Interleukin (IL)-21 and IL-15 genetic transfer synergistically augments therapeutic antitumor immunity and promotes regression of metastatic lymphoma

Abstract

IL-21 supports proliferation of mature T and B cells and facilitates expansion and maturation of natural killer (NK) cells in synergy with IL-15. However, the biological implications of IL-21 in vivo have not been fully elucidated. IL-21 and IL-15 expression plasmids were intravenously injected under high pressure into the tail veins of mice, which were subsequently challenged by an intravenous injection of RLmale1 lymphoma cells. The IL15 gene transfection significantly reduced the numbers of metastatic tumor foci in the liver. In contrast, when IL21 and IL15 genes were cotransfected, complete regression was achieved in 80% of the mice. The cytokine gene therapy was also performed in mice that had been intravenously inoculated with the tumor cells. Forty percent of mice that received a single injection of a mixture of cytokine genes successfully rejected the preestablished metastatic lymphoma and showed tumor-free survival for more than 300 days. IL-21 significantly elevated the cytotoxic T lymphocyte activity in the spleens of tumor-inoculated mice, while the two cytokines augmented NK killing activity in a synergistic manner. These results strongly suggest that the codelivery of IL-21 and IL-15 elicits powerful antitumor immune responses, resulting in marked therapeutic efficacy against metastatic tumors.

Sonoporation using microbubble BR14 promotes pDNA/siRNA transduction to murine heart

“…The plasmids pGEG.GL3 [28], pGE-G.EGFP [29], and pGEG.b [30] carried GL3 firefly luciferase (Luc), EGFP, and Escherichia coli b-galactosidase (b-gal) genes, respectively, under the control of the CAG promoter. Each plasmid also contained Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1) gene and EBV oriP sequence [31].…”

Combining Antibody-Directed Presentation of IL-15 and 4-1BBL in a Trifunctional Fusion Protein for Cancer Immunotherapy

“…On the other hand, improved therapeutic effects could be achieved by the combination of IL-15 with other immunomodulatory approaches, for example, cytokines (IL-21, IL-7, IL-12; refs. 6,15,16), agonistic anti-CD40 mAb (17), or inhibitory checkpoint blockers (anti-CTLA-4 mAb, anti-PD-L1 mAb; ref. 18).…”

Structural impact of hydrodynamic injection on mouse liver

“…In the past few years, the method of hydrodynamic delivery 1,2 has provided a new means for delivery of nucleic acids to hepatocytes in rodents. [3][4][5] Since its establishment, this technique has been widely used for function analysis of coding [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] and non-coding sequences, [23][24][25][26][27][28][29] and for assessment of therapeutic potential of selected DNA and RNA sequences in animal models. [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][30][31][32][33] In addition, hydrodynamic delivery of siRNA, short hairpin RNA (shRNA) or plasmid constructs encoding an shRNA has been e...…”