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Eradication of systemic B-cell tumors by genetically targeted human T lymphocytes co-stimulated by CD80 and interleukin-15

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Abstract

The genetic transfer of antigen receptors provides a means to rapidly generate autologous tumor-reactive T lymphocytes. However, recognition of tumor antigens by cytotoxic T cells is only one step towards effective cancer immunotherapy. Other crucial biological prerequisites must be fulfilled to expand tumor-reactive T cells that retain a functional phenotype, including in vivo cytolytic activity and the ability to travel to tumor sites without prematurely succumbing to apoptosis. We show that these requirements are met by expanding peripheral blood T cells genetically targeted to the CD19 antigen in the presence of CD80 and interleukin-15 (IL-15). T cells expanded in the presence of IL-15 uniquely persist in tumor-bearing severe combined immunodeficiency (SCID)-Beige mice and eradicate disseminated intramedullary tumors. Their anti-tumor activity is further enhanced by in vivo co-stimulation. In addition, transduced T cells from patients with chronic lymphocytic leukemia (CLL) effectively lyse autologous tumor cells. These findings strongly support the clinical feasibility of this therapeutic strategy.

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Figure 1: 19z1-transduced T cells specifically lyse CD19+ tumor cells.
Figure 2: Rapid expansion of 19z1+ T cells using AAPCs expressing CD19 and CD80 with exogenous IL-15.
Figure 3: Eradication of established Raji tumors in SCID-Beige mice by 19z1+CD8+ T cells expanded on AAPCs with exogenous IL-15.
Figure 4: Tumor cell eradication by 19z1+ T cells is dependent on in vivo T-cell co-stimulation.
Figure 5: 51Cr-release assays of 19z1 (♦, ▪)- and Pz1 (, □)-transduced T cells, derived from patients with CLL, targeting autologous tumor cells.

Change history

  • 10 February 2003

    This was incorrect in AOP version but corrected in print. Added NIH grant AI44926 to acknowledgments as per note.

Notes

  1. NOTE: In the version of this article initially published online, NIH grant AI44926 was omitted from the acknowledgments. This mistake has been corrected for the HTML and print versions of the article.

References

  1. Collins, R.H. et al. Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation. J. Clin. Oncol. 15, 433–444 (1997).

    Article  PubMed  Google Scholar 

  2. Riddell, S.R., Murata, M., Bryant, S. & Warren, E.H. T-cell therapy of leukemia. Cancer Control 9, 114–122 (2002).

    Article  PubMed  Google Scholar 

  3. Papadopoulos, E.B. et al. Infusions of donor leukocytes to treat Epstein-Barr virus-associated lymphoproliferative disorders after allogeneic bone marrow transplantation. N. Engl. J. Med. 330, 1185–1191 (1994).

    CAS  Article  PubMed  Google Scholar 

  4. Savoldo, B., Heslop, H.E. & Rooney, C.M. The use of cytotoxic T cells for the prevention and treatment of Epstein-Barr virus induced lymphoma in transplant recipients. Leukemia Lymphoma 39, 455–464 (2000).

    CAS  Article  PubMed  Google Scholar 

  5. Melief, C.J. et al. Strategies for immunotherapy of cancer. Adv. Immunol. 75, 235–282 (2000).

    CAS  Article  PubMed  Google Scholar 

  6. Sadelain, M., Rivière, I. & Brentjens, R. Targeting tumors with genetically enhanced T lymphocytes. Nat. Rev. Cancer 3, 35–45 (2003).

    CAS  Article  PubMed  Google Scholar 

  7. Eshhar, Z. et al. The T-body approach: potential for cancer immunotherapy. Springer Semin. Immunopathol. 18, 199–209 (1996).

    CAS  Article  PubMed  Google Scholar 

  8. Schumacher, T.N. T-cell-receptor gene therapy. Nat. Rev. Immunol. 2, 512–519 (2002).

    CAS  Article  PubMed  Google Scholar 

  9. Uckun, F.M. et al. Detailed studies on expression and function of CD19 surface determinant by using B43 monoclonal antibody and the clinical potential of anti- CD19 immunotoxins. Blood 71, 13–29 (1988).

    CAS  PubMed  Google Scholar 

  10. Gong, M.C. et al. Cancer patient T cells genetically targeted to prostate-specific membrane antigen specifically lyse prostate cancer cells and release cytokines in response to prostate-specific membrane antigen. Neoplasia 1, 123–127 (1999).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. Latouche, J.B. & Sadelain, M. Induction of human cytotoxic T lymphocytes by artificial antigen-presenting cells. Nat. Biotechnol. 18, 405–409 (2000).

    CAS  Article  PubMed  Google Scholar 

  12. Maher, J., Brentjens, R.J., Gunset, G., Riviere, I. & Sadelain, M. Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCR-ζ/CD28 receptor. Nat. Biotechnol. 20, 70–75 (2002).

    CAS  Article  PubMed  Google Scholar 

  13. Rosenberg, S.A. Progress in human tumour immunology and immunotherapy. Nature 411, 380–384 (2001).

    CAS  Article  PubMed  Google Scholar 

  14. Rossi, E. et al. ζ chain and CD28 are poorly expressed on T lymphocytes from chronic lymphocytic leukemia. Leukemia 10, 494–497 (1996).

    CAS  PubMed  Google Scholar 

  15. Chen, X. et al. Impaired expression of the CD3-ζ chain in peripheral blood T cells of patients with chronic myeloid leukaemia results in an increased susceptibility to apoptosis. Br. J. Haematol. 111, 817–825 (2000).

    CAS  PubMed  Google Scholar 

  16. Hanson, H.L. et al. Eradication of established tumors by CD8+ T cell adoptive immunotherapy. Immunity 13, 265–276 (2000).

    CAS  Article  PubMed  Google Scholar 

  17. Ochsenbein, A.F. et al. Roles of tumour localization, second signals and cross priming in cytotoxic T-cell induction. Nature 411, 1058–1064 (2001).

    CAS  Article  PubMed  Google Scholar 

  18. Sadelain, M. & Rivière, I. Sturm und Drang over suicidal lymphocytes. Mol. Ther. 5, 655–657 (2002).

    CAS  Article  PubMed  Google Scholar 

  19. Dudley, M.E. et al. A phase I study of nonmyeloablative chemotherapy and adoptive transfer of autologous tumor antigen-specific T lymphocytes in patients with metastatic melanoma. J. Immunother. 25, 243–251 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. Boussiotis, V.A., Lee, B.J., Freeman, G.J., Gribben, J.G. & Nadler, L.M. Induction of T cell clonal anergy results in resistance, whereas CD28-mediated costimulation primes for susceptibility to Fas- and Bax-mediated programmed cell death. J. Immunol. 159, 3156–3167 (1997).

    CAS  PubMed  Google Scholar 

  21. Vella, A.T. et al. CD28 engagement and proinflammatory cytokines contribute to T cell expansion and long-term survival in vivo. J. Immunol. 158, 4714–4720 (1997).

    CAS  PubMed  Google Scholar 

  22. Brocker, T. Chimeric Fv-ζ or Fv-ε receptors are not sufficient to induce activation or cytokine production in peripheral T cells. Blood 96, 1999–2001 (2000).

    CAS  PubMed  Google Scholar 

  23. Fehniger, T.A., Cooper, M.A. & Caligiuri, M.A. Interleukin-2 and interleukin-15: immunotherapy for cancer. Cytokine Growth Factor Rev. 13, 169–183 (2002).

    CAS  Article  PubMed  Google Scholar 

  24. Waldmann, T.A., Dubois, S. & Tagaya, Y. Contrasting roles of IL-2 and IL-15 in the life and death of lymphocytes: implications for immunotherapy. Immunity 14, 105–110 (2001).

    CAS  PubMed  Google Scholar 

  25. Bulfone-Paus, S. et al. Interleukin-15 protects from lethal apoptosis in vivo. Nat. Med. 3, 1124–1128 (1997).

    CAS  Article  PubMed  Google Scholar 

  26. Marks-Konczalik, J. et al. IL-2-induced activation-induced cell death is inhibited in IL-15 transgenic mice. Proc. Natl. Acad. Sci. USA 97, 11445–11450 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. Li, X.C. et al. IL-15 and IL-2: a matter of life and death for T cells in vivo. Nat. Med. 7, 114–118 (2001).

    CAS  Article  PubMed  Google Scholar 

  28. Zhang, X., Sun, S., Hwang, I., Tough, D.F. & Sprent, J. Potent and selective stimulation of memory-phenotype CD8+ T cells in vivo by IL-15. Immunity 8, 591–599 (1998).

    CAS  Article  PubMed  Google Scholar 

  29. Ku, C.C., Murakami, M., Sakamoto, A., Kappler, J. & Marrack, P. Control of homeostasis of CD8+ memory T cells by opposing cytokines. Science 288, 675–678 (2000).

    CAS  Article  PubMed  Google Scholar 

  30. Oppenheimer-Marks, N., Brezinschek, R.I., Mohamadzadeh, M., Vita, R. & Lipsky, P.E. Interleukin 15 is produced by endothelial cells and increases the transendothelial migration of T cells in vitro and in the SCID mouse-human rheumatoid arthritis model in vivo. J. Clin. Invest. 101, 1261–1272 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. Jourdan, P. et al. Cytokines and cell surface molecules independently induce CXCR4 expression on CD4+ CCR7+ human memory T cells. J. Immunol. 165, 716–724 (2000).

    CAS  Article  PubMed  Google Scholar 

  32. Peled, A. et al. Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4. Science 283, 845–848 (1999).

    CAS  Article  PubMed  Google Scholar 

  33. Burger, J.A., Burger, M. & Kipps, T.J. Chronic lymphocytic leukemia B cells express functional CXCR4 chemokine receptors that mediate spontaneous migration beneath bone marrow stromal cells. Blood 94, 3658–3667 (1999).

    CAS  PubMed  Google Scholar 

  34. Blazar, B.R. et al. CD28/B7 interactions are required for sustaining the graft-versus-leukemia effect of delayed post-bone marrow transplantation splenocyte infusion in murine recipients of myeloid or lymphoid leukemia cells. J. Immunol. 159, 3460–3473 (1997).

    CAS  PubMed  Google Scholar 

  35. Maric, M., Zheng, P., Sarma, S., Guo, Y. & Liu, Y. Maturation of cytotoxic T lymphocytes against a B7-transfected nonmetastatic tumor: a critical role for costimulation by B7 on both tumor and host antigen-presenting cells. Cancer Res. 58, 3376–3384 (1998).

    CAS  PubMed  Google Scholar 

  36. Krause, A. et al. Antigen-dependent CD28 signaling selectively enhances survival and proliferation in genetically modified activated human primary T lymphocytes. J. Exp. Med. 188, 619–626 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. Geiger, T.L., Nguyen, P., Leitenberg, D. & Flavell, R.A. Integrated src kinase and costimulatory activity enhances signal transduction through single-chain chimeric receptors in T lymphocytes. Blood 98, 2364–2371 (2001).

    CAS  Article  PubMed  Google Scholar 

  38. Hombach, A. et al. Tumor-specific T cell activation by recombinant immunoreceptors: CD3-ζ signaling and CD28 costimulation are simultaneously required for efficient IL-2 secretion and can be integrated into one combined CD28/CD3-ζ signaling receptor molecule. J. Immunol. 167, 6123–6131 (2001).

    CAS  Article  PubMed  Google Scholar 

  39. Haynes, N.M. et al. Single-chain antigen recognition receptors that co-stimulate potent rejection of established experimental tumors. Blood 100, 3155–3163 (2002).

  40. Greenlee, R.T., Hill-Harmon, M.B., Murray, T. & Thun, M. Cancer Statistics, 2001. CA Cancer J. Clin. 51, 15–36 (2001).

    CAS  Article  PubMed  Google Scholar 

  41. Byrd, J.C. et al. Rituximab using a thrice weekly dosing schedule in B-cell chronic lymphocytic leukemia and small lymphocytic lymphoma demonstrates clinical activity and acceptable toxicity. J. Clin. Oncol. 19, 2153–2164 (2001).

    CAS  Article  PubMed  Google Scholar 

  42. Gallardo, H.F., Tan, C. & Sadelain, M. The internal ribosomal entry site of the encephalomyocarditis virus enables reliable coexpression of two transgenes in human primary T lymphocytes. Gene Ther. 4, 1115–1119 (1997).

    CAS  Article  PubMed  Google Scholar 

  43. Rivière, I., Brose, K. & Mulligan, R.C. Effects of retroviral vector design on expression of human adenosine deaminase in murine bone marrow transplant recipients engrafted with genetically modified cells. Proc. Natl. Acad. Sci. USA 92, 6733–6737 (1995).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Tedder, T.F. & Isaacs, C.M. Isolation of cDNAs encoding the CD19 antigen of human and mouse B lymphocytes. A new member of the immunoglobulin superfamily. J. Immunol. 143, 712–717 (1989).

    CAS  PubMed  Google Scholar 

  45. Adonai, N. et al. Ex vivo cell labeling with 64Cu-pyruvaldehyde-bis(N4-methylthiosemicarbazone) for imaging cell trafficking in mice with positron-emission tomography. Proc. Natl. Acad. Sci. USA 99, 3030–3035 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by US National Institutes of Health grants CA-59350, CA-86438, CA-08748, CA-83084 and AI44926; the Translational and Integrative Medicine Research Fund at the Memorial Sloan-Kettering Cancer Center; the Lymphoma Research Foundation (formerly the Cure for Lymphoma Foundation; fellowship award to R.J.B.); the Goodwin ETC fund; Golfers Against Cancer; and US Department of Energy grant ER-62039.*Footnote 1

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Correspondence to Michel Sadelain.

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Brentjens, R., Latouche, JB., Santos, E. et al. Eradication of systemic B-cell tumors by genetically targeted human T lymphocytes co-stimulated by CD80 and interleukin-15. Nat Med 9, 279–286 (2003). https://doi.org/10.1038/nm827

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