Adoptive transfer of tumor specific T cells from allogeneic donors is feasible, effective and safe alternative to autologous T cell based tumor immunotherapy

  • Eliza P. Kwiatkowska-Borowczyk Department of Cancer Immunology, Poznan University of Medical Sciences, Poland Diagnostic and Immunology Department, Greater Poland Cancer Centre, Poznan, Poland
  • Anna Kozłowska Department of Cancer Immunology, Poznan University of Medical Sciences, Poland
  • Klaudia Maruszak Department of Pathology, MSW Hospital, Olsztyn, Poland
  • Luiza Kańczuga-Koda Department of Pathology, MSW Hospital, Olsztyn, Poland
  • Mariusz Koda Department of Pathology, MSW Hospital, Olsztyn, Poland
  • Monika Dajnowiec Department of Pathophysiology, Faculty of Medicine, University of Warmia and Mazury in Olsztyn, Poland
  • Andrzej Mackiewicz Department of Cancer Immunology, Poznan University of Medical Sciences, Poland Diagnostic and Immunology Department, Greater Poland Cancer Centre, Poznan, Poland
  • Dariusz W. Kowalczyk Department of Pathophysiology, Faculty of Medicine, University of Warmia and Mazury in Olsztyn, Poland
Keywords: adoptive cell transfer, tumor immunotherapy, cancer, GVHD, allogeneic T cells, murine model


Donor lymphocyte infusion is used to increase the graft versus tumor (GVT) effect after allogeneic hematopoietic cell transplant. The limited spectrum of activity and high risk of graft versus host disease (GVHD) remain major limitations of this approach. The finding of new cell populations for adoptive immunotherapy, with the ability to separate GVT from GVHD, would be useful. In the present manuscript, we tested in mouse model the use of allogeneic MHC partially matched effector cells for adoptive T cell immunotherapy of cancer. We sought to maximize graft-versus-tumor effect while minimizing GVHD using tumor-specific allogeneic effector T cells rather than open-repertoire T cells. A F1 hybrid (Balb/c x C57BL/6) -MethA-EGFP–bearing mice received a preparative regimen of nonmyeloablating cyclophosphamide lymphodepletion followed by adoptive transfer of bulk Balb/c derived allogeneic T cells specific for the MethA-EGFP tumor cells. Adoptively transferred allogeneic tumor-specific T lymphocytes prevented tumor formation without graft versus host disease – like symptoms. We found that the risk of GVHD was low even with high number of transferred tumor-specific T cells. These data indicate that the use of tumor-specific allogeneic T cells is feasible, effective and safe alternative to autologous T cell based tumor immunotherapy.


Dudley ME, Wunderlich JR, Yang JC et al. Adoptive cell transfer therapy following non-myeloablative but lympho- -depleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol. 2005;23:2346–2357.

Rosenberg SA, Restifo NP, Yang JC, Morgan RA, Dudley ME. Adoptive cell transfer: a clinical path to effective cancer immunotherapy. Nat Rev Cancer. 2008;8:299–308.

Dudley ME, Wunderlich JR, Shelton TE, Even J, Rosenberg SA. Generation of tumor-infiltrating lymphocyte cultures for use in adoptive transfer therapy for melanoma patients. J Immunother. 2003;26:332–342.

Wynn RF, Arkwright PD, Haque T et al. Treatment of Epstein-Barr-virus-associated primary CNS B cell lymphoma with allogeneic T-cell immunotherapy and stem-cell transplantation. Lancet Oncol. 2005;6:344–346.

Haque T, Wilkie GM, Taylor C et al. Treatment of Epstein-Barr-virus-positive post-transplantation lymphoproliferative disease with partly HLA-matched allogeneic cytotoxic T cells. Lancet. 2002;360:436–442.

Haque T, Wilkie GM, Jones MM et al. Allogeneic cytotoxic T-cell therapy for EBV-positive posttransplantation lymphoproliferative disease: results of a phase 2 multicenter clinical trial. Blood. 2007;110:1123–1131.

Bartels CJ, Rosenberg SA, Yang JC. Adoptive cellular immunotherapy of cancer in mice using allogeneic T-cells. Ann Surg Oncol. 1996;3:67–73.

Zakrzewski JL, Suh D, Markley JC et al. Tumor immunotherapy across MHC barriers using allogeneic T-cell precursors. Nat Biotechnol. 2008;26:453–461.

Boni A, Muranski P, Lydie Cassard, Wrzesinski C, Paulos CM, Palmer DC, Gattinoni L, Hinrichs CS, Chan CC, Rosenberg SA, Restifo NP. Adoptive transfer of allogeneic tumor-specific T cells mediates effective regression of large tumors across major histocompatibility barriers. Blood. 2008; 112: 4746–4754.

Gattinoni L, Powell DJ, Jr, Rosenberg SA, Restifo NP. Adoptive immunotherapy for cancer: building on success. Nat Rev Immunol. 2006;6:383–393.

Huang J, Khong HT, Dudley ME et al. Survival, persistence, and progressive differentiation of adoptively transferred tumor-reactive T cells associated with tumor regression. J Immunother. 2005;28:258–267.

Zhou J, Shen X, Huang J, Hodes RJ, Rosenberg SA, Robbins PF. Telomere length of transferred lymphocytes correlates with in vivo persistence and tumor regression in melanoma patients receiving cell transfer therapy. J Immunol. 2005;175:7046–7052.

Lee TH, Donegan E, Slichter S, Busch MP. Transient increase in circulating donor leukocytes after allogeneic transfusions in immunocompetent recipients compatible with donor cell proliferation. Blood. 1995;85:1207–1214.

Adams PT, Davenport RD, Reardon DA, Roth MS. Detection of circulating donor white blood cells in patients receiving multiple transfusions. Blood. 1992;80:551–555.

Leitman SF, Tisdale JF, Bolan CD et al. Transfusion-associated GVHD after fludarabine therapy in a patient with systemic lupus erythematosus. Transfusion. 2003;43:1667–1671.

Gambotto A, Dworacki G, Cicinnati V, Kenniston T, Steitz J, Tüting T, Robbins PD, DeLeo AB. Immunogenicity of enhanced green fluorescent protein (EGFP) in BALB/c mice: identification of an H2-Kd-restricted CTL epitope. Gene Ther. 2000;7:2036–40.

Wysocki PJ, Kwiatkowska EP, Kazimierczak U, Suchorska W, Kowalczyk DW, Mackiewicz A. Captopril, an angiotensin-converting enzyme inhibitor, promotes growth of immunogenic tumors in mice. Clin Cancer Res. 2006;12:4095–102.

Gattinoni L, Finkelstein SE, Klebanoff CA et al. Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells. J Exp Med. 2005;202:907–912.

Wrzesinski C, Paulos CM, Gattinoni L et al. Hematopoietic stem cells promote the expansion and function of adoptively transferred antitumor CD8 T cells. J Clin Invest. 2007;117:492–501.

Felix NJ, Allen PM. Specificity of T-cell alloreactivity. Nat Rev Immunol. 2007;7:942–953.

Gattinoni L, Klebanoff CA, Palmer DC et al. Acquisition of full effector function in vitro paradoxically impairs the in vivo antitumor efficacy of adoptively transferred CD8+ T cells. J Clin Invest. 2005;115:1616–1626.

Klebanoff CA, Gattinoni L, Restifo NP. CD8+ T-cell memory in tumor immunology and immunotherapy. Immunol Rev. 2006;211:214–224.

Wong SB, Bos R, Sherman LA. Tumor-specific CD4+ T cells render the tumor environment permissive for infiltration by low-avidity CD8+ T cells. J Immunol. 2008;180:3122–3131.

Ossendorp F, Mengede E, Camps M, Filius R, Melief CJ. Specific T helper cell requirement for optimal induction of cytotoxic T lymphocytes against major histocompatibility complex class II negative tumors. J Exp Med. 1998;187:693–702.

Corthay A, Skovseth DK, Lundin KU et al. Primary antitumor immune response mediated by CD4+ T cells. Immunity. 2005;22:371–383.

Janssen EM, Lemmens EE, Wolfe T, Christen U, von Herrath MG, Schoenberger SP. CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes. Nature. 2003;421:852–856.

Shedlock DJ, Shen H. Requirement for CD4 T cell help in generating functional CD8 T cell memory. Science. 2003;300:337–339.

Smith CM, Wilson NS, Waithman J et al. Cognate CD4(+) T cell licensing of dendritic cells in CD8(+) T cell immunity. Nat Immunol. 2004;5:1143–1148.

Muranski P, Boni A, Wrzesinski C et al. Increased intensity lymphodepletion and adoptive immunotherapy: how far can we go? Nat Clin Pract Oncol. 2006;3:668–681.

Sprent J, Cho JH, Boyman O, Surh CD. T cell homeostasis. Immunol Cell Biol. 2008;86:312–319.

Bellone M, Mondino A, Corti A. Vascular targeting, chemotherapy and active immunotherapy: teaming up to attack cancer. Trends Immunol. 2008;29:235–241.

Williamson LM, Wimperis JZ, Wood ME, Woodcock B. Fludarabine treatment and transfusion-associated graft-versus-host disease. Lancet. 1996;348:472–473.

Hinrichs CS, Palmer DC, Rosenberg SA, Restifo NP. Glucocorticoids do not inhibit antitumor activity of activated CD8+ T cells. J Immunother. 2005;28:517–524.

Popat U, Carrum G, May R et al. CD52 and CD45 monoclonal antibodies for reduced intensity hemopoietic stem cell transplantation from HLA matched and one antigen mismatched unrelated donors. Bone Marrow Transplant. 2005;35:1127–1132.

Ge X, Brown J, Sykes M, Boussiotis VA. CD134-allodepletion allows selective elimination of alloreactive human T cells without loss of virus-specific and leukemia-specific effectors. Biol Blood Marrow Transplant. 2008;14:518–530.

Nagler A, Ackerstein A, Or R, Naparstek E, Slavin S. Adoptive immunotherapy with haploidentical allogeneic peripheral blood lymphocytes following autologous bone marrow transplantation. Exp Hematol. 2000;28:1225–1231.

Kennedy-Nasser AA, Brenner MK. T-cell therapy after hematopoietic stem cell transplantation. Curr Opin Hematol. 2007;14:616–624.

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

Mielke S, Nunes R, Rezvani K et al. A clinical-scale selective allodepletion approach for the treatment of HLA-mismatched and matched donor-recipient pairs using expanded T lymphocytes as antigen-presenting cells and a TH9402-based photodepletion technique. Blood. 2008;111:4392–4402.

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.

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

Anderson BE, Taylor PA, McNiff JM et al. Effects of donor T-cell trafficking and priming site on graft-versus-host disease induction by naive and memory phenotype CD4 T cells. Blood. 2008;111:5242–5251.

Fowler DH, Breglio J, Nagel G, Eckhaus MA, Gress RE. Allospecific CD8+ Tc1 and Tc2 populations in graft-versus-leukemia effect and graft-versus-host disease. J Immunol. 1996;157:4811–4821.

How to Cite
Kwiatkowska-Borowczyk, E. P., Kozłowska, A., Maruszak, K., Kańczuga-Koda, L., Koda, M., Dajnowiec, M., Mackiewicz, A., & Kowalczyk, D. W. (2016). Adoptive transfer of tumor specific T cells from allogeneic donors is feasible, effective and safe alternative to autologous T cell based tumor immunotherapy. Journal of Medical Science, 83(1), 21-28. Retrieved from
Original Papers