Intratumoral delivery of IL-12 gene by polyvinyl polymeric vector system to murine renal and colon carcinoma results in potent antitumor immunity

Abstract

We have utilized a nonviral, polymeric interactive non-conoptimal doses of 24 and 48 g, respectively. While polydensing (PINC) gene delivery system to deliver IL-12 to morphonuclear cells (PMNs) were partially involved in the two different types of murine tumors, an immunogenic development of the antitumor immune response elicited by renal cell carcinoma, Renca, and a non-immunogenic IL-12/PVP treatment, CD8 + T cells were found to be the colon cell carcinoma, CT26. The delivery of IL-12/polyvinyl primary effectors. In contrast, CD4 + T cells did not appear pyrrolidone (PVP) complexes into Renca led to the to play a significant role in the development of tumor speexpression of IL-12 (146 ± 89 pg/mg) and IFN-␥ cific immunity. Finally, mice that rejected the tumors follow-(160 ± 82 pg/mg) from explanted tumors in culture supering IL-12/PVP treatment were protected against a second natants. Treated tumors showed increased infiltration of challenge with the same tumor. These data provide evi-NK, CD4+ and CD8 + T cells and up-regulation of MHC dence that a nonviral IL-12 gene delivery system is well class I molecules on leukocytes in both tumors and lymph tolerated and generates a potent immune response against nodes. Fifty per cent of tumor-bearing mice rejected Renca established tumors. or CT26 tumors following IL-12/PVP treatments given at

Intramuscular electroporation delivery of IL-12 gene for treatment of squamous cell carcinoma located at distant site

“…The elimination of CD4 + cells from mice bearing CT-26 colon adenocarcinoma dramatically potentiates antitumor activity of IL-12, and depletion of CD4 + cells has significantly increased the survival of Renca -and CT26 -bearing mice. 12,21 Taken together, these findings indicate that the decreased CD4 + cells we observed in our study may also contribute to the antitumor activity in our model.…”

“…The structure of the construct, which contains both subunits of IL -12, is depicted in their publication. 12 The backbone elements of this construct are described in our previous publication. 13 The control construct is the result of deletion of IL -12 cDNA.…”

Effective transfer of interleukin-12 gene to solid tumors using a novel gene delivery system, poly [D,L-2,4-diaminobutyric acid]

“…Furthermore, nonviral vectors may be good clinical options because they may be more efficient and less labor intensive than viral vectors, although the present gene transfection efficiencies still need to be improved. Recently, nonviral gene delivery systems with polyvinylpyrrolidone (PVP), 16 poly[a-(4-aminobutyl)-L-glycolic acid] (PAGA), 17,18 and water-soluble lipopolymers (WSLP) 19 have been developed and reported. However, the best method for intratumoral delivery of the IL-12 gene remains to be determined.…”

Biodegradable polymer-based interleukin-12 gene delivery: role of induced cytokines, tumor infiltrating cells and nitric oxide in anti-tumor activity

“…Earlier reports have shown that IL-12 acts independently to promote a Th1 type response against tumor growth and metastasis, as well as by inducing other anti-tumor cytokines such as IFN-␥, TNF-␣ and granulocyte-macrophage colony-stimulating factor (GM-CSF) which can act synergistically to reduce and in some cases completely eradicate the tumor. 3,7,[19][20][21] There is evidence that IL-12 inhibits angiogenesis and induces apoptosis, as well as extensive necrosis in murine tumor. 22 Our studies show that use of PAGA/pmIL-12 complexes significantly enhances the levels of IL-12 p70 production compared with naked pmIL-12 and 5% (w/v) glucose-injected groups ( Figure 1), which would reduce the potential of tumor growth and metastasis.…”

“…7 Although these systems produced mIL-12 and mIFN-␥, the levels of transgene expression and tumor regression were low, possibly due to little protection of plasmid DNA by PVP. Moreover, no comparison was made between naked pmIL-12 in saline and PVP/pmIL-12-based formulations for transgene expression and tumor regression.…”