Electroporation-mediated IL-12 gene therapy in a transplantable canine cancer model

Tien Fu Chuang, Shan Chih Lee, Kuang Wen Liao, Ya Wen Hsiao, Chia Hui Lo, Bor Luen Chiang, Xi-Zhang Lin, Mi Hua Tao, Rea Min Chu

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Abstract

Interleukin-12 (IL-12) is effective in treating many types of rodent tumors, but has been unsuccessful in most human clinical trials, suggesting that animal models of more clinical relevance are required for evaluating human cancer immunotherapy. Herein, we report on the effectiveness of gene therapy with plasmid encoding human IL-12 (pIL-12) through in vivo electroporation in the treatment of beagles with a canine tumor, the canine transmissible venereal tumor (CTVT). The optimal electroporation conditions for gene transfer into CTVTs were tested by luciferase activity and determined to be a voltage of 200 V and duration of 50 msec, with the number of shocks set at 10 pulses, and the use of an electrode with 2 needles. Under these conditions, intratumoral administration of as little as 0.1 mg pIL-12 followed by electroporation significantly inhibited the growth of well-established tumors and eventually led to complete tumor regression. Furthermore, local pIL-12 treatment also induced a strong systemic effect that prevented new tumor growth and cured established tumors at distant locations. Intratumoral administration of pIL-12 greatly elevated the IL-12 level in the tumor masses, but produced only a trace amount in the serum. A high level of IFN-gamma mRNA was also detected in the treated tumor masses. pIL-12 gene therapy attracted significantly more lymphocytes infiltrating the tumors, including CD4+ and CD8+ T cells, and the surface expression of MHC I and MHC II molecules on CTVT cells was greatly increased after pIL-12 therapy. This treatment also induced apoptosis of the tumor cells as detected by Annexin V. More importantly, delivery of pIL-12 with intratumoral electroporation did not result in any detectable toxicity in the dogs. We conclude that intratumoral electroporation of the pIL-12 gene could cause profound immunologic host responses and efficiently treat CTVT in beagle dogs. The results also indicate that CTVT is an excellent large animal cancer model for testing immunogene therapies mediated by electroporation.

Original languageEnglish
Pages (from-to)698-707
Number of pages10
JournalInternational Journal of Cancer
Volume125
Issue number3
DOIs
Publication statusPublished - 2009 Aug 1

Fingerprint

Electroporation
Interleukin-12
Genetic Therapy
Canidae
Veterinary Venereal Tumors
Plasmids
Neoplasms
Electrochemotherapy
Animal Models
Dogs
Tumor-Infiltrating Lymphocytes
Annexin A5
Therapeutics
Growth
Luciferases
Immunotherapy
Genes
Needles
Rodentia
Shock

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Chuang, T. F., Lee, S. C., Liao, K. W., Hsiao, Y. W., Lo, C. H., Chiang, B. L., ... Chu, R. M. (2009). Electroporation-mediated IL-12 gene therapy in a transplantable canine cancer model. International Journal of Cancer, 125(3), 698-707. https://doi.org/10.1002/ijc.24418
Chuang, Tien Fu ; Lee, Shan Chih ; Liao, Kuang Wen ; Hsiao, Ya Wen ; Lo, Chia Hui ; Chiang, Bor Luen ; Lin, Xi-Zhang ; Tao, Mi Hua ; Chu, Rea Min. / Electroporation-mediated IL-12 gene therapy in a transplantable canine cancer model. In: International Journal of Cancer. 2009 ; Vol. 125, No. 3. pp. 698-707.
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abstract = "Interleukin-12 (IL-12) is effective in treating many types of rodent tumors, but has been unsuccessful in most human clinical trials, suggesting that animal models of more clinical relevance are required for evaluating human cancer immunotherapy. Herein, we report on the effectiveness of gene therapy with plasmid encoding human IL-12 (pIL-12) through in vivo electroporation in the treatment of beagles with a canine tumor, the canine transmissible venereal tumor (CTVT). The optimal electroporation conditions for gene transfer into CTVTs were tested by luciferase activity and determined to be a voltage of 200 V and duration of 50 msec, with the number of shocks set at 10 pulses, and the use of an electrode with 2 needles. Under these conditions, intratumoral administration of as little as 0.1 mg pIL-12 followed by electroporation significantly inhibited the growth of well-established tumors and eventually led to complete tumor regression. Furthermore, local pIL-12 treatment also induced a strong systemic effect that prevented new tumor growth and cured established tumors at distant locations. Intratumoral administration of pIL-12 greatly elevated the IL-12 level in the tumor masses, but produced only a trace amount in the serum. A high level of IFN-gamma mRNA was also detected in the treated tumor masses. pIL-12 gene therapy attracted significantly more lymphocytes infiltrating the tumors, including CD4+ and CD8+ T cells, and the surface expression of MHC I and MHC II molecules on CTVT cells was greatly increased after pIL-12 therapy. This treatment also induced apoptosis of the tumor cells as detected by Annexin V. More importantly, delivery of pIL-12 with intratumoral electroporation did not result in any detectable toxicity in the dogs. We conclude that intratumoral electroporation of the pIL-12 gene could cause profound immunologic host responses and efficiently treat CTVT in beagle dogs. The results also indicate that CTVT is an excellent large animal cancer model for testing immunogene therapies mediated by electroporation.",
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Chuang, TF, Lee, SC, Liao, KW, Hsiao, YW, Lo, CH, Chiang, BL, Lin, X-Z, Tao, MH & Chu, RM 2009, 'Electroporation-mediated IL-12 gene therapy in a transplantable canine cancer model', International Journal of Cancer, vol. 125, no. 3, pp. 698-707. https://doi.org/10.1002/ijc.24418

Electroporation-mediated IL-12 gene therapy in a transplantable canine cancer model. / Chuang, Tien Fu; Lee, Shan Chih; Liao, Kuang Wen; Hsiao, Ya Wen; Lo, Chia Hui; Chiang, Bor Luen; Lin, Xi-Zhang; Tao, Mi Hua; Chu, Rea Min.

In: International Journal of Cancer, Vol. 125, No. 3, 01.08.2009, p. 698-707.

Research output: Contribution to journalArticle

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