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Cellular Therapy

Activated MHC-mismatched T helper-1 lymphocyte infusion enhances GvL with limited GvHD

Bone Marrow Transplantation volume 49, pages 1076–1083 (2014)Cite this article

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Abstract

DLI is traditionally used to provide graft-versus-leukemia (GvL) effects when given to patients relapsing post-hematopoietic cell transplantation (HCT). However, it is often associated with significant GvHD and has only modest efficacy against acute leukemias. Therefore, novel cellular therapies are needed to improve the outcome of high-risk or relapsed leukemia patients following HCT. Activated T helper-1 (aTh-1) lymphocytes are CD4+CD25+CD40L+CD62Llo effector memory cells that produce large amounts of IFN-γ and TNF-α. We demonstrate that post-transplant adoptive aTh-1 cell therapy enhances GvL with limited GvHD in an MHC-mismatched murine BMT model. aTh-1 infusions result in superior leukemia-free survival when compared with unstimulated splenocytes (SC), purified CD4+ T-cells and T-cell-enriched SC. aTh-1 cells display cytotoxicity against A20 leukemia cells in vitro and persist in vivo for at least 2 months following adoptive transfer. Furthermore, in contrast to unstimulated SC, aTh-1 cell infusion is associated with only transient, mild suppression of donor-derived hematopoiesis. aTh-1 cell therapy is safe, effective and warrants further investigation as an alternative to DLI.

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References

  1. Weiden PL, Flournoy N, Sanders JE, Sullivan KM, Thomas ED . Antileukemic effect of graft-versus-host disease contributes to improved survival after allogeneic marrow transplantation. Transplant Proc 1981; 13 (Pt 1): 248–251.

    CAS  PubMed  Google Scholar 

  2. Horowitz MM, Gale RP, Sondel PM, Goldman JM, Kersey J, Kolb HJ et al. Graft-versus-leukemia reactions after bone marrow transplantation. Blood 1990; 75: 555–562.

    CAS  PubMed  Google Scholar 

  3. Gale RP, Champlin RE . How does bone-marrow transplantation cure leukaemia? Lancet 1984; 2: 28–30.

    Article  CAS  PubMed  Google Scholar 

  4. Gale RP, Horowitz MM, Ash RC, Champlin RE, Goldman JM, Rimm AA et al. Identical-twin bone marrow transplants for leukemia. Ann Int Med 1994; 120: 646–652.

    Article  CAS  PubMed  Google Scholar 

  5. Soiffer RJ, Lerademacher J, Ho V, Kan F, Artz A, Champlin RE et al. Impact of immune modulation with anti-T-cell antibodies on the outcome of reduced-intensity allogeneic hematopoietic stem cell transplantation for hematologic malignancies. Blood 2011; 117: 6963–6970.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. D'Sa S, Peggs K, Pizzey A, Verfuerth S, Thuraisundaram D, Watts M et al. T- and B-cell immune reconstitution and clinical outcome in patients with multiple myeloma receiving T-cell-depleted, reduced-intensity allogeneic stem cell transplantation with an alemtuzumab-containing conditioning regimen followed by escalated donor lymphocyte infusions. Br J Haematol 2003; 123: 309–322.

    Article  CAS  PubMed  Google Scholar 

  7. Bastien JP, Roy J, Roy DC . Selective T-cell depletion for haplotype-mismatched allogeneic stem cell transplantation. Semin Oncol 2012; 39: 674–682.

    Article  CAS  PubMed  Google Scholar 

  8. Perruccio K, Topini F, Tosti A, Carotti A, Burchielli E, Ruggeri L et al. Optimizing a photoallodepletion protocol for adoptive immunotherapy after haploidentical SCT. Bone Marrow Transplant 2012; 47: 1196–1200.

    Article  CAS  PubMed  Google Scholar 

  9. Amrolia PJ, Muccioli-Casadei G, Huls H, Adams S, Durett A, Gee A et al. Adoptive immunotherapy with allodepleted donor T-cells improves immune reconstitution after haploidentical stem cell transplantation. Blood 2006; 108: 1797–1808.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Askenasy N, Mizrahi K, Ash S, Askenasy EM, Yaniv I, Stein J . Depletion of naive lymphocytes with fas ligand ex vivo prevents graft-versus-host disease without impairing T cell support of engraftment or graft-versus-tumor activity. Biol Blood Marrow Transplant 2013; 19: 185–195.

    Article  CAS  PubMed  Google Scholar 

  11. Kochenderfer JN, Dudley ME, Carpenter RO, Kassim SH, Rose JJ, Telford WG et al. Donor-derived CD19-targeted T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation. Blood 2013; 122: 4129–4139.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kolb HJ, Mittermuller J, Clemm C, Holler E, Ledderose G, Brehm G et al. Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients. Blood 1990; 76: 2462–2465.

    CAS  PubMed  Google Scholar 

  13. Kolb HJ, Schattenberg A, Goldman JM, Hertenstein B, Jacobsen N, Arcese W et al. Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. Blood 1995; 86: 2041–2050.

    CAS  PubMed  Google Scholar 

  14. Tomblyn M, Lazarus HM . Donor lymphocyte infusions: the long and winding road: how should it be traveled? Bone Marrow Transplant 2008; 42: 569–579.

    Article  CAS  PubMed  Google Scholar 

  15. Har-Noy M, Zeira M, Weiss L, Slavin S . Completely mismatched allogeneic CD3/CD28 cross-linked Th1 memory cells elicit anti-leukemia effects in unconditioned hosts without GVHD toxicity. Leuk Res 2008; 32: 1903–1913.

    Article  CAS  PubMed  Google Scholar 

  16. Zeis M, Uharek L, Glass B, Vosskotter W, Dreger P, Schmitz N et al. Eradication of residual disease by administration of leukemia-specific T cells after experimental allogeneic bone marrow transplantation. Exp Hematol 1998; 26: 1068–1073.

    CAS  PubMed  Google Scholar 

  17. Burich A, Hershberg R, Waggie K, Zeng W, Brabb T, Westrich G et al. Helicobacter-induced inflammatory bowel disease in IL-10- and T cell-deficient mice. Am J Physiol Gastrointest Liver Physiol 2001; 281: G764–G778.

    Article  CAS  PubMed  Google Scholar 

  18. He L, Feng H, Raymond A, Kreeger M, Zeng Y, Graner M et al. Dendritic-cell-peptide immunization provides immunoprotection against bcr-abl-positive leukemia in mice. Cancer Immunol Immunother 2001; 50: 31–40.

    Article  CAS  PubMed  Google Scholar 

  19. Janikashvili N, LaCasse CJ, Larmonier C, Trad M, Herrell A, Bustamante S et al. Allogeneic effector/memory Th-1 cells impair FoxP3+ regulatory T lymphocytes and synergize with chaperone-rich cell lysate vaccine to treat leukemia. Blood 2011; 117: 1555–1564.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Har-Noy M, Zeira M, Weiss L, Fingerut E, Or R, Slavin S . Allogeneic CD3/CD28 cross-linked Th1 memory cells provide potent adjuvant effects for active immunotherapy of leukemia/lymphoma. Leuk Res 2009; 33: 525–538.

    Article  CAS  PubMed  Google Scholar 

  21. Sykes M, Chester CH, Sundt TM, Romick ML, Hoyles KA, Sachs DH . Effects of T cell depletion in radiation bone marrow chimeras. III. Characterization of allogeneic bone marrow cell populations that increase allogeneic chimerism independently of graft-vs-host disease in mixed marrow recipients. J Immunol 1989; 143: 3503–3511.

    CAS  PubMed  Google Scholar 

  22. Anderson BE, McNiff J, Yan J, Doyle H, Mamula M, Shlomchik MJ et al. Memory CD4+ T cells do not induce graft-versus-host disease. J Clin Invest 2003; 112: 101–108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Chen BJ, Cui X, Sempowski GD, Liu C, Chao NJ . Transfer of allogeneic CD62L- memory T cells without graft-versus-host disease. Blood 2004; 103: 1534–1541.

    Article  CAS  PubMed  Google Scholar 

  24. Zheng H, Matte-Martone C, Li H, Anderson BE, Venketesan S, Sheng Tan H et al. Effector memory CD4+ T cells mediate graft-versus-leukemia without inducing graft-versus-host disease. Blood 2008; 111: 2476–2484.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Wysocki CA, Panoskaltsis-Mortari A, Blazar BR, Serody JS . Leukocyte migration and graft-versus-host disease. Blood 2005; 105: 4191–4199.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Chakraverty R, Cote D, Buchli J, Cotter P, Hsu R, Zhao G et al. An inflammatory checkpoint regulates recruitment of graft-versus-host reactive T cells to peripheral tissues. J Exp Med 2006; 203: 2021–2031.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Mapara MY, Leng C, Kim YM, Bronson R, Lokshin A, Luster A et al. Expression of chemokines in GVHD target organs is influenced by conditioning and genetic factors and amplified by GVHR. Biol Blood Marrow Transplant 2006; 12: 623–634.

    Article  CAS  PubMed  Google Scholar 

  28. Zorn E, Wang KS, Hochberg EP, Canning C, Alyea EP, Soiffer RJ et al. Infusion of CD4+ donor lymphocytes induces the expansion of CD8+ donor T cells with cytolytic activity directed against recipient hematopoietic cells. Clin Cancer Res 2002; 8: 2052–2060.

    CAS  PubMed  Google Scholar 

  29. Martin PJ, Hansen JA, Torok-Storb B, Moretti L, Press O, Storb R et al. Effects of treating marrow with a CD3-specific immunotoxin for prevention of acute graft-versus-host disease. Bone Marrow Transplant 1988; 3: 437–444.

    CAS  PubMed  Google Scholar 

  30. Marmont AM, Horowitz MM, Gale RP, Sobocinski K, Ash RC, van Bekkum DW et al. T-cell depletion of HLA-identical transplants in leukemia. Blood 1991; 78: 2120–2130.

    CAS  PubMed  Google Scholar 

  31. Kernan NA, Bordignon C, Heller G, Cunningham I, Castro-Malaspina H, Shank B et al. Graft failure after T-cell-depleted human leukocyte antigen identical marrow transplants for leukemia: I. Analysis of risk factors and results of secondary transplants. Blood 1989; 74: 2227–2236.

    CAS  PubMed  Google Scholar 

  32. Schmeiser T, Wiesneth M, Bunjes D, Arnold R, Hertenstein B, Heit W et al. Infectious complications after allogeneic bone marrow transplantation with and without T-cell depletion of donor marrow. Infection 1989; 17: 124–130.

    Article  CAS  PubMed  Google Scholar 

  33. Soiffer RJ, Murray C, Mauch P, Anderson KC, Freedman AS, Rabinowe SN et al. Prevention of graft-versus-host disease by selective depletion of CD6-positive T lymphocytes from donor bone marrow. J Clin Oncol 1992; 10: 1191–1200.

    Article  CAS  PubMed  Google Scholar 

  34. Wagner JE, Thompson JS, Carter SL, Kernan NA . Effect of graft-versus-host disease prophylaxis on 3-year disease-free survival in recipients of unrelated donor bone marrow (T-cell Depletion Trial): a multi-centre, randomised phase II-III trial. Lancet 2005; 366: 733–741.

    Article  CAS  PubMed  Google Scholar 

  35. Jakubowski AA, Small TN, Young JW, Kernan NA, Castro-Malaspina H, Hsu KC et al. T cell depleted stem-cell transplantation for adults with hematologic malignancies: sustained engraftment of HLA-matched related donor grafts without the use of antithymocyte globulin. Blood 2007; 110: 4552–4559.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Tsao GJ, Allen JA, Logronio KA, Lazzeroni LC, Shizuru JA . Purified hematopoietic stem cell allografts reconstitute immunity superior to bone marrow. Proc Natl Acad Sci USA 2009; 106: 3288–3293.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Muller AM, Linderman JA, Florek M, Miklos D, Shizuru JA . Allogeneic T cells impair engraftment and hematopoiesis after stem cell transplantation. Proc Natl Acad Sci USA 2010; 107: 14721–14726.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. de Bruin AM, Demirel O, Hooibrink B, Brandts CH, Nolte MA . Interferon-gamma impairs proliferation of hematopoietic stem cells in mice. Blood 2013; 121: 3578–3585.

    Article  CAS  PubMed  Google Scholar 

  39. Caux C, Moreau I, Saeland S, Banchereau J . Interferon-gamma enhances factor-dependent myeloid proliferation of human CD34+ hematopoietic progenitor cells. Blood 1992; 79: 2628–2635.

    CAS  PubMed  Google Scholar 

  40. Kawano Y, Takaue Y, Hirao A, Abe T, Saito S, Matsunaga K et al. Synergistic effect of recombinant interferon-gamma and interleukin-3 on the growth of immature human hematopoietic progenitors. Blood 1991; 77: 2118–2121.

    CAS  PubMed  Google Scholar 

  41. Reddy P, Negrin R, Hill GR . Mouse models of bone marrow transplantation. Biol Blood Marrow Transplant 2008; 14 (Suppl 1): 129–135.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Dr Nicolas Larmonier for helpful discussion and critical reading of the manuscript. We also thank Alexis Lorenz, Martin Asimis, Neale Hanke, Collin LaCasse and Darya Alizadeh for technical assistance and Kim Carpenter and Vanessa Frisinger for administrative assistance. Financial disclosure: This work was supported by the National Institutes of Health Grant R01 CA104926 (to EK), Hyundai Hope on Wheels, Tee Up for Tots and a University of Arizona Faculty Seed Grant (to YZ).

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  1. Y Zeng and J Stokes: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pediatrics, Steele Children’s Research Center, The University of Arizona, Tucson, AZ, USA,

    Y Zeng, J Stokes, S Hahn, E Hoffman & E Katsanis

  2. Department of Immunobiology, The University of Arizona, Tucson, AZ, USA

    E Katsanis

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Correspondence to E Katsanis.

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Zeng, Y., Stokes, J., Hahn, S. et al. Activated MHC-mismatched T helper-1 lymphocyte infusion enhances GvL with limited GvHD. Bone Marrow Transplant 49, 1076–1083 (2014). https://doi.org/10.1038/bmt.2014.91

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