Skip to main content
SpringerLink
Log in

Gene Therapy of Patient-Derived T Lymphocytes to Target and Eradicate Colorectal Hepatic Metastases

  • Published:
Diseases of the Colon & Rectum

Abstract

PURPOSE: The overall aim of this study was to develop a novel treatment for colorectal cancer based on the use of gene therapy. Genetic modification of T lymphocytes has been used to specifically target and kill tumor cell lines directly. To test the efficacy of this method with clinically relevant materials, this study investigated the potential of T lymphocytes derived from patients with advanced colorectal disease to target autologous primary tumor material. METHODS: T lymphocytes isolated preoperatively were modified genetically with recombinant retroviruses encoding CD3ζ-based chimeric immune receptors and were tested for functional activity against freshly isolated autologous tumor cells harvested from hepatic colorectal metastases. RESULTS: Patient-derived T cells were successfully transduced, and chimeric immune receptor expression was confirmed. Carcinoembryonic antigen expression on freshly isolated colorectal tumor cells was also demonstrated by molecular and immunohistochemical techniques. T cells expressing the anticarcinoembryonic antigen receptor were specifically activated by coculture with disaggregated or intact, diced tumor, whereas control non-carcinoembryonic antigen-targeted T-cell populations failed to activate. CONCLUSIONS: These results indicate that gene-targeted primary T lymphocytes depict specific functional activity against autologous colorectal tumor cells. This evidence indicates that chimeric immune receptor-expressing T cells may be able to circumvent the mechanisms used by tumor cells to avoid immune cell activity in vivo. This study emphasizes the potential of this approach as a therapy for carcinoembryonic antigen-expressing primary colorectal tumor and its metastases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. SS Yoon KK Tanabe (1998) ArticleTitleMultidisciplinary management of metastatic colorectal cancer Surg Oncol 7 197–207

    Google Scholar 

  2. S Casillas RJ Pelley JW Milsom (1997) ArticleTitleAdjuvant therapy for colorectal cancer Dis Colon Rectum 40 977–992

    Google Scholar 

  3. N Kemeny Y Huang AM Cohen et al. (1999) ArticleTitleHepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer N Engl J Med 341 2039–2048

    Google Scholar 

  4. TS Maughan (2001) ArticleTitleAdjuvant chemotherapy for colorectal cancer Br J Cancer 85 1422–1424

    Google Scholar 

  5. R Midgley D Kerr (1999) ArticleTitleColorectal cancer Lancet 353 391–399

    Google Scholar 

  6. I Taylor AR Gillams (2000) ArticleTitleColorectal liver metastases J R Soc Med 93 576–579

    Google Scholar 

  7. JN Primrose (2002) ArticleTitleTreatment of colorectal metastases Gut 50 1–5

    Google Scholar 

  8. MJ Chen GA Chung-Faye PF Searle LS Young DJ Kerr (2001) ArticleTitleGene therapy for colorectal cancer BioDrugs 15 357–367

    Google Scholar 

  9. Z Esshar T Waks A Bendavid D Schindler (2001) ArticleTitleFunctional expression of chimeric receptor genes in human T cells J Immunol Methods 248 67–76

    Google Scholar 

  10. G Gross T Waks Z Eshhar (1989) ArticleTitleExpression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity Proc Natl Acad Sci USA 86 10024–8

    Google Scholar 

  11. M Movassagh O Boyer M Burland V Leclercq D Klatzman F Lemoine (2000) ArticleTitleRetrovirus-mediated gene transfer into T cells Hum Gene Ther 11 1189–1200

    Google Scholar 

  12. DE Gilham A O’Neil C Hughes et al. (2002) ArticleTitlePrimary polyclonal human T lymphocytes targeted to carcino-embryonic and neural cell adhesion molecule tumor antigens by CD3zeta based chimeric immune receptors J Immunother 25 139–151

    Google Scholar 

  13. E Beecham S Ortiz-Pujols R Junghans (2000) ArticleTitleDynamics of tumour cell killing by human T lymphocytes armed with an anti-carcinoembryonic antigen chimeric immunoglobulin T-cell receptor J Immunother 23 332–343

    Google Scholar 

  14. KF Nolan CO Yun Y Akamatsu et al. (1999) ArticleTitleBypassing immunization Clin Cancer Res 5 3928–3941

    Google Scholar 

  15. A Hombach C Schneider D Sent et al. (2000) ArticleTitleAn entirely humanized CD3 ζ-chain signaling receptor that directs peripheral blood t cells to specific lysis of carcinoembryonic antigen-positive tumour cells Int J Cancer 88 115–120

    Google Scholar 

  16. AJ Sheen DJ Sherlock J Irlam R Hawkins DE Gilham (2003) ArticleTitleT lymphocytes isolated from patients with advanced colorectal cancer are suitable as targets for gene immunotherapy approaches Br J Cancer 88 1119–1127

    Google Scholar 

  17. S Bourne K Patel F Walsh C Popham H Coakham J Kemshead (1991) ArticleTitleA monoclonal antibody (ERIC-1), raised against retinoblastoma, that recognises the neural cell adhesion molecule (NCAM) expressed on brain and tumours arising from the neuroectoderm J Neurooncol 10 111–119

    Google Scholar 

  18. U Lamelli (1970) ArticleTitleCleavage of structural proteins during the assembly of the head of bacteriophage T4 Nature 227 680–685

    Google Scholar 

  19. RM Bukowski P Rayman R Uzzo et al. (1998) ArticleTitleSignal transduction abnormalities in T lymphocytes from patients with advanced renal carcinoma Clin Cancer Res 4 2337–2347

    Google Scholar 

  20. S Rosenberg J Yannelli S Topalian et al. (1994) ArticleTitleTreatment of patients with metastatic melanoma with autologous tumour-infiltrating lymphocytes and interleukin-2 J Natl Cancer Inst 86 1159–1166

    Google Scholar 

  21. KF Yoong DH Adams (1998) ArticleTitleInterleukin 2 restores CD3-zeta chain expression but fails to generate tumour-specific lytic activity in tumour-infiltrating lymphocytes derived from human colorectal hepatic metastases Br J Cancer 77 1072–1081

    Google Scholar 

  22. T Moritz P Dutt X Xiao et al. (1996) ArticleTitleFibronectin improves transduction of reconstituting hematopoietic stem cells by retroviral vectors Blood 88 855–862

    Google Scholar 

  23. M Hahne D Rimoldi M Schroter et al. (1996) ArticleTitleMelanoma cell expression of Fas(Apo-1/CD95) ligand Science 274 1363–1366

    Google Scholar 

  24. P Holliger O Manzke M Span et al. (1999) ArticleTitleCarcinoembryonic antigen (CEA)-specific T-cell activation in colon carcinoma induced by anti-CD3 × anti-CEA bispecific diabodies and B7 × anti-CEA bispecific fusion proteins Cancer Res 59 2909–2916

    Google Scholar 

  25. G Cook JD Campbell CE Carr KS Boyd IM Franklin (1999) ArticleTitleTransforming growth factor beta from multiple myeloma cells inhibits proliferation and IL-2 responsiveness in T lymphocytes J Leukoc Biol 66 981–988

    Google Scholar 

  26. D Eaton DE Gilham A O’Neill RE Hawkins (2002) ArticleTitleRetroviral transduction of human peripheral blood lymphocytes with bcl-x(L) promotes in vitro lymphocyte survival in pro-apoptotic conditions Gene Ther 9 527–535

    Google Scholar 

  27. ET Wong SM Ngoi CG Lee (2002) ArticleTitleImproved co-expression of multiple genes in vectors containing internal ribosome entry sites (IRESes) from human genes Gene Ther 9 337–344

    Google Scholar 

  28. A Hombach D Koch R Sircar et al. (1999) ArticleTitleA chimeric receptor that selectively targets membrane-bound carcinoembryonic antigen (mCEA) in the presence of soluble CEA Gene Ther 6 300–304

    Google Scholar 

  29. R Mitsuyasu P Anton S Deeks et al. (2000) ArticleTitleProlonged survival and tissue trafficking following adoptive transfer of CD4ζ gene-modified autologous CD4+ and CD8+ T cells in human immunodeficiency virus-infected subjects Blood 96 785–793

    Google Scholar 

  30. MS Rodgers JL McCall (2000) ArticleTitleSurgery for colorectal liver metastases with hepatic lymph node involvement Br J Surg 87 1142–1155

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Cancer Research United Kingdom, Department of Medical Oncology, Paterson Institute for Cancer Research, University of Manchester, and Department of Surgery, North Manchester Healthcare NHS Trust, Manchester, United Kingdom

    Aali J. Sheen F.R.C.S., Joely Irlam B.Sc., Natalia Kirillova M.Sc., Ryan D. Guest Ph.D., David J. Sherlock M.S., F.R.C.S., Robert E. Hawkins Ph.D., F.R.C.P. & David E. Gilham Ph.D.

Authors
  1. Aali J. Sheen F.R.C.S.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joely Irlam B.Sc.
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Natalia Kirillova M.Sc.
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ryan D. Guest Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. David J. Sherlock M.S., F.R.C.S.
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Robert E. Hawkins Ph.D., F.R.C.P.
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. David E. Gilham Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

About this article

Cite this article

Sheen, A.J., Irlam, J., Kirillova, N. et al. Gene Therapy of Patient-Derived T Lymphocytes to Target and Eradicate Colorectal Hepatic Metastases. Dis Colon Rectum 46, 793–804 (2003). https://doi.org/10.1007/s10350-004-6659-1

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10350-004-6659-1

Keywords

Search

Navigation