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Tumor gene therapy by MVA-mediated expression of T-cell–stimulating antibodies

Cancer Gene Therapy volume 9, pages 470–477 (2002)Cite this article

Abstract

Immune responses to tumor-associated antigens are often dampened by a tumor-induced state of immune anergy. Previous work has attempted to overcome tumor-induced T-cell anergy by the direct injection of vectors carrying the genes encoding one of a variety of cytokines. We hypothesised that the polyclonal stimulation of T cells, preferably through the TCR complex, would result in a cascade of cytokines associated with T-cell activation and would be best able to overcome T-cell anergy. Here we use the highly attenuated MVA poxvirus to express on tumor cells, in vitro and in vivo, either of three membrane-bound monoclonal antibodies specific for murine TCR complex. Using this system, we have expressed antibodies specific for the CD3ɛ chain (KT3), TCRα/β complex (H57-597), and Vβ7 chain (TR310). Tumor cells bristling with these antibodies are capable of inducing murine T-cell proliferation and cytokine production. When injected into growing tumors (P815, RenCa, and B16F10), these constructs induce the activation of immune effector cells and result in the rejection of the tumor. Histological and FACS analysis of tumor-infiltrating leukocytes reveal that the injection of recombinant virus-expressing antibodies specific for the TCR complex attracts and activates (CD25+, CD69+) CD4 and CD8 lymphocytes. This approach represents a novel strategy to overcome T-cell anergy in tumors and allow the stimulation of tumor-specific T cells.

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References

  1. Weijtens ME, Willemsen RA, Valerio D, Stam K, Bolhuis RL . Single chain Ig/gamma gene-redirected human T lymphocytes produce cytokines, specifically lyse tumor cells, and recycle lytic capacity J Immunol 1996 157: 836–843

    CAS  PubMed  Google Scholar 

  2. Tibben JG et al. Pharmacokinetics, biodistribution and biological effects of intravenously administered bispecific monoclonal antibody OC/TR F(ab′)2 in ovarian carcinoma patients Int J Cancer 1996 66: 477–483

    Article  CAS  Google Scholar 

  3. Chattopadhyay U . Tumour immunotherapy: developments and strategies Immunol Today 1999 20: 480–482

    Article  CAS  Google Scholar 

  4. Nanni P, Forni G, Lollini PL . Cytokine gene therapy: hopes and pitfalls Ann Oncol 1999 10: 261–266

    Article  CAS  Google Scholar 

  5. Meuer SC et al. Antigen-like effects of monoclonal antibodies directed at receptors on human T cell clones J Exp Med 1983 158: 988–993

    Article  CAS  Google Scholar 

  6. Ellenhorn JD, Hirsch R, Schreiber H, Bluestone JA . In vivo administration of anti-CD3 prevents malignant progressor tumor growth Science 1988 242: 569–571

    Article  CAS  Google Scholar 

  7. Liao KW, Lo YC, Roffler SR . Activation of lymphocytes by anti–CD3 single-chain antibody dimers expressed on the plasma membrane of tumor cells Gene Ther 2000 7: 339–347

    Article  CAS  Google Scholar 

  8. de Ines C, Cochlovius B, Schmidt S, Kipriyanov S, Rode HJ, Little M . Apoptosis of a human melanoma cell line specifically induced by membrane-bound single-chain antibodies JImmunol 1999 163: 3948–3956

    CAS  Google Scholar 

  9. Paul S, Snary D, Hoebeke J et al. Redirection of macrophage cytotoxicity using a non-replicative live vector expressing a tumor-specific scFv Hum Gene Ther 2000 11: 1417–1428

    Article  CAS  Google Scholar 

  10. Xie YC, Hwang C, Overwijk W et al. Induction of tumor antigen-specific immunity in vivo by a novel vaccinia vector encoding safety-modified simian virus 40 T antigen J Natl Cancer Inst 1999 91: 169–175

    Article  CAS  Google Scholar 

  11. Venkatesan S, Baroudy BM, Moss B . Distinctive nucleotide sequences adjacent to multiple initiation and termination sites of an early vaccinia virus gene Cell 1981 25: 805–813

    Article  CAS  Google Scholar 

  12. Chen L . Overcoming T cell ignorance by providing costimulation. Implications for the immune response against cancer Adv Exp Med Biol 1998 451: 159–165

    Article  CAS  Google Scholar 

  13. Anilionis A, Wunner WH, Curtis PJ . Structure of the glycoprotein gene in rabies virus Nature 1981 294: 275–278

    Article  CAS  Google Scholar 

  14. Mendiratta SK et al. Intratumoral delivery of IL-12 gene by polyvinyl polymeric vector system to murine renal and colon carcinoma results in potent antitumor immunity Gene Ther 1999 6: 833–839

    Article  CAS  Google Scholar 

  15. Tomonari K . A rat antibody against a structure functionally related to the mouse T-cell receptor/T3 complex Immunogenetics 1988 28: 455–458

    Article  CAS  Google Scholar 

  16. Kubo RT, Born W, Kappler JW, Marrack P, Pigeon M . Characterization of a monoclonal antibody which detects all murine alpha beta T cell receptors J Immunol 1989 142: 2736–2742

    CAS  PubMed  Google Scholar 

  17. Okada CY, Holzmann B, Guidos C, Palmer E, Weissman IL . Characterization of a rat monoclonal antibody specific for a determinant encoded by the V beta 7 gene segment. Depletion of V beta 7+ T cells in mice with Mls-1a haplotype JImmunol 1990 144: 3473–3477

    CAS  Google Scholar 

  18. Paul S et al. Redirected cellular cytotoxicity by infection of effector cells with a recombinant vaccinia virus encoding a tumor-specific monoclonal antibody Cancer Gene Ther 2000 7: 615–623

    Article  CAS  Google Scholar 

  19. Gajewski TF, Schell SR, Nau G, Fitch FW . Regulation of T-cell activation: differences among T-cell subsets Immunol Rev 1989 111: 79–110

    Article  CAS  Google Scholar 

  20. Krutmann J, Kirnbauer R, Kock A et al. Cross-linking Fc receptors on monocytes triggers IL-6 production. Role in anti–CD3-induced T cell activation J Immunol 1990 145: 1337–1342

    CAS  PubMed  Google Scholar 

  21. Zanders ED, Lamb JR, Feldmann M, Green N, Beverley PC . Tolerance of T-cell clones is associated with membrane antigen changes Nature 1983 303: 625–627

    Article  CAS  Google Scholar 

  22. Norman DJ et al. A US clinical study of Orthoclone OKT3 in renal transplantation Transplant Proc 1987 19: 21–27

    CAS  PubMed  Google Scholar 

  23. Henrickson M, Reid J, Bellet JS, Sawchuk SS, Hirsch R . Comparison of in vivo efficacy and mechanism of action of antimurine monoclonal antibodies directed against TCR alpha beta (H57-597) and CD3 (145-2C11) Transplantation 1995 60: 828–835

    Article  CAS  Google Scholar 

  24. Weijtens ME, Hart EH, Bolhuis RL . Functional balance between T cell chimeric receptor density and tumor associated antigen density: CTL mediated cytolysis and lymphokine production Gene Ther 2000 7: 35–42

    Article  CAS  Google Scholar 

  25. Takahashi K, Ono K, Hirabayashi Y, Taniguchi M . Escape mechanisms of melanoma from immune system by soluble melanoma antigen J Immunol 1988 140: 3244–3248

    CAS  PubMed  Google Scholar 

  26. Banat GA, Christ O, Cochlovirus B, Pralle HB, Zoller M . Tumour-induced suppression of immune response and its correction Cancer Immunol Immunother 2001 49: 573–586

    Article  CAS  Google Scholar 

  27. Gregorian SK, Battisto JR . Immunosuppression in murine renal cell carcinoma: I. Characterization of extent, severity and sources Cancer Immunol Immunother 1990 31: 325–334

    Article  CAS  Google Scholar 

  28. Gregorian SK, Battisto JR . Immunosuppression in murine renal cell carcinoma: II. Identification of responsible lymphoid cell phenotypes and examination of elimination of suppression Cancer Immunol Immunother 1990 31: 335–341

    Article  CAS  Google Scholar 

  29. Cavallo F, Martin-Fontecha A, Bellone M et al. Co-expression of B7-1 and ICAM-1 on tumors is required for rejection and the establishment of a memory response Eur J Immunol 1995 25: 1154–1162

    Article  CAS  Google Scholar 

  30. Kufer P et al. Construction and biological activity of a recombinant bispecific single-chain antibody designed for therapy of minimal residual colorectal cancer Cancer Immunol Immunother 1997 45: 193–197

    Article  CAS  Google Scholar 

  31. Richards J, Auger J, Peace D et al. Phase I evaluation of humanized OKT3: toxicity and immunomodulatory effects of hOKT3gamma4 Cancer Res 1999 59: 2096–2101

    CAS  Google Scholar 

  32. Gilboa E . How tumors escape immune destruction and what we can do about it Cancer Immunol Immunother 1999 48: 382–385

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors sincerely thank K Dott and J Kintz for technical assistance, and P Slos and P Erbs for help in statistical analysis. This work was supported, in part, by the Convention Industrielle pour la Formation par la Recherche CIFRE.

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Authors and Affiliations

  1. Clinical and Experimental Immunology Laboratory, Transgene, Strasbourg, 67082, France

    Stephane Paul, Ronald Rooke, Fabienne Stoeckel & R Bruce Acres

  2. Molecular Immunology Laboratory, Transgene, Strasbourg, 67082, France

    Etienne Regulier, Michel Geist, Horst Homann, Jean-Marc Balloul, Dominique Villeval & Yves Poitevin

  3. INSERM U74, Strasbourg, 67000, France

    Marie-Paule Kieny

Authors
  1. Stephane Paul
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  2. Etienne Regulier
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Correspondence to Stephane Paul.

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Paul, S., Regulier, E., Rooke, R. et al. Tumor gene therapy by MVA-mediated expression of T-cell–stimulating antibodies. Cancer Gene Ther 9, 470–477 (2002). https://doi.org/10.1038/sj.cgt.7700461

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