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Springer Seminars in Immunopathology

, Volume 18, Issue 2, pp 199–209 | Cite as

The T-body approach: potential for cancer immunotherapy

  • Zelig Eshhar
  • Nathan Bach
  • Cheryl J. Fitzer-Attas
  • Gidi Grosse
  • Joseph Lustgarten
  • Tova Waks
  • Daniel G. Schindler
Article

Conclusions

Chimeric receptors containing antibody-derived Fv or scFv as their extracellular recognition elements can redirect the specificity of T cells in an MHC-independent manner.

Upon encountering their target cells, such T-bodies are able to undergo specific stimulation for interleukin/cytokine production, and kill hapten-modified or tumor cells in both in vitro and in vivo model systems. T cells expressing chimeric receptors are able to discriminate between antigen-expressing and normal cells, with negligible bystander cytotoxicity. Unlike antibodies, T cells are well suited to penetrate and destroy solid tumors. Further in vivo studies should be carried out to evaluate and optimize the persistence, homing patterns, and reactivation potential of T-bodies in vivo.

Several technical obstacles must be overcome before this approach may be applied clinically. A most urgent problem is the low efficiency of T cell transfection techniques and the particular difficulty of transducing primary T cell populations. While retroviral-mediated gene transfer is more efficient than conventional techniques such as electroporation, the proportion of transfected cells remains low, necessitating an enrichment step. In addition, antibodies with improved discrimination between cell-bound and soluble forms of tumor antigens must be obtained to expand the repertoire of tumor antigens which may be targeted. For each antigen-antibody system, the optimal design of the scFv must be determined.

In the future application of this technology, the recognition element used for chimeric TCR is not limited to antibody-derived fragments [27]. Various ligands may be coupled to a T cell-triggering molecule in an attempt to redirect cytotoxic function towards target cells expressing a particular receptor molecule. Although still experimental, we feel that with fine tuning, the T-body approach shows promise as an efficient and broad-spectrum modality for tumor immunotherapy.

Keywords

Tumor Antigen Cancer Immunotherapy Receptor Molecule Approach Show Recognition Element 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Bach N, Waks T, Eshhar Z (1995) Specific lysis of tumor cells by a natural-killer-like cell line transfected with chimeric receptor genes. Tumor Targetting. 1: 203Google Scholar
  2. 2.
    Bach NL, Waks T, Schindler DG, Eshhar Z (1994) Functional expression in mast cells of chimeric receptors with antibody specificity. Cell Biophys. 24: 229Google Scholar
  3. 3.
    Becker MLB, Near R, Mudgett-Hunter M, Margolies MN, Kubo RT, Kaye J, Hedrick SM (1989) Expression of a hybrid immunoglobulin-T cell receptor protein in transgenic mice. Cell 58: 911Google Scholar
  4. 4.
    Bird RE, Hardman KD, Jacobson JW, Johnson S, Kaufman BM, Lee S-M, Lee T, Pope SH, Riordan GS, Whitlow M (1988) Single chain antigen binding proteins. Science 242: 423Google Scholar
  5. 5.
    Brocker T, Peter A, Traunecker A, Karjalainen K (1993) A new simplified molecular design for functional T cell receptor. Eur J Immunol 23: 1435Google Scholar
  6. 6.
    Brocker T, Karjalainen K (1995) Signals through T cell receptor-zeta chain alone are insufficient to prime resting T lymphocytes. J Exp Med 181: 1653Google Scholar
  7. 7.
    Classon BJ, Brown MH, Garnett D, Somoza C, Barclay AN, Willis AC, Williams AF (1992) The hinge region of the CD8cα chain: structure, antigenicity, and utility in expression of immunoglobulin superfamily domains. International Immunol 2: 215Google Scholar
  8. 8.
    Eshhar Z, Waks T, Gross G, Schindler DG (1993) Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the gamma or zeta subunits of the immunoglobulin and T-cell receptors. Proc Natl Acad Sci USA 90: 720Google Scholar
  9. 9.
    Eshhar Z, Gross G, Waks T, Lustgarten J, Bach N, Ratner A, Treisman J, Schindler DG (1995) Tbodies: chimeric T-cell receptors with antibody-type specificity. METHODS — A Companion to Meth. in Enzymol. 8: 133Google Scholar
  10. 10.
    Goverman J, Gomez SM, Segesman KD, Hunkapiller T, Lang WE, Hood L (1990) Chimeric immunoglobulin-T cell receptor proteins form functional receptors: implications for T cell receptor complex formation and activation. Cell 60: 929Google Scholar
  11. 11.
    Gross G, Gorochov G, Waks T, Eshhar Z (1989) Generation of effector T cells expressing chimeric T cell receptors with antibody type specificity. Transplant Proc 21: 127Google Scholar
  12. 12.
    Gross G, Waks T, Eshhar Z (1989) Expression of immunoglobulin/T cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc Natl Acad Sci USA 86: 10024Google Scholar
  13. 13.
    Gross G, Eshhar Z (1992) Endowing T cells with antibody specificity using chimeric T cell receptors. FASEB J 6: 3370Google Scholar
  14. 14.
    Gross G, Levy S, Levy R, Waks T, Eshhar Z (1995) Chimeric T cell receptors specific to a B lymphoma idiotype: A model for tumor immunotherapy. Biochem Soc Trans 23: 1079Google Scholar
  15. 15.
    Huston JS, Levinson D, Mudget-Hunter M, Tai M-S, Novotny J, Margolies MN, Ridge RJ, Bruccoleri RE, Haber E, Crea R, Oppermann H (1988) Protein engineering of antibody binding sites: recovery of specific activity in an anti-digoxin single chain Fv analogue produced in Escherichia coli. Proc Natl Acad Sci USA 85: 5879Google Scholar
  16. 16.
    Hwu P, Shafer GE, Treisman J, Schindler DG, Gross G, Cowherd R, Rosenberg SA, Eshhar Z (1993) Lysis of ovarian cancer cells by human lymphocytes redirected with a chimeric gene composed of an antibody variable region and the Fc receptor y chain. J Exp Med 178: 361Google Scholar
  17. 17.
    Hwu P, Yang JC, Cowherd R, Treisman J, Shafer GE, Eshhar Z, Rosenberg SA (1995) In vivo antitumor activity of T cells redirected with chimeric antibody/T-cell receptor genes. Cancer Res 55: 3369Google Scholar
  18. 18.
    Jain RK (1994) Barriers to drug delivery in solid tumors. Sci Am 271: 42Google Scholar
  19. 19.
    Kuwana Y, Asakura Y, Utsunomiya N, Nakanishi M, Arata Y, Itoh S, Nagase F, Kurosawa Y (1987) Expression of chimeric receptor composed of immunoglobulin-derived V regions and T-cell receptorderived C regions. Biochem Biophys Res Commun 149: 960Google Scholar
  20. 20.
    Lustgarten J, Eshhar Z (1995) Specific elimination of IgE production using T cell lines expressing chimeric T cell receptor genes. Eur J Immunol. 25: 2985Google Scholar
  21. 21.
    Miller AD (1992) Human gene therapy comes of age. Nature 357: 455Google Scholar
  22. 22.
    Moritz D, Wels W, Mattem J, Groner B (1994) Cytotoxic T lymphocytes with a grafted recognition specificity for ErbB-2-expressing tumor cells. Proc Natl Acad Sci USA 91: 4318Google Scholar
  23. 23.
    Moritz D, Groner B (1995) A spacer region between the single chain antibody and the CD3 ( chain domain of chimeric T cell receptor components is required for efficient ligand binding and signalling activity. Gene Ther 2: 539Google Scholar
  24. 24.
    Orloff DG, Ra C, Frank SJ, Mausner RD, Kinet J-P (1990) Family of disulphide-linked dimers containing the zeta and eta chains of the T-cell receptor and the gamma chain of Fc receptors. Nature 347: 189Google Scholar
  25. 25.
    Ravetch JV, Kinet J-P (1991) Fc receptors. Annu Rev Immunol 9: 457Google Scholar
  26. 26.
    Riethmuller G (1993) Monoclonal antibodies in cancer therapy. Curr Opin Immunol 5: 732Google Scholar
  27. 27.
    Romeo C, Seed B (1991) Cellular immunity to HIV activated by CD4 fused to T cell or Fc receptor polypeptides. Cell 64: 1037Google Scholar
  28. 28.
    Rosenberg SA, Packard BS, Aebersold PM, Solomon D, Topalian SL, Toy ST, Simon P, Lotze MT, Yang JC, Seipp CA, et al (1989) Use of tumor infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report. N Engl J Med 319: 1676Google Scholar
  29. 29.
    Stancovski I, Schindler DG, Waks T, Yarden Y, Sela M, Eshhar Z (1993) Targeting of T lymphocytes to Neu/HER2-expressing cells using chimeric single chain Fv receptors. J Immunol 151: 6577Google Scholar
  30. 30.
    Tran A-C, Zhang D, Byrn R, Roberts MR (1995) Chimeric (-receptors direct human natural killer (NK) effector function to permit killing of NK-resistant tumor cells and HIV-infected T lymphocytes. J Immunol 155: 1001Google Scholar
  31. 31.
    Winter G, Griffiths AD, Hawkins RE, Hoogenboom HR (1994) Making antibodies by phage display technology. Annu Rev Immunol 12: 433Google Scholar

Copyright information

© Springer-Verlag 1996

Authors and Affiliations

  • Zelig Eshhar
    • 1
  • Nathan Bach
    • 2
  • Cheryl J. Fitzer-Attas
    • 1
  • Gidi Grosse
    • 3
  • Joseph Lustgarten
    • 4
  • Tova Waks
    • 1
  • Daniel G. Schindler
    • 1
  1. 1.Department of ImmunologyThe Weizmann Institute of ScienceRehovotIsrael
  2. 2.Bristol Myers Squibb Pharmaceutical Research InstituteSeattleWAUSA
  3. 3.Migal BiotechnologiesGalilee Industrial CenterKiryat ShmonaIsrael
  4. 4.Department of ImmunologyScripps Research InstituteLa JollaUSA

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