Gene Therapy for Antitumor Vaccination

  • Seunghee Kim-Schulze
  • Howard L. Kaufman
Part of the Methods in Molecular Biology™ book series (MIMB, volume 542)


Tumor immunotherapy depends on the interactions between the host, the tumor, and the immune system. Recent data suggests that priming of antigen-specific T cells alone may not be adequate for mediating regression of established tumors because of the immune inhibitory influences within the tumor microenvironment. Thus, we developed a recombinant vaccinia virus vector to express single or multiple T cell costimulatory molecules as a vector for local gene therapy in patients with malignant melanoma. This approach is feasible and generated local and systemic tumor immunity and induced objective clinical responses in patients with metastatic disease. This chapter reviews the details and major issues related to using live, replicating, recombinant poxviruses for gene delivery and antitumor vaccination within the tumor microenvironment.

Key Words

Antitumor vaccination mmunotherapy melanoma tumor antigen vaccinia virus 



We thank Dr. Bret Taback, Gail DeRaffele, RN, and Josephine Mitcham for clinical and data management support; and Dae Won Kim and Dorota Moroziewicz for technical assistance. This work was supported by National Institutes of Health (NIH) grant RO1 CA093696.


  1. 1.
    Zippelius, A., Batard, P. Rubio-Godoy, V. Bioley, G. Lienard, F. Lejeune, D. Rimoldi, P. Guillaume, N. Meidenbauer, A. Mackensen, N. Rufer, N. Lubenow, D. Speiser, J. C. Cerottini, P. Romero, and M. J. Pittet. (2004) Effector function of human tumor-specific CD8 T cells in melanoma lesions: a state of local functional tolerance. Cancer Res. 64, 2865–2873.PubMedCrossRefGoogle Scholar
  2. 2.
    Frumento, G., T. Piazza, E. Di Carlo, and S. Ferrini. (2006) Targeting tumor-related immunosuppression for cancer immunotherapy. Endocr Metab Immune Disord Drug Targets. 6, 233–237.PubMedCrossRefGoogle Scholar
  3. 3.
    Gajewski, T. F. (2000) Monitoring specific T-cell responses to melanoma vaccines: ELISPOT, tetramers, and beyond. Clin Diagn Lab Immunol. 7, 141–144.PubMedGoogle Scholar
  4. 4.
    Kaufman, H., J. Schlom, and J. Kantor. (1991) A recombinant vaccinia virus expressing human carcinoembryonic antigen (CEA). Int J Cancer. 48, 900–907.PubMedCrossRefGoogle Scholar
  5. 5.
    McAneny, D., C. A. Ryan, R. M. Beazley, and H. L. Kaufman. (1996) Results of a phase I trial of a recombinant vaccinia virus that expresses carcinoembryonic antigen in patients with advanced colorectal cancer. Ann Surg Oncol. 3, 495–500.PubMedCrossRefGoogle Scholar
  6. 6.
    Zang, X., andJ. P. Allison. (2007) The B7 family and cancer therapy: costimulation and coinhibition. Clin Cancer Res. 13, 5271–5279.PubMedCrossRefGoogle Scholar
  7. 7.
    7.Hodge, J., S. Abrams, J. Schlom, and J. Kantor. (1994) Induction of antitumor immunity by recombinant vaccinia viruses expressing B7–1 or B7–2 costimulatory molecules. Cancer Res. 54, 5552–5555.PubMedGoogle Scholar
  8. 8.
    Horig, H., D. S. Lee, W. Conkright, J. Divito, H. Hasson, M. LaMare, A. Rivera, D. Park, J. Tine, K. Guito, K. W. Tsang, J. Schlom, andH. L. Kaufman. (2000) Phase I clinical trial of a recombinant canarypoxvirus (ALVAC) vaccine expressing human carcinoembryonic antigen and the B7.1 co-stimulatory molecule. Cancer Immunol Immunother. 49, 504–514.PubMedCrossRefGoogle Scholar
  9. 9.
    Hodge, J. W., D. W. Grosenbach, A. N. Rad, M. Giuliano, H. Sabzevari, andJ. Schlom. (2001) Enhancing the potency of peptide-pulsed antigen presenting cells by vector-driven hyperexpression of a triad of costimulatory molecules. Vaccine. 19, 3552–3567.PubMedCrossRefGoogle Scholar
  10. 10.
    Hodge, J. W., J. W. Greiner, K. Y. Tsang, H. Sabzevari, C. Kudo-Saito, D. W. Grosenbach, J. L. Gulley, P. M. Arlen, J. L. Marshall, D. Panicali, andJ. Schlom. (2006) Costimulatory molecules as adjuvants for immunotherapy. Front Biosci. 11, 788–803.PubMedCrossRefGoogle Scholar
  11. 11.
    Kaufman, H. L., S. Kim-Schulze, K. Manson, G. Deraffele, J. Mitcham, K. S. Seo, D. W. Kim, andJ. Marshall. (2007) Poxvirus-based vaccine therapy for patients with advanced pancreatic cancer. J Transl Med. 5, 60.PubMedCrossRefGoogle Scholar
  12. 12.
    Hodge, J. W., H. Sabzevari, A. G. Yafal, L. Gritz, M. G. Lorenz, and J. Schlom. (1999) A triad of costimulatory molecules synergize to amplify T-cell activation. Cancer Res. 59, 5800–5807.PubMedGoogle Scholar
  13. 13.
    Marshall, J. L., R. J. Hoyer, M. A. Toomey, K. Faraguna, P. Chang, E. Richmond, J.E. Pedicano, E. Gehan, R. A. Peck, P. Arlen, K. Y. Tsang, and J. Schlom. (2000) Phase I study in advanced cancer patients of a diversified prime-and-boost vaccination protocol using recombinant vaccinia virus and recombinant nonreplicating avipox virus to elicit anti-carcinoembryonic antigen immune responses. J Clin Oncol. 18, 3964–3973.PubMedGoogle Scholar
  14. 14.
    Tirapu, I., E. Huarte, C. Guiducci, A. Arina, M. Zaratiegui, O. Murillo, A. Gonzalez, C. Berasain, P. Berraondo, P. Fortes, J. Prieto, M. P. Colombo, L. Chen, andI. Melero. (2006) Low surface expression of B7–1 (CD80) is an immunoescape mechanism of colon carcinoma. Cancer Res. 66, 2442–2450.PubMedCrossRefGoogle Scholar
  15. 15.
    Kaufman, H. L., G. DeRaffele, J. Mitcham, D. Moroziewicz, S. M. Cohen, K. S. Hurst-Wicker, K. Cheung, D. S. Lee, J. Divito, M. Voulo, J. Donovan, K. Dolan, K. Manson, D. Panicali, E. Wang, H. Hörig, and F. M. Marincola. (2005) Targeting the local tumor microenvironment with vaccinia virus expressing B7.1 for the treatment of melanoma. J Clin Invest. 115, 1903–-1912.PubMedCrossRefGoogle Scholar
  16. 16.
    Kaufman, H. L., S. Cohen, K. Cheung, G. DeRaffele, J. Mitcham, D. Moroziewicz, J. Schlom, and C. Hesdorffer. (2006) Local delivery of vaccinia virus expressing multiple costimulatory molecules for the treatment of established tumors. Hum Gene Ther. 17, 239–244.PubMedCrossRefGoogle Scholar
  17. 17.
    Kaufman, H. L., W. Conkright, J. Divito, H. Horig, R. Kaleya, D. Lee, S. Mani, D. Panicali, L. Rajdev, T. S. Ravikumar, S. Wise-Campbell, and M. J. Surhland. (2000) A phase I trial of intra lesional RV-B7.1 vaccine in the treatment of malignant melanoma. Hum Gene Ther. 11, 1065–1082.PubMedCrossRefGoogle Scholar
  18. 18.
    Kaufman, H. L., G. DeRaffele, J. Divito, H. Horig, D. Lee, D. Panicali, andM. Voulo. (2001) A phase I trial of intralesional rV-Tricom vaccine in the treatment of malignant melanoma. Hum Gene Ther. 12, 1459–1480.PubMedCrossRefGoogle Scholar
  19. 19.
    Panelli, M. C., E. Wang, G. Phan, M. Puhlmann, L. Miller, G. A. Ohnmacht, H. G. Klein, andF. M. Marincola. (2002) Gene-expression profiling of the response of peripheral blood mononuclear cells and melanoma metastases to systemic IL-2 administration. Genome Biol 3, RESEARCH0035.PubMedCrossRefGoogle Scholar
  20. 20.
    Panelli, M. C., E. Wang, V. Monsurro, and F. M. Marincola. (2002) The role of quantitative PCR for the immune monitoring of cancer patients. Expert Opin Biol Ther. 2, 557–564.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press, a part of Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Seunghee Kim-Schulze
    • 1
  • Howard L. Kaufman
    • 1
  1. 1.The Tumor Immunology Laboratory, Division of Surgical OncologyColumbia UniversityNew YorkUSA

Personalised recommendations