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. 1995 Sep;222(3):298–310. doi: 10.1097/00000658-199509000-00008

The role of immunosuppression in the efficacy of cancer gene therapy using adenovirus transfer of the herpes simplex thymidine kinase gene.

A A Elshami 1, J C Kucharczuk 1, D H Sterman 1, W R Smythe 1, H C Hwang 1, K M Amin 1, L A Litzky 1, S M Albelda 1, L R Kaiser 1
PMCID: PMC1234809  PMID: 7677460

Abstract

OBJECTIVE: To determine whether the immune system limits or improves the therapeutic efficacy of an adenovirus vector expressing the herpes simplex thymidine kinase (HSVtk) gene in a subcutaneous tumor model. BACKGROUND DATA: Enhanced immune reactions against tumors may be therapeutically useful. However, recent studies with adenoviral vectors show that immune responses limit the efficacy and persistence of gene expression. The effect of the immune response on cancer gene therapy with HSVtk gene delivery by an adenovirus vector followed by treatment with ganciclovir is unclear. METHODS: After adenoviral transduction of a Fischer rat syngeneic mesothelioma cell line with the HSVtk gene in vitro, subcutaneous flank tumors were established. The ability of the HSVtk/ganciclovir system to inhibit tumor growth was compared among normal Fischer rats, immunodeficient nude rats, and Fischer rats immunosuppressed with cyclosporin. RESULTS: HSVtk/ganciclovir therapy was more effective in nude rats and immunosuppressed Fischer rats than in immunocompetent Fischer rats. CONCLUSION: These results indicate that the immune response against adenovirally transduced cells limits the efficacy of the HSVtk/ganciclovir system and that immunosuppression appears to be a useful adjunct. These findings have important implications for clinical trials using currently available adenovirus vectors as well as for future vector design.

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Selected References

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  1. Benz E. J., Jr The molecular genetics of cancer. Introduction to principles of recombinant DNA technology. Cancer. 1990 Feb 1;65(3 Suppl):731–741. doi: 10.1002/1097-0142(19900201)65:3+<731::aid-cncr2820651318>3.0.co;2-w. [DOI] [PubMed] [Google Scholar]
  2. Berkner K. L. Development of adenovirus vectors for the expression of heterologous genes. Biotechniques. 1988 Jul-Aug;6(7):616–629. [PubMed] [Google Scholar]
  3. Bi W. L., Parysek L. M., Warnick R., Stambrook P. J. In vitro evidence that metabolic cooperation is responsible for the bystander effect observed with HSV tk retroviral gene therapy. Hum Gene Ther. 1993 Dec;4(6):725–731. doi: 10.1089/hum.1993.4.6-725. [DOI] [PubMed] [Google Scholar]
  4. Caruso M., Panis Y., Gagandeep S., Houssin D., Salzmann J. L., Klatzmann D. Regression of established macroscopic liver metastases after in situ transduction of a suicide gene. Proc Natl Acad Sci U S A. 1993 Aug 1;90(15):7024–7028. doi: 10.1073/pnas.90.15.7024. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Caskey C. T. Molecular medicine. A spin-off from the helix. JAMA. 1993 Apr 21;269(15):1986–1992. doi: 10.1001/jama.269.15.1986. [DOI] [PubMed] [Google Scholar]
  6. Chen S. H., Shine H. D., Goodman J. C., Grossman R. G., Woo S. L. Gene therapy for brain tumors: regression of experimental gliomas by adenovirus-mediated gene transfer in vivo. Proc Natl Acad Sci U S A. 1994 Apr 12;91(8):3054–3057. doi: 10.1073/pnas.91.8.3054. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Colston M. J., Fieldsteel A. H., Dawson P. J. Growth and regression of human tumor cell lines in congenitally athymic (rnu/rnu) rats. J Natl Cancer Inst. 1981 May;66(5):843–848. [PubMed] [Google Scholar]
  8. Craighead J. E., Akley N. J., Gould L. B., Libbus B. L. Characteristics of tumors and tumor cells cultured from experimental asbestos-induced mesotheliomas in rats. Am J Pathol. 1987 Dec;129(3):448–462. [PMC free article] [PubMed] [Google Scholar]
  9. Culver K. W., Ram Z., Wallbridge S., Ishii H., Oldfield E. H., Blaese R. M. In vivo gene transfer with retroviral vector-producer cells for treatment of experimental brain tumors. Science. 1992 Jun 12;256(5063):1550–1552. doi: 10.1126/science.1317968. [DOI] [PubMed] [Google Scholar]
  10. Engelhardt J. F., Litzky L., Wilson J. M. Prolonged transgene expression in cotton rat lung with recombinant adenoviruses defective in E2a. Hum Gene Ther. 1994 Oct;5(10):1217–1229. doi: 10.1089/hum.1994.5.10-1217. [DOI] [PubMed] [Google Scholar]
  11. Engelhardt J. F., Simon R. H., Yang Y., Zepeda M., Weber-Pendleton S., Doranz B., Grossman M., Wilson J. M. Adenovirus-mediated transfer of the CFTR gene to lung of nonhuman primates: biological efficacy study. Hum Gene Ther. 1993 Dec;4(6):759–769. doi: 10.1089/hum.1993.4.6-759. [DOI] [PubMed] [Google Scholar]
  12. Engelhardt J. F., Ye X., Doranz B., Wilson J. M. Ablation of E2A in recombinant adenoviruses improves transgene persistence and decreases inflammatory response in mouse liver. Proc Natl Acad Sci U S A. 1994 Jun 21;91(13):6196–6200. doi: 10.1073/pnas.91.13.6196. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Freeman S. M., Abboud C. N., Whartenby K. A., Packman C. H., Koeplin D. S., Moolten F. L., Abraham G. N. The "bystander effect": tumor regression when a fraction of the tumor mass is genetically modified. Cancer Res. 1993 Nov 1;53(21):5274–5283. [PubMed] [Google Scholar]
  14. Howard R. B., Chu H., Zeligman B. E., Marcell T., Bunn P. A., McLemore T. L., Mulvin D. W., Cowen M. E., Johnston M. R. Irradiated nude rat model for orthotopic human lung cancers. Cancer Res. 1991 Jun 15;51(12):3274–3280. [PubMed] [Google Scholar]
  15. Hwang H. C., Smythe W. R., Elshami A. A., Kucharczuk J. C., Amin K. M., Williams J. P., Litzky L. A., Kaiser L. R., Albelda S. M. Gene therapy using adenovirus carrying the herpes simplex-thymidine kinase gene to treat in vivo models of human malignant mesothelioma and lung cancer. Am J Respir Cell Mol Biol. 1995 Jul;13(1):7–16. doi: 10.1165/ajrcmb.13.1.7598939. [DOI] [PubMed] [Google Scholar]
  16. Ishibashi S., Brown M. S., Goldstein J. L., Gerard R. D., Hammer R. E., Herz J. Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery. J Clin Invest. 1993 Aug;92(2):883–893. doi: 10.1172/JCI116663. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Jaffe H. A., Danel C., Longenecker G., Metzger M., Setoguchi Y., Rosenfeld M. A., Gant T. W., Thorgeirsson S. S., Stratford-Perricaudet L. D., Perricaudet M. Adenovirus-mediated in vivo gene transfer and expression in normal rat liver. Nat Genet. 1992 Aug;1(5):372–378. doi: 10.1038/ng0892-372. [DOI] [PubMed] [Google Scholar]
  18. Kozarsky K. F., Wilson J. M. Gene therapy: adenovirus vectors. Curr Opin Genet Dev. 1993 Jun;3(3):499–503. doi: 10.1016/0959-437x(93)90126-a. [DOI] [PubMed] [Google Scholar]
  19. Maruo K., Ueyama Y., Kuwahara Y., Hioki K., Saito M., Nomura T., Tamaoki N. Human tumour xenografts in athymic rats and their age dependence. Br J Cancer. 1982 May;45(5):786–789. doi: 10.1038/bjc.1982.122. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Matthews T., Boehme R. Antiviral activity and mechanism of action of ganciclovir. Rev Infect Dis. 1988 Jul-Aug;10 (Suppl 3):S490–S494. doi: 10.1093/clinids/10.supplement_3.s490. [DOI] [PubMed] [Google Scholar]
  21. Moolten F. L. Drug sensitivity ("suicide") genes for selective cancer chemotherapy. Cancer Gene Ther. 1994 Dec;1(4):279–287. [PubMed] [Google Scholar]
  22. Moolten F. L., Wells J. M. Curability of tumors bearing herpes thymidine kinase genes transferred by retroviral vectors. J Natl Cancer Inst. 1990 Feb 21;82(4):297–300. doi: 10.1093/jnci/82.4.297. [DOI] [PubMed] [Google Scholar]
  23. Mulligan R. C. The basic science of gene therapy. Science. 1993 May 14;260(5110):926–932. doi: 10.1126/science.8493530. [DOI] [PubMed] [Google Scholar]
  24. Prince G. A., Porter D. D., Jenson A. B., Horswood R. L., Chanock R. M., Ginsberg H. S. Pathogenesis of adenovirus type 5 pneumonia in cotton rats (Sigmodon hispidus). J Virol. 1993 Jan;67(1):101–111. doi: 10.1128/jvi.67.1.101-111.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Ram Z., Culver K. W., Walbridge S., Blaese R. M., Oldfield E. H. In situ retroviral-mediated gene transfer for the treatment of brain tumors in rats. Cancer Res. 1993 Jan 1;53(1):83–88. [PubMed] [Google Scholar]
  26. Simon R. H., Engelhardt J. F., Yang Y., Zepeda M., Weber-Pendleton S., Grossman M., Wilson J. M. Adenovirus-mediated transfer of the CFTR gene to lung of nonhuman primates: toxicity study. Hum Gene Ther. 1993 Dec;4(6):771–780. doi: 10.1089/hum.1993.4.6-771. [DOI] [PubMed] [Google Scholar]
  27. Smythe W. R., Hwang H. C., Amin K. M., Eck S. L., Davidson B. L., Wilson J. M., Kaiser L. R., Albelda S. M. Use of recombinant adenovirus to transfer the herpes simplex virus thymidine kinase (HSVtk) gene to thoracic neoplasms: an effective in vitro drug sensitization system. Cancer Res. 1994 Apr 15;54(8):2055–2059. [PubMed] [Google Scholar]
  28. Smythe W. R., Hwang H. C., Elshami A. A., Amin K. M., Eck S. L., Davidson B. L., Wilson J. M., Kaiser L. R., Albelda S. M. Treatment of experimental human mesothelioma using adenovirus transfer of the herpes simplex thymidine kinase gene. Ann Surg. 1995 Jul;222(1):78–86. doi: 10.1097/00000658-199507000-00013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Smythe W. R., Kaiser L. R., Hwang H. C., Amin K. M., Pilewski J. M., Eck S. J., Wilson J. M., Albelda S. M. Successful adenovirus-mediated gene transfer in an in vivo model of human malignant mesothelioma. Ann Thorac Surg. 1994 Jun;57(6):1395–1401. doi: 10.1016/0003-4975(94)90090-6. [DOI] [PubMed] [Google Scholar]
  30. Vile R. G., Nelson J. A., Castleden S., Chong H., Hart I. R. Systemic gene therapy of murine melanoma using tissue specific expression of the HSVtk gene involves an immune component. Cancer Res. 1994 Dec 1;54(23):6228–6234. [PubMed] [Google Scholar]
  31. White M. F., Kahn C. R. The insulin signaling system. J Biol Chem. 1994 Jan 7;269(1):1–4. [PubMed] [Google Scholar]
  32. Yang Y., Nunes F. A., Berencsi K., Furth E. E., Gönczöl E., Wilson J. M. Cellular immunity to viral antigens limits E1-deleted adenoviruses for gene therapy. Proc Natl Acad Sci U S A. 1994 May 10;91(10):4407–4411. doi: 10.1073/pnas.91.10.4407. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Yang Y., Nunes F. A., Berencsi K., Gönczöl E., Engelhardt J. F., Wilson J. M. Inactivation of E2a in recombinant adenoviruses improves the prospect for gene therapy in cystic fibrosis. Nat Genet. 1994 Jul;7(3):362–369. doi: 10.1038/ng0794-362. [DOI] [PubMed] [Google Scholar]

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