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Tumor immunotherapy across MHC barriers using allogeneic T-cell precursors

Nature Biotechnology volume 26, pages 453–461 (2008)Cite this article

An Author Correction to this article was published on 26 March 2024

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Abstract

We present a strategy for adoptive immunotherapy using T-lineage committed lymphoid precursor cells generated by Notch1-based culture. We found that allogeneic T-cell precursors can be transferred to irradiated individuals irrespective of major histocompatibility complex (MHC) disparities and give rise to host-MHC restricted and host-tolerant functional allogeneic T cells, improving survival in irradiated recipients as well as enhancing anti-tumor responses. T-cell precursors transduced to express a chimeric receptor targeting hCD19 resulted in significant additional anti-tumor activity, demonstrating the feasibility of genetic engineering of these cells. We conclude that ex vivo generated MHC-disparate T-cell precursors from any donor can be used universally for 'off-the-shelf' immunotherapy, and can be further enhanced by genetic engineering for targeted immunotherapy.

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Figure 1: Adoptively transferred allogeneic T-cell precursors enhance T and NK cell reconstitution and do not induce GVHD.
Figure 2: Adoptively transferred allogeneic T-cell precursors develop into host MHC restricted and donor/host tolerant T cells.
Figure 3: Adoptively transferred allogeneic T-cell precursors enhance T and NK cell reconstitution and improve survival in irradiated hosts.
Figure 4: Adoptively transferred allogeneic T-cell precursors mediate significant anti-tumor responses.
Figure 5: Response to immunotherapy with T-cell precursors depends on the immunogenicity of the tumor but not on MHC disparity.
Figure 6: Genetically engineered antigen-specific T-cell precursors give rise to tumor-responsive CD8+ and CD4+ T cells coexpressing chimeric antigen receptor and endogenous TCR.

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References

  1. Mackall, C.L. & Gress, R.E. Thymic aging and T-cell regeneration. Immunol. Rev. 160, 91–102 (1997).

    Article  CAS  PubMed  Google Scholar 

  2. Grunebaum, E., Sharfe, N. & Roifman, C.M. Human T cell immunodeficiency: when signal transduction goes wrong. Immunol. Res. 35, 117–126 (2006).

    Article  CAS  PubMed  Google Scholar 

  3. Fischer, A. et al. Naturally occurring primary deficiencies of the immune system. Annu. Rev. Immunol. 15, 93–124 (1997).

    Article  CAS  PubMed  Google Scholar 

  4. Chinen, J., Finkelman, F. & Shearer, W.T. Advances in basic and clinical immunology. J. Allergy Clin. Immunol. 118, 489–495 (2006).

    Article  CAS  PubMed  Google Scholar 

  5. Lehrnbecher, T., Foster, C., Vázquez, N., Mackall, C.L. & Chanock, S.J. Therapy-induced alterations in host defense in children receiving therapy for cancer. J. Pediatr. Hematol. Oncol. 19, 399–417 (1997).

    Article  CAS  PubMed  Google Scholar 

  6. Yarilin, A.A. et al. Late T cell deficiency in victims of the Chernobyl radiation accident: possible mechanisms of induction. Int. J. Radiat. Biol. 63, 519–528 (1993).

    Article  CAS  PubMed  Google Scholar 

  7. Appelbaum, F.R. Haematopoietic cell transplantation as immunotherapy. Nature 411, 385–389 (2001).

    Article  CAS  PubMed  Google Scholar 

  8. Joao, C. et al. Early lymphocyte recovery after autologous stem cell transplantation predicts superior survival in mantle-cell lymphoma. Bone Marrow Transplant. 37, 865–871 (2006).

    Article  CAS  PubMed  Google Scholar 

  9. Leemhuis, T., Wells, S., Scheffold, C., Edinger, M. & Negrin, R.S. A phase I trial of autologous cytokine-induced killer cells for the treatment of relapsed Hodgkin disease and non-Hodgkin lymphoma. Biol. Blood Marrow Transplant. 11, 181–187 (2005).

    Article  PubMed  Google Scholar 

  10. Gordan, L.N. et al. Correlation of early lymphocyte recovery and progression-free survival after autologous stem-cell transplant in patients with Hodgkin's and non-Hodgkin's Lymphoma. Bone Marrow Transplant. 31, 1009–1013 (2003).

    Article  CAS  PubMed  Google Scholar 

  11. Porrata, L.F. et al. Early lymphocyte recovery is a predictive factor for prolonged survival after autologous hematopoietic stem cell transplantation for acute myelogenous leukemia. Leukemia 16, 1311–1318 (2002).

    Article  CAS  PubMed  Google Scholar 

  12. Porrata, L.F. et al. Early lymphocyte recovery post-autologous haematopoietic stem cell transplantation is associated with better survival in Hodgkin's disease. Br. J. Haematol. 117, 629–633 (2002).

    Article  PubMed  Google Scholar 

  13. Porrata, L.F. et al. Early lymphocyte recovery predicts superior survival after autologous hematopoietic stem cell transplantation in multiple myeloma or non-Hodgkin lymphoma. Blood 98, 579–585 (2001).

    Article  CAS  PubMed  Google Scholar 

  14. Porrata, L.F., Ingle, J.N., Litzow, M.R., Geyer, S. & Markovic, S.N. Prolonged survival associated with early lymphocyte recovery after autologous hematopoietic stem cell transplantation for patients with metastatic breast cancer. Bone Marrow Transplant. 28, 865–871 (2001).

    Article  CAS  PubMed  Google Scholar 

  15. Kolb, H.J. et al. Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. European Group for Blood and Marrow Transplantation Working Party Chronic Leukemia. Blood 86, 2041–2050 (1995).

    Article  CAS  PubMed  Google Scholar 

  16. Gottschalk, S., Heslop, H.E. & Rooney, C.M. Adoptive immunotherapy for EBV-associated malignancies. Leuk. Lymphoma 46, 1–10 (2005).

    Article  CAS  PubMed  Google Scholar 

  17. Gottschalk, S., Heslop, H.E. & Rooney, C.M. Treatment of Epstein-Barr virus-associated malignancies with specific T cells. Adv. Cancer Res. 84, 175–201 (2002).

    Article  CAS  PubMed  Google Scholar 

  18. Rooney, C.M. et al. Infusion of cytotoxic T cells for the prevention and treatment of Epstein-Barr virus-induced lymphoma in allogeneic transplant recipients. Blood 92, 1549–1555 (1998).

    Article  CAS  PubMed  Google Scholar 

  19. Rooney, C.M. et al. Use of gene-modified virus-specific T lymphocytes to control Epstein–Barr-virus-related lymphoproliferation. Lancet 345, 9–13 (1995).

    Article  CAS  PubMed  Google Scholar 

  20. Heslop, H.E., Brenner, M.K. & Rooney, C.M. Donor T cells to treat EBV-associated lymphoma. N. Engl. J. Med. 331, 679–680 (1994).

    Article  CAS  PubMed  Google Scholar 

  21. Yotnda, P. et al. Cytotoxic T cell response against the chimeric p210 BCR–ABL protein in patients with chronic myelogenous leukemia. J. Clin. Invest. 101, 2290–2296 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Luznik, L. et al. Successful therapy of metastatic cancer using tumor vaccines in mixed allogeneic bone marrow chimeras. Blood 101, 1645–1652 (2003).

    Article  CAS  PubMed  Google Scholar 

  23. Schmitt, T.M. & Zúñiga-Pflücker, J.C. Induction of T cell development from hematopoietic progenitor cells by Delta-like-1 in vitro. Immunity 17, 749–756 (2002).

    Article  CAS  PubMed  Google Scholar 

  24. Ohishi, K., Varnum-Finney, B. & Bernstein, I.D. Delta-1 enhances marrow and thymus repopulating ability of human CD34(+)CD38(−)cord blood cells. J. Clin. Invest. 110, 1165–1174 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. De Smedt, M., Hoebeke, I. & Plum, J. Human bone marrow CD34+ progenitor cells mature to T cells on OP9–DL1 stromal cell line without thymus microenvironment. Blood Cells Mol. Dis. 33, 227–232 (2004).

    Article  CAS  PubMed  Google Scholar 

  26. La Motte-Mohs, R.N., Herer, E. & Zúñiga-Pflücker, J.C. Induction of T cell development from human cord blood hematopoietic stem cells by Delta-like 1 in vitro. Blood 105, 1431–1439 (2005).

    Article  CAS  PubMed  Google Scholar 

  27. Zakrzewski, J.L. et al. Adoptive transfer of T-cell precursors enhances T-cell reconstitution after allogeneic hematopoietic stem cell transplantation. Nat. Med. 12, 1039–1047 (2006).

    Article  CAS  PubMed  Google Scholar 

  28. Dallas, M.H., Varnum-Finney, B., Martin, P.J. & Bernstein, I.D. Enhanced T-cell reconstitution by hematopoietic progenitors expanded ex vivo using the Notch ligand Delta1. Blood 109, 3579–3587 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Schmitt, T.M. et al. Induction of T cell development and establishment of T cell competence from embryonic stem cells differentiated in vitro. Nat. Immunol. 5, 410–417 (2004).

    Article  CAS  PubMed  Google Scholar 

  30. Cooke, K.R. et al. An experimental model of idiopathic pneumonia syndrome after bone marrow transplantation: I. The roles of minor H antigens and endotoxin. Blood 88, 3230–3239 (1996).

    Article  CAS  PubMed  Google Scholar 

  31. Hill, G.R. et al. Total body irradiation and acute graft-versus-host disease: the role of gastrointestinal damage and inflammatory cytokines. Blood 90, 3204–3213 (1997).

    Article  CAS  PubMed  Google Scholar 

  32. Acha-Orbea, H. & MacDonald, H.R. Superantigens of mouse mammary tumor virus. Annu. Rev. Immunol. 13, 459–486 (1995).

    Article  CAS  PubMed  Google Scholar 

  33. Abe, R., Kanagawa, O., Sheard, M.A., Malissen, B. & Foo-Phillips, M. Characterization of a new minor lymphocyte stimulatory system. I. Cluster of self antigens recognized by “I-E-reactive” V beta s, V beta 5, V beta 11, and V beta 12 T cell receptors for antigen. J. Immunol. 147, 739–749 (1991).

    Article  CAS  PubMed  Google Scholar 

  34. Woodland, D., Happ, M.P., Bill, J. & Palmer, E. Requirement for cotolerogenic gene products in the clonal deletion of I-E reactive T cells. Science 247, 964–967 (1990).

    Article  CAS  PubMed  Google Scholar 

  35. Bill, J., Kanagawa, O., Woodland, D.L. & Palmer, E. The MHC molecule I-E is necessary but not sufficient for the clonal deletion of V beta 11-bearing T cells. J. Exp. Med. 169, 1405–1419 (1989).

    Article  CAS  PubMed  Google Scholar 

  36. Vacchio, M.S. & Hodes, R.J. Decreased expression of specific V beta families is associated with expression of multiple MHC and non-MHC gene products. J. Exp. Med. 170, 1335–1346 (1989).

    Article  CAS  PubMed  Google Scholar 

  37. Anderson, G. & Jenkinson, E.J. Lymphostromal interactions in thymic development and function. Nat. Rev. Immunol. 1, 31–40 (2001).

    Article  CAS  PubMed  Google Scholar 

  38. Kessels, H.W., Wolkers, M.C., van den Boom, M.D., van der Valk, M.A. & Schumacher, T.N. Immunotherapy through TCR gene transfer. Nat. Immunol. 2, 957–961 (2001).

    Article  CAS  PubMed  Google Scholar 

  39. Brentjens, R.J. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  41. Morgan, R.A. et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314, 126–129 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Zhao, Y. et al. Extrathymic generation of tumor-specific T cells from genetically engineered human hematopoietic stem cells via Notch signaling. Cancer Res. 67, 2425–2429 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Bousso, P., Bhakta, N.R., Lewis, R.S. & Robey, E. Dynamics of thymocyte-stromal cell interactions visualized by two-photon microscopy. Science 296, 1876–1880 (2002).

    Article  CAS  PubMed  Google Scholar 

  44. Ernst, B.B., Surh, C.D. & Sprent, J. Bone marrow-derived cells fail to induce positive selection in thymus reaggregation cultures. J. Exp. Med. 183, 1235–1240 (1996).

    Article  CAS  PubMed  Google Scholar 

  45. Bix, M. & Raulet, D. Inefficient positive selection of T cells directed by haematopoietic cells. Nature 359, 330–333 (1992).

    Article  CAS  PubMed  Google Scholar 

  46. Wu, L., Li, C.L. & Shortman, K. Thymic dendritic cell precursors: relationship to the T lymphocyte lineage and phenotype of the dendritic cell progeny. J. Exp. Med. 184, 903–911 (1996).

    Article  CAS  PubMed  Google Scholar 

  47. Shen, H.Q. et al. T/NK bipotent progenitors in the thymus retain the potential to generate dendritic cells. J. Immunol. 171, 3401–3406 (2003).

    Article  CAS  PubMed  Google Scholar 

  48. Liggins, A.P., Guinn, B.A. & Banham, A.H. Identification of lymphoma-associated antigens using SEREX. Methods Mol. Med. 115, 109–128 (2005).

    CAS  PubMed  Google Scholar 

  49. Greiner, J. et al. Expression of tumor-associated antigens in acute myeloid leukemia: Implications for specific immunotherapeutic approaches. Blood 108, 4109–4117 (2006).

    Article  CAS  PubMed  Google Scholar 

  50. Cohen, J.I. Benign and malignant Epstein-Barr virus-associated B-cell lymphoproliferative diseases. Semin. Hematol. 40, 116–123 (2003).

    Article  PubMed  Google Scholar 

  51. Yang, L., Qin, X.F., Baltimore, D. & van Parijs, L. Generation of functional antigen-specific T cells in defined genetic backgrounds by retrovirus-mediated expression of TCR cDNAs in hematopoietic precursor cells. Proc. Natl. Acad. Sci. USA 99, 6204–6209 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. June, C.H. Adoptive T cell therapy for cancer in the clinic. J. Clin. Invest. 117, 1466–1476 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Terwey, T.H. et al. CCR2 is required for CD8-induced graft-versus-host disease. Blood 106, 3322–3330 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. May, C. et al. Therapeutic haemoglobin synthesis in β-thalassaemic mice expressing lentivirus-encoded human β-globin. Nature 406, 82–86 (2000).

    Article  CAS  PubMed  Google Scholar 

  55. Vardi, Y., Ying, Z. & Zhang, C.H. Two-sample tests for growth curves under dependent right censoring. Biometrika 88, 949–960 (2001).

    Article  Google Scholar 

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Acknowledgements

This work was supported by grants HL69929, CA33049 and CA107096 from the National Institutes of Health (NIH), by awards from the Leukemia and Lymphoma Society, the Ryan Gibson Foundation, the Elsa U. Pardee Foundation, the Byrne Fund, the Emerald Foundation and The Experimental Therapeutics Center of Memorial Sloan-Kettering Cancer Center funded by William H. Goodwin and Alice Goodwin and the Commonwealth Foundation for Cancer Research (M.R.M.v.d.B.). J.L.Z. is the recipient of a fellowship grant from the Lymphoma Research Foundation, J.C.M. and G.R. are supported by a Cancer Research Institute Pre-Doctoral Fellowship and by NIH MSTP grant GM07739, M.S. and J.C.M are supported by NIH grant CA40350, M.S., I.R. and J.C.M. are supported by NIH grant CA59350, and J.C.Z.-P. is supported by a Canada Research Chair in Developmental Immunology. Technical services provided by the MSKCC Small-Animal Imaging Core Facility, supported in part by NIH Small-Animal Imaging Research Program (SAIRP) grant R24 CA83084 and NIH Center grant P30 CA08748, are gratefully acknowledged. The authors would like to thank the staff of the Research Animal Resource Center for excellent animal care. A20, a B-cell lymphoma cell line derived from BALB/c mice, and Renca, a renal cell carcinoma cell line derived from BALB/c mice, were kindly provided by A. Houghton (Memorial Sloan Kettering Cancer Center).

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Authors and Affiliations

  1. Department Immunology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, 10021, New York, USA

    Johannes L Zakrzewski, David Suh, Odette M Smith, Christopher King, Gabrielle L Goldberg, Robert Jenq, Amanda M Holland, Jeremy Grubin, Javier Cabrera-Perez, Sydney X Lu, Gabrielle Rizzuto, Derek B Sant'Angelo & Marcel R M van den Brink

  2. Department of Molecular Pharmacology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, 10021, New York, USA

    John C Markley, Isabelle Riviere & Michel Sadelain

  3. Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, 10021, New York, USA

    Robert Jenq, Renier J Brentjens, Michel Sadelain & Marcel R M van den Brink

  4. Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, 10021, New York, USA

    Glenn Heller

  5. Department of Immunology, University of Toronto, Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, M4N 3M5, Ontario, Canada

    Juan Carlos Zúñiga-Pflücker

  6. Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, 32610, Florida, USA

    Chen Lu

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  1. Johannes L Zakrzewski
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Contributions

J.L.Z designed experiments, performed tissue culture, in vivo bioluminescence imaging studies and flow cytometric studies, analyzed data, generated figures and wrote the manuscript. D.S., O.M.S., C.K., A.M.H., J.G. and J.C.-P. assisted with performance of T-cell precursor transfer and tumor experiments, hematopoietic stem cell sorting, organ harvests, GVHD scoring and monitoring of survival. J.C.M. generated vectors and designed experiments regarding genetic engineering of T-cell precursors, M.S. designed experiments regarding genetic engineering of T-cell precursors and analyzed data, R.J.B. constructed the 19z1 vector, I.R. provided the 19z1-specific antibody, G.R. performed ELISPOT studies, C.L. performed histopathological studies, G.H. performed statistical analyses, G.L.G., S.X.L. and R.J. analyzed data, D.B.S. and J.C.Z.-P. designed experiments and analyzed data, M.R.M.v.d.B. designed experiments, analyzed data, supervised the study and edited the manuscript.

Corresponding author

Correspondence to Marcel R M van den Brink.

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Zakrzewski, J., Suh, D., Markley, J. et al. Tumor immunotherapy across MHC barriers using allogeneic T-cell precursors. Nat Biotechnol 26, 453–461 (2008). https://doi.org/10.1038/nbt1395

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