Abstract
To circumvent the toxicity caused by systemic injection of cytokines, cytokine cDNA genes encoding the human interleukin IL-2 cDNA (Ad-IL-2) and murine interferon IFN-γ gene (Ad- IFN-γ) were inserted into adenoviral vectors. These constructs were used for intratumoral gene therapy of murine renal adenocarcinoma Renca tumors. Treatment with three doses of Ad-IL-2 or Ad- IFN-γ, given a day apart, was more effective than single-dose gene therapy. We found that tumor irradiation enhanced the therapeutic efficacy of Ad-IL-2 and Ad-IFN-γ intratumoral gene therapy. Tumor irradiation, administered 1 day prior to three doses of Ad-IL-2 treatment, was more effective than radiation or Ad-IL-2 alone, resulting in tumor growth arrest in all mice, increased survival and a consistent increase in complete tumor regression response rate. Complete responders rejected Renca tumor challenge and demonstrated specific cytotoxic T-cell activity, indicative of specific tumor immunity. The effect of radiation combined with three doses of Ad-IFN-γ was less pronounced and did not lead to tumor immunity. Histological observations showed that irradiation of the tumor prior to gene therapy increased tumor destruction and inflammatory infiltrates in the tumor nodules. These findings demonstrate that tumor irradiation improves the efficacy of Ad-IL-2 gene therapy for induction of antitumor immune response.
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References
Greenlee RT, Murray T, Bolden S, et al. Cancer statistics, 2000. CA Cancer J Clin. 2000;50:7–33.
Mulders P, Figlin R, deKernion JB, et al. Renal cell carcinoma: recent progress and future directions. Cancer Res. 1997;57:5189–5195.
Chow WH, Gridley G, McLaughlin JK, et al. Protein intake and risk of renal cell cancer. J Natl Cancer Inst. 1994;86:1131–1139.
Haas GP, Hillman GG . Update on the role of immunotherapy in the management of kidney cancer. Cancer Control. 1996;3:66–71.
Motzer RJ, Bander NH, Nanus DM . Renal-cell carcinoma. New England J Med. 1996;335:865–875.
Kim S, Haas GP, Hillman GG . Development of immunotherapy for the treatment of malignacies refractory to conventional therapies. Cytokines Mol Ther. 1996;2:13–19.
Hillman GG, Haas GP, Wahl WH, et al. Adoptive immunotherapy of cancer: biological response modifiers and cytotoxic cell therapy. Biotherapy. 1992;5:119–129.
Rosenberg SA, Lotze MT, Yang JC, et al. Prospective randomized trial of high-dose interleukin-2 alone or in conjunction with lymphokine-activated killer cells for the treatment of patients with advanced cancer. J Natl Cancer Inst. 1993;85:622–632.
Dybal EJ, Maughan RL, Sud S, et al. Synergy of radiation therapy and immunotherapy in murine renal cell carcinoma. J Urol. 1992;148:1331–1337.
Younes E, Haas GP, Dezso B, et al. Local tumor irradiation augments the response to IL-2 therapy in a murine renal adenocarcinoma. Cell Immunol. 1995;165:243–251.
Dezso B, Haas GP, Hamzavi F, et al. The mechanism of local tumor irradiation combined with interleukin 2 therapy in murine renal carcinoma: histological evaluation of pulmonary metastases. Clin Cancer Res. 1996;2:1543–1552.
Hillman GG, Visscher D, Ali E, et al. Systemic treatment with interleukin-4 induces regression of pulmonary metastases in a murine renal cell carcinoma model. Cell Immunol. 1995;160:257–263.
Hillman GG, Visscher D, Hamzavi F, et al. Inhibition of murine renal carcinoma pulmonary metastases by systemic administration of interferon gamma: mechanism of action and potential for combination with IL-4. Clin Cancer Res. 1997;3:1799–1806.
Addison CL, Braciak T, Ralston R, et al. Intratumoral injection of an adenovirus expressing interleukin 2 induces regression and immunity in a murine breast cancer model. Proc Natl Acad Sci USA. 1995;92:8522–8526.
Addison CL, Bramson JL, Hitt MM, et al. Intratumoral coinjection of adenoviral vectors expressing IL-2 and IL-12 results in enhanced frequency of regression of injected and untreated distal tumors. Gene Ther. 1998;5:1400–1409.
Cordier L, Duffour MT, Sabourin JC, et al. Complete recovery of mice from a pre-established tumor by direct intratumoral delivery of an adenovirus vector harboring the murine IL-2 gene. Gene Ther. 1995;2:16–21.
Huang H, Chen SH, Kosai K, et al. Gene therapy for hepatocellular carcinoma: long-term remission of primary and metastatic tumors in mice by interleukin-2 gene therapy in vitro. Gene Ther. 1996;3:980–987.
Toloza EM, Hunt K, Swisher S, et al. In vitro cancer gene therapy with a recombinant interleukin-2 adenovirus vector. Cancer Gene Ther. 1996;3:11–17.
Saffran DC, Horton HM, Yankauckas MA, et al. Immunotherapy of established tumors in mice by intratumoral injection of interleukin-2 plasmid DNA: induction of CD8+T-cell immunity. Cancer Gene Ther. 1998;5:321–330.
Slos P, De Meyer M, Leroy P, et al. Immunotherapy of established tumors in mice by intratumoral injection of an adenovirus vector harboring the human IL-2 cDNA: induction of CD8(+) T-cell immunity and NK activity. Cancer Gene Ther. 2001;8:321–332.
Chartier C, Degryse E, Gantzer M, et al. Efficient generation of recombinant adenovirus vectors by homologous recombination in Escherichia coli. J Virol. 1996;70:4805–4810.
Chroboczek J, Bieber F, Jacrot B . The sequence of the genome of adenovirus type 5 and its comparison with the genome of adenovirus type 2. Virology. 1992;186:280–285.
Fallaux FJ, Bout A, van der Velde I, et al. New helper cells and matched early region 1-deleted adenovirus vectors prevent generation of replication-competent adenoviruses. Hum Gene Ther. 1998;9:1909–1917.
Lusky M, Christ M, Rittner K, et al. In vitro and in vivo biology of recombinant adenovirus vectors with E1, E1/E2a, or E1/E4 deleted. J Virol. 1998;72:2022–2032.
Hillman GG, Maughan RL, Grignon DJ, et al. Neutron or photon irradiation for prostate tumors: enhancement of cytokine therapy in a metastatic tumor model. Clin Cancer Res. 2001;7:136–144.
Zeng M, Cerniglia GJ, Eck SL, et al. High-efficiency stable gene transfer of adenovirus into mammalian cells using ionizing radiation. Hum Gene Ther. 1997;8:1025–1032.
Hillman GG, Maughan RL, Grignon DJ, et al. Responsiveness of experimental prostate carcinoma bone tumors to neutron or photon radiation combined with cytokine therapy. Int J Rad Onc Biol Phys. 2003;56:1426–1437.
Bellone M, Iezzi G, Rovere P, et al. Processing of engulfed apoptotic bodies yields T cell epitopes. J Immunol. 1997;159:5391–5399.
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Hillman, G., Slos, P., Wang, Y. et al. Tumor irradiation followed by intratumoral cytokine gene therapy for murine renal adenocarcinoma. Cancer Gene Ther 11, 61–72 (2004). https://doi.org/10.1038/sj.cgt.7700656
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DOI: https://doi.org/10.1038/sj.cgt.7700656
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