Gene-based vaccines and immunotherapeutics.
Journal: 2004/November - Proceedings of the National Academy of Sciences of the United States of America
ISSN: 0027-8424
Abstract:
DNA vaccines, comprised of plasmid DNA encoding proteins from pathogens, allergens, and tumors, are being evaluated as prophylactic vaccines and therapeutic treatments for infectious diseases, allergies, and cancer; plasmids encoding normal human proteins are likewise being tested as vaccines and treatments for autoimmune diseases. Examples of in vivo prophylaxis and immunotherapy, based on different types of immune responses (humoral and cellular), in a variety of disease models and under evaluation in early phase human clinical trials are presented. Viral vectors continue to show better levels of expression than those achieved by DNA plasmid vectors. We have focused our clinical efforts, at this time, on the use of recombinant viral vectors for both vaccine as well as cytokine gene transfer studies. We currently have four clinical programs in cancer immunotherapy. Two nonspecific immunotherapy programs are underway that apply adenoviral vectors for the transfer of cytokine genes into tumors in situ. An adenovirus-IFN gamma construct (TG1042) is currently being tested in phase II clinical trials in cutaneous lymphoma. A similar construct, adenovirus-IL2 (TG1024), also injected directly into solid tumors, is currently being tested in patients with solid tumors (about one-half of which are melanoma). Encouraging results are seen in both programs. Two cancer vaccine immunotherapy programs focus on two cancer-associated antigens: human papilloma virus E6 and E7 proteins and the epithelial cancer-associated antigen MUC1. Both are encoded by a highly attenuated vaccinia virus vector [modified vaccinia Ankara (MVA)] and both are coexpressed with IL-2. Encouraging results seen in both of these programs are described.
Relations:
Content
Citations
(27)
References
(20)
Diseases
(7)
Drugs
(1)
Chemicals
(4)
Organisms
(1)
Similar articles
Articles by the same authors
Discussion board
Proc Natl Acad Sci U S A 101(Suppl 2): 14567-14571

Gene-based vaccines and immunotherapeutics

Transgene, 11 Rue de Molsheim, 67082 Strasbourg, France
To whom correspondence should be addressed. E-mail: rf.enegsnart@uil.
M.L. is the vice president of the board of directors of Transgene.

Abstract

DNA vaccines, comprised of plasmid DNA encoding proteins from pathogens, allergens, and tumors, are being evaluated as prophylactic vaccines and therapeutic treatments for infectious diseases, allergies, and cancer; plasmids encoding normal human proteins are likewise being tested as vaccines and treatments for autoimmune diseases. Examples of in vivo prophylaxis and immunotherapy, based on different types of immune responses (humoral and cellular), in a variety of disease models and under evaluation in early phase human clinical trials are presented. Viral vectors continue to show better levels of expression than those achieved by DNA plasmid vectors. We have focused our clinical efforts, at this time, on the use of recombinant viral vectors for both vaccine as well as cytokine gene transfer studies. We currently have four clinical programs in cancer immunotherapy. Two nonspecific immunotherapy programs are underway that apply adenoviral vectors for the transfer of cytokine genes into tumors in situ. An adenovirus-IFNγ construct (TG1042) is currently being tested in phase II clinical trials in cutaneous lymphoma. A similar construct, adenovirus-IL2 (TG1024), also injected directly into solid tumors, is currently being tested in patients with solid tumors (about one-half of which are melanoma). Encouraging results are seen in both programs. Two cancer vaccine immunotherapy programs focus on two cancer-associated antigens: human papilloma virus E6 and E7 proteins and the epithelial cancer-associated antigen MUC1. Both are encoded by a highly attenuated vaccinia virus vector [modified vaccinia Ankara (MVA)] and both are coexpressed with IL-2. Encouraging results seen in both of these programs are described.

Abstract

It has been a dream of immunologists, starting with the impressive results of William Coley at the beginning of the last century (1) and reactivated in the 1970s, that the power of the immune response could be harnessed and applied to the specific elimination of cancerous cells. Cytokine molecules, which boost the immune system, first purified from tissue culture, then cloned and made available in recombinant form, have been applied to the treatment of cancer by systemic injection. This treatment has resulted in some serious dose-limiting toxicities. Nevertheless, recombinant IL-2 and IFN-α are now applied to the treatment of kidney cancer and melanoma. In this overview, we describe two cytokine gene therapy vectors that Transgene has produced and is testing clinically. These recombinant adenoviruses are injected directly into solid tumors and result in the intratumoral expression of cytokine genes in cells within the tumor. This way, high doses of cytokine are produced locally, but there is much reduced toxicity known to be associated with systemic delivery of the recombinant cytokine protein (2).

Since the 1980s (3) antigens associated with cancer cells have been identified and cloned. These cancer-associated antigens have been applied to the immunotherapy of cancer by vaccination. It has become clear that simple vaccination as applied to healthy individuals for the prevention of pathological infections rarely, if ever, works in the cancer setting. This appears to be the result of immune regulation. As part of the selective process for the growth of a tumor, the tumor itself produces a variety of immunosuppressive molecules or it reduces its own expression of antigens or antigen-presenting molecules. In addition, most tumor-associated antigens are “self” antigens and therefore are protected from immune attack by a complex immune tolerance mechanism. Nevertheless, our understanding of these mechanisms improves continually, and various cancer vaccine immunotherapy strategies are now being tested in the clinic. Below we describe two such vaccines currently in clinical development at Transgene. Both rely on the highly attenuated vaccinia pox virus, modified vaccinia Ankara (MVA) (4). One such vector, MVA-HPV-IL2 expresses the human papilloma virus (HPV)-associated oncogenes HPV16-E6 and -E7 (both mutated to maintain antigenicity but to interrupt oncogenic potential). This vector also expresses the cytokine IL-2 to provide, locally, a boost to the immune response in cancer patients whose immune system is impaired. Because the antigens E6 and E7 are viral antigens, the issue of “self-tolerance” should not pose any problems. Clinical studies with this vector are briefly described below. A second cancer vaccine immunotherapeutic, involving the epithelial cancer-associated molecule MUC1, is also described. This vector is applicable to a wide variety of common cancers. Both MUC1 and IL-2 are expressed with the intention of overcoming not only the immune anergy associated with advanced cancer, but also the self-tolerance associated with MUC1.

Notes

This paper results from the Arthur M. Sackler Colloquium of the National Academy of Sciences, “Therapeutic Vaccines: Realities of Today and Hopes for Tomorrow,” held April 1–3, 2004, at the National Academy of Sciences in Washington, DC.

Abbreviations: HPV, human papilloma virus; MVA, modified vaccinia Ankara; PSA, prostate-specific antigen.

Notes
This paper results from the Arthur M. Sackler Colloquium of the National Academy of Sciences, “Therapeutic Vaccines: Realities of Today and Hopes for Tomorrow,” held April 1–3, 2004, at the National Academy of Sciences in Washington, DC.
Abbreviations: HPV, human papilloma virus; MVA, modified vaccinia Ankara; PSA, prostate-specific antigen.

Footnotes

Scholl, S., Acres, B., Schatz, C., Kieny, M-P., Balloul, J.-M., Vincent-Salomon, V., Deneaux, L., Tartour, E., Fridman, H. & Pouillart, P. (1997) Breast Cancer Res. Treat. Vol. 46, p. 67 (abstr.).

Footnotes

References

  • 1. Coley, W. B. (1906) Am. J. Med. Sci.131, 375-428. [PubMed]
  • 2. MacFarlane, M. P., Yang, J. C., Guleria, A. S., White, R. L., Jr., Seipp, C. A., Einhorn, J. H., White, D. E. & Rosenberg, S. A. (1995) Cancer75, 1030-1037. [[PubMed]
  • 3. Knuth, A., Wolfel, T., Klehmann, E., Boon, T. & Meyer zum Buschenfelde, K. H. (1989) Proc. Natl. Acad. Sci. USA86, 2804-2808.
  • 4. Sutter, G. & Moss, B. (1992) Proc. Natl. Acad. Sci. USA89, 10847-10851.
  • 5. Slos, P., De Meyer, M., Leroy, P., Rousseau, C. & Acres, B. (2001) Cancer Gene Ther.8, 321-332. [[PubMed]
  • 6. Dummer, R., Hassel, J. C., Maier, T., Slos, P., Eichmüller, S., Acres, B., Bleuzen, P., Bataille, V., Squiban, P., Burg, G. & Urosevic, M. (July 8, 2004) Blood, 10.1182/blood-2004-01-0360.
  • 7. Griffiths, A. B., Burchell, J., Gendler, S., Lewis, A., Blight, K., Tilly, R. & Taylor-Papadimitriou, J. (1987) Int. J. Cancer40, 319-327. [[PubMed]
  • 8. Hayes, D. F., Sekine, H., Ohno, T., Abe, M., Keefe, K. & Kufe, D. W. (1985) J. Clin. Invest.75, 1671-1678.
  • 9. Burchell, J. & Taylor-Papadimitriou, J. (1989) Cancer Invest.7, 53-61. [[PubMed]
  • 10. Teh, J. G., Xing, P. X. & McKenzie, I. F. (1990) Immunol. Cell Biol.68, 207-216. [[PubMed]
  • 11. Brossart, P., Heinrich, K. S., Stuhler, G., Behnke, L., Reichardt, V. L., Stevanovic, S., Muhm, A., Rammensee, H. G., Kanz, L. & Brugger, W. (1999) Blood93, 4309-4317. [[PubMed]
  • 12. Scholl, S. M., Balloul, J. M., Le Goc, G., Bizouarne, N., Schatz, C., Kieny, M. P., von Mensdorff-Pouilly, S., Vincent-Salomon, A., Deneux, L., Tartour, E., et al. (2000) J. Immunother.23, 570-580. [[PubMed]
  • 13. Barnd, D. L., Lan, M. S., Metzgar, R. S. & Finn, O. J. (1989) Proc. Natl. Acad. Sci. USA86, 7159-7163.
  • 14. Wajchman, H. J., Pierce, C. W., Varma, V. A., Issa, M. M., Petros, J. & Dombrowski, K. E. (2004) Cancer Res.64, 1171-1180. [[PubMed]
  • 15. Blades, R. A., Keating, P. J., McWilliam, L. J., George, N. J. & Stern, P. L. (1995) Urology46, 681-686; discussion 686-687. [[PubMed]
  • 16. Sharpe, J. C., Abel, P. D., Gilbertson, J. A., Brawn, P. & Foster, C. S. (1994) Br. J. Urol.74, 609-616. [[PubMed]
  • 17. Pantuck, A. J., van Ophoven, A., Gitlitz, B. J., Tso, C.-L., Acres, B., Squiban, P., Ross, M. E., Belldegrun, A. S. & Figlin, R. A. (2004) J. Immunother.27, 240-253. [[PubMed]
  • 18. Scholl, S., Squiban, P., Bizouarne, N., Baudin, M., Acres, B., Von Mensdorff-Pouilly, S., Shearer, M., Beuzeboc, P., Van Belle, S., Uzielly, B., et al. (2003) J. Biomed. Biotechnol.3, 194-201.
  • 19. Rochlitz, C., Figlin, R., Squiban, P., Salzberg, M., Pless, M., Herrmann, R., Tartour, E., Zhao, Y., Bizouarne, N., Baudin, M. & Acres, B. (2003) J. Gene Med.5, 690-699. [[PubMed]
  • 20. Lin, K. Y., Guarnieri, F. G., Staveley-O'Carroll, K. F., Levitsky, H. I., August, J. T., Pardoll, D. M. & Wu, T. C. (1996) Cancer Res.56, 21-26. [[PubMed]
  • 21. Phan, G. Q., Yang, J. C., Sherry, R. M., Hwu, P., Topalian, S. L., Schwartzentruber, D. J., Restifo, N. P., Haworth, L. R., Seipp, C. A., Freezer, L. J., et al. (2003) Proc. Natl. Acad. Sci. USA100, 8372-8377.
  • 22. McHugh, R. S., Whitters, M. J., Piccirillo, C. A., Young, D. A., Shevach, E. M., Collins, M. & Byrne, M. C. (2002) Immunity16, 311-323. [[PubMed]
Collaboration tool especially designed for Life Science professionals.Drag-and-drop any entity to your messages.