Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1997 Nov 1;100(9):2218–2226. doi: 10.1172/JCI119759

Phase I trial of recombinant adenovirus gene transfer in lung cancer. Longitudinal study of the immune responses to transgene and viral products.

H Gahéry-Ségard 1, V Molinier-Frenkel 1, C Le Boulaire 1, P Saulnier 1, P Opolon 1, R Lengagne 1, E Gautier 1, A Le Cesne 1, L Zitvogel 1, A Venet 1, C Schatz 1, M Courtney 1, T Le Chevalier 1, T Tursz 1, J G Guillet 1, F Farace 1
PMCID: PMC508417  PMID: 9410899

Abstract

Animal studies indicate that the use of replication-deficient adenovirus for human gene therapy is limited by host antivector immune responses that result in transient recombinant protein expression and blocking of gene transfer when rechallenged. Therefore, we have examined immune responses to an adenoviral vector and to the beta-galactosidase protein in four patients with lung cancer given a single intratumor injection of 10(9) plaque-forming units of recombinant adenovirus. The beta-galactosidase protein was expressed in day-8 tumor biopsies from all patients at variable levels. Recombinant virus DNA was detected by PCR in day-30 and day-60 tumor biopsies from all patients except patient 1. A high level of neutralizing antiadenovirus antibodies was detected in patient 1 before Ad-beta-gal injection whereas it was low (patient 3) or undetectable in the other two patients. All patients developed potent CD4 type 1 helper T cell (Th1) responses to adenoviral particles which increased gradually over time after injection. Antiadenovirus cytotoxic T lymphocyte responses were consistently boosted in the two patients examined (patients 3 and 4). Sustained production of anti-beta-galactosidase IgG was observed in all patients except patient 1. Consistent with anti-beta-gal antibody production, all patients except patient 1 developed intense, dose-dependent Th1 responses to soluble beta-galactosidase which increased over time. Strong beta-galactosidase-specific cytotoxic T lymphocyte responses were detected in patients 2, 3, and 4. Our results clearly show that despite the intensity of antiadenovirus responses, transgene protein expression was sufficient to induce strong and prolonged immunity in three patients. Recombinant adenovirus injected directly into the tumor is a highly efficient vector for immunizing patients against the transgene protein.

Full Text

The Full Text of this article is available as a PDF (298.7 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Addison C. L., Braciak T., Ralston R., Muller W. J., Gauldie J., Graham F. L. Intratumoral injection of an adenovirus expressing interleukin 2 induces regression and immunity in a murine breast cancer model. Proc Natl Acad Sci U S A. 1995 Aug 29;92(18):8522–8526. doi: 10.1073/pnas.92.18.8522. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Both G. W., Lockett L. J., Janardhana V., Edwards S. J., Bellamy A. R., Graham F. L., Prevec L., Andrew M. E. Protective immunity to rotavirus-induced diarrhoea is passively transferred to newborn mice from naive dams vaccinated with a single dose of a recombinant adenovirus expressing rotavirus VP7sc. Virology. 1993 Apr;193(2):940–950. doi: 10.1006/viro.1993.1203. [DOI] [PubMed] [Google Scholar]
  3. Chen P. W., Wang M., Bronte V., Zhai Y., Rosenberg S. A., Restifo N. P. Therapeutic antitumor response after immunization with a recombinant adenovirus encoding a model tumor-associated antigen. J Immunol. 1996 Jan 1;156(1):224–231. [PMC free article] [PubMed] [Google Scholar]
  4. Clayman G. L., el-Naggar A. K., Roth J. A., Zhang W. W., Goepfert H., Taylor D. L., Liu T. J. In vivo molecular therapy with p53 adenovirus for microscopic residual head and neck squamous carcinoma. Cancer Res. 1995 Jan 1;55(1):1–6. [PubMed] [Google Scholar]
  5. Flomenberg P., Piaskowski V., Truitt R. L., Casper J. T. Human adenovirus-specific CD8+ T-cell responses are not inhibited by E3-19K in the presence of gamma interferon. J Virol. 1996 Sep;70(9):6314–6322. doi: 10.1128/jvi.70.9.6314-6322.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Gallichan W. S., Johnson D. C., Graham F. L., Rosenthal K. L. Mucosal immunity and protection after intranasal immunization with recombinant adenovirus expressing herpes simplex virus glycoprotein B. J Infect Dis. 1993 Sep;168(3):622–629. doi: 10.1093/infdis/168.3.622. [DOI] [PubMed] [Google Scholar]
  7. Juillard V., Villefroy P., Godfrin D., Pavirani A., Venet A., Guillet J. G. Long-term humoral and cellular immunity induced by a single immunization with replication-defective adenovirus recombinant vector. Eur J Immunol. 1995 Dec;25(12):3467–3473. doi: 10.1002/eji.1830251239. [DOI] [PubMed] [Google Scholar]
  8. Liu T. J., el-Naggar A. K., McDonnell T. J., Steck K. D., Wang M., Taylor D. L., Clayman G. L. Apoptosis induction mediated by wild-type p53 adenoviral gene transfer in squamous cell carcinoma of the head and neck. Cancer Res. 1995 Jul 15;55(14):3117–3122. [PubMed] [Google Scholar]
  9. McElvaney N. G., Crystal R. G. IL-6 release and airway administration of human CFR cDNA adenovirus vector. Nat Med. 1995 Mar;1(3):182–184. doi: 10.1038/nm0395-182b. [DOI] [PubMed] [Google Scholar]
  10. O'Malley B. W., Jr, Chen S. H., Schwartz M. R., Woo S. L. Adenovirus-mediated gene therapy for human head and neck squamous cell cancer in a nude mouse model. Cancer Res. 1995 Mar 1;55(5):1080–1085. [PubMed] [Google Scholar]
  11. Quantin B., Perricaudet L. D., Tajbakhsh S., Mandel J. L. Adenovirus as an expression vector in muscle cells in vivo. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):2581–2584. doi: 10.1073/pnas.89.7.2581. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Rodrigues E. G., Zavala F., Eichinger D., Wilson J. M., Tsuji M. Single immunizing dose of recombinant adenovirus efficiently induces CD8+ T cell-mediated protective immunity against malaria. J Immunol. 1997 Feb 1;158(3):1268–1274. [PubMed] [Google Scholar]
  13. Rosenfeld M. A., Yoshimura K., Trapnell B. C., Yoneyama K., Rosenthal E. R., Dalemans W., Fukayama M., Bargon J., Stier L. E., Stratford-Perricaudet L. In vivo transfer of the human cystic fibrosis transmembrane conductance regulator gene to the airway epithelium. Cell. 1992 Jan 10;68(1):143–155. doi: 10.1016/0092-8674(92)90213-v. [DOI] [PubMed] [Google Scholar]
  14. Stratford-Perricaudet L. D., Levrero M., Chasse J. F., Perricaudet M., Briand P. Evaluation of the transfer and expression in mice of an enzyme-encoding gene using a human adenovirus vector. Hum Gene Ther. 1990 Fall;1(3):241–256. doi: 10.1089/hum.1990.1.3-241. [DOI] [PubMed] [Google Scholar]
  15. Stratford-Perricaudet L. D., Makeh I., Perricaudet M., Briand P. Widespread long-term gene transfer to mouse skeletal muscles and heart. J Clin Invest. 1992 Aug;90(2):626–630. doi: 10.1172/JCI115902. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Taswell C. Limiting dilution assays for the determination of immunocompetent cell frequencies. I. Data analysis. J Immunol. 1981 Apr;126(4):1614–1619. [PubMed] [Google Scholar]
  17. Tripathy S. K., Black H. B., Goldwasser E., Leiden J. M. Immune responses to transgene-encoded proteins limit the stability of gene expression after injection of replication-defective adenovirus vectors. Nat Med. 1996 May;2(5):545–550. doi: 10.1038/nm0596-545. [DOI] [PubMed] [Google Scholar]
  18. Tursz T., Cesne A. L., Baldeyrou P., Gautier E., Opolon P., Schatz C., Pavirani A., Courtney M., Lamy D., Ragot T. Phase I study of a recombinant adenovirus-mediated gene transfer in lung cancer patients. J Natl Cancer Inst. 1996 Dec 18;88(24):1857–1863. doi: 10.1093/jnci/88.24.1857. [DOI] [PubMed] [Google Scholar]
  19. Van Ginkel F. W., Liu C., Simecka J. W., Dong J. Y., Greenway T., Frizzell R. A., Kiyono H., McGhee J. R., Pascual D. W. Intratracheal gene delivery with adenoviral vector induces elevated systemic IgG and mucosal IgA antibodies to adenovirus and beta-galactosidase. Hum Gene Ther. 1995 Jul;6(7):895–903. doi: 10.1089/hum.1995.6.7-895. [DOI] [PubMed] [Google Scholar]
  20. Venet A., Bourgault I., Aubertin A. M., Kiény M. P., Levy J. P. Cytotoxic T lymphocyte response against multiple simian immunodeficiency virusA (SIV) proteins in SIV-infected macaques. J Immunol. 1992 May 1;148(9):2899–2908. [PubMed] [Google Scholar]
  21. Warnier G., Duffour M. T., Uyttenhove C., Gajewski T. F., Lurquin C., Haddada H., Perricaudet M., Boon T. Induction of a cytolytic T-cell response in mice with a recombinant adenovirus coding for tumor antigen P815A. Int J Cancer. 1996 Jul 17;67(2):303–310. doi: 10.1002/(SICI)1097-0215(19960717)67:2<303::AID-IJC24>3.0.CO;2-A. [DOI] [PubMed] [Google Scholar]
  22. Wesseling J. G., Godeke G. J., Schijns V. E., Prevec L., Graham F. L., Horzinek M. C., Rottier P. J. Mouse hepatitis virus spike and nucleocapsid proteins expressed by adenovirus vectors protect mice against a lethal infection. J Gen Virol. 1993 Oct;74(Pt 10):2061–2069. doi: 10.1099/0022-1317-74-10-2061. [DOI] [PubMed] [Google Scholar]
  23. Wilson J. M. Cystic fibrosis. Vehicles for gene therapy. Nature. 1993 Oct 21;365(6448):691–692. doi: 10.1038/365691a0. [DOI] [PubMed] [Google Scholar]
  24. Xiang Z. Q., Yang Y., Wilson J. M., Ertl H. C. A replication-defective human adenovirus recombinant serves as a highly efficacious vaccine carrier. Virology. 1996 May 1;219(1):220–227. doi: 10.1006/viro.1996.0239. [DOI] [PubMed] [Google Scholar]
  25. Yang Y., Ertl H. C., Wilson J. M. MHC class I-restricted cytotoxic T lymphocytes to viral antigens destroy hepatocytes in mice infected with E1-deleted recombinant adenoviruses. Immunity. 1994 Aug;1(5):433–442. doi: 10.1016/1074-7613(94)90074-4. [DOI] [PubMed] [Google Scholar]
  26. Yang Y., Li Q., Ertl H. C., Wilson J. M. Cellular and humoral immune responses to viral antigens create barriers to lung-directed gene therapy with recombinant adenoviruses. J Virol. 1995 Apr;69(4):2004–2015. doi: 10.1128/jvi.69.4.2004-2015.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. 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]
  28. Yang Y., Trinchieri G., Wilson J. M. Recombinant IL-12 prevents formation of blocking IgA antibodies to recombinant adenovirus and allows repeated gene therapy to mouse lung. Nat Med. 1995 Sep;1(9):890–893. doi: 10.1038/nm0995-890. [DOI] [PubMed] [Google Scholar]
  29. Zabner J., Couture L. A., Gregory R. J., Graham S. M., Smith A. E., Welsh M. J. Adenovirus-mediated gene transfer transiently corrects the chloride transport defect in nasal epithelia of patients with cystic fibrosis. Cell. 1993 Oct 22;75(2):207–216. doi: 10.1016/0092-8674(93)80063-k. [DOI] [PubMed] [Google Scholar]
  30. Zabner J., Ramsey B. W., Meeker D. P., Aitken M. L., Balfour R. P., Gibson R. L., Launspach J., Moscicki R. A., Richards S. M., Standaert T. A. Repeat administration of an adenovirus vector encoding cystic fibrosis transmembrane conductance regulator to the nasal epithelium of patients with cystic fibrosis. J Clin Invest. 1996 Mar 15;97(6):1504–1511. doi: 10.1172/JCI118573. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Zhai Y., Yang J. C., Kawakami Y., Spiess P., Wadsworth S. C., Cardoza L. M., Couture L. A., Smith A. E., Rosenberg S. A. Antigen-specific tumor vaccines. Development and characterization of recombinant adenoviruses encoding MART1 or gp100 for cancer therapy. J Immunol. 1996 Jan 15;156(2):700–710. [PubMed] [Google Scholar]
  32. Zhang J. F., Hu C., Geng Y., Selm J., Klein S. B., Orazi A., Taylor M. W. Treatment of a human breast cancer xenograft with an adenovirus vector containing an interferon gene results in rapid regression due to viral oncolysis and gene therapy. Proc Natl Acad Sci U S A. 1996 Apr 30;93(9):4513–4518. doi: 10.1073/pnas.93.9.4513. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES