Cytokine gene therapy using adenovirally transduced, tumor-seeking activated natural killer cells.

Abstract

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.

• Authors: Stephen R Goding, Qin Yang, Kristina B Knudsen, Douglas M Potter, Per H Basse
• Journal: Human gene therapy (Hum Gene Ther) Vol. 18 Issue 8 Pg. 701-11 (Aug 2007) ISSN: 1043-0342 [Print] United States
• PMID: 17678438 (Publication Type: Journal Article)

Chemical References

• Interleukin-2
• Interleukin-12

Topics

• Adenoviridae
• Animals
• Genetic Therapy
• Genetic Vectors
• Interleukin-12 (biosynthesis, genetics)
• Interleukin-2 (therapeutic use)
• Killer Cells, Natural (immunology, transplantation)
• Lymphocyte Activation (immunology)
• Lymphocyte Subsets (immunology)
• Mice
• Mice, Inbred C57BL
• Neoplasms (immunology, therapy)
• Transduction, Genetic