor-infiltrating A-NK cells enhances their antitumor activity while reducing their requirement for systemically administered IL-2.
Department of Immunology, Graduate School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA. srg33@pitt.edu
Stephen R
SR
Goding
Qin
Q
Yang
Kristina B
KB
Knudsen
Douglas M
DM
Potter
Per H
PH
Basse
D000256:Adenoviridae; D000818:Animals; D015316:Genetic Therapy; D005822:Genetic Vectors; D018664:Interleukin-12 / Q000096:biosynthesis / Q000235:genetics*; D007376:Interleukin-2 / Q000627:therapeutic use; D007694:Killer Cells, Natural / Q000276:immunology* / Q000637:transplantation; D008213:Lymphocyte Activation / Q000276:immunology; D016131:Lymphocyte Subsets / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D014161:Transduction, Genetic
D007376:Interleukin-2; D018664:Interleukin-12