Phase I/II feasibility study evaluating the generation of leukemia-reactive cytotoxic T lymphocyte lines for treatment of patients with relapsed leukemia after allogeneic stem cell transplantation.

BACKGROUND AND OBJECTIVES Graft-versus-host-disease may be avoided and the likelihood of a graft-versus-leukemia reaction increased by infusion of in vitro generated, leukemia-reactive, cytotoxic T lymphocyte (CTL) lines as treatment for patients with relapsed leukemia after allogeneic stem cell transplantation, instead of donor lymphocyte infusion. The aim of this study phase I/II study was to assess the feasibility of large-scale in vitro generation of leukemia-reactive CTL for clinical use. DESIGN AND METHODS Using a modified limiting dilution culture system donor T cells were stimulated with HLA-identical leukemic antigen presenting cells. Feasibility experiments demonstrated that in 16 of 27 donor-recipient pairs tested a CTL line could be generated. Twelve of these 16 patients developed a relapse and for 11 of these 12 patients a CTL line was generated under Good Manufacturing Practice conditions. RESULTS The CTL lines showed moderate to high cytotoxic activity against original recipient leukemic cells in vitro. Eight patients with a relapse received from one to seven CTL lines. One patient entered a complete remission after CTL infusion only, one entered a complete remission after combined CTL infusion and donor lymphocyte infusion, two patients had temporarily stable disease, and in four patients no response was observed. INTERPRETATION AND CONCLUSIONS Although the current procedure to generate these CTL lines is feasible, the strategy is logistically complex and time-consuming, and needs further improvement. Key words: cellular immunotherapy, CTL, leukemia, allogeneic stem cell transplantation.

[1]  J. Serody,et al.  A Novel System for Simultaneous in Vivo Tracking and Biological Assessment of Leukemia Cells and ex Vivo Generated Leukemia-Reactive Cytotoxic T Cells , 2004, Cancer Research.

[2]  M. A. van der Hoorn,et al.  The progenitor cell inhibition assay to measure the anti-leukemic reactivity of T cell clones against acute and chronic myeloid leukemia. , 2003, Methods.

[3]  J. Falkenburg,et al.  Minor histocompatibility antigens in human stem cell transplantation. , 2003, Experimental hematology.

[4]  J. Falkenburg,et al.  An animal model for human cellular immunotherapy: specific eradication of human acute lymphoblastic leukemia by cytotoxic T lymphocytes in NOD/scid mice. , 2002, Blood.

[5]  M. V. van Oers,et al.  Donor lymphocyte infusions for relapsed multiple myeloma after allogeneic stem-cell transplantation: predictive factors for response and long-term outcome. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  S. Opal,et al.  Anti-inflammatory cytokines. , 2000, Chest.

[7]  J. Falkenburg,et al.  Expression and induction of costimulatory and adhesion molecules on acute myeloid leukemic cells: implications for adoptive immunotherapy. , 2000, Experimental hematology.

[8]  W. M. Smit,et al.  Complete remission of accelerated phase chronic myeloid leukemia by treatment with leukemia-reactive cytotoxic T lymphocytes. , 1999, Blood.

[9]  WM Kast,et al.  Effects of TGF-β on the immune system: implications for cancer immunotherapy , 1999, Leukemia.

[10]  R. Champlin,et al.  Dendritic Cells Derived In Vitro From Acute Myelogenous Leukemia Cells Stimulate Autologous, Antileukemic T-Cell Responses , 1999 .

[11]  L. Kearney,et al.  The in-vitro generation of dendritic cells from blast cells in acute leukaemia. , 1998, British journal of haematology.

[12]  J. Falkenburg,et al.  T cells recognizing leukemic CD34(+) progenitor cells mediate the antileukemic effect of donor lymphocyte infusions for relapsed chronic myeloid leukemia after allogeneic stem cell transplantation. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[13]  J. Falkenburg,et al.  Generation of leukemia-reactive cytotoxic T lymphocytes from HLA-identical donors of patients with chronic myeloid leukemia using modifications of a limiting dilution assay , 1998, Bone Marrow Transplantation.

[14]  Robert H. Collins,et al.  Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation. , 1997, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[15]  F. Sallusto,et al.  Origin, maturation and antigen presenting function of dendritic cells. , 1997, Current opinion in immunology.

[16]  J. Gribben,et al.  Pre-B acute lymphoblastic leukemia cells may induce T-cell anergy to alloantigen. , 1996, Blood.

[17]  J. Falkenburg,et al.  Generation of CD4+ cytotoxic T-lymphocyte clones from a patient with severe graft-versus-host disease after allogeneic bone marrow transplantation: implications for graft-versus-leukemia reactivity. , 1995, Blood.

[18]  A Ferrant,et al.  Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. , 1995, Blood.

[19]  P. Neiman,et al.  CLINICAL MANIFESTATIONS OF GRAFT‐VERSUS-HOST DISEASE IN HUMAN RECIPIENTS OF MARROW FROM HL‐A-MATCHED SIBLING DONOR,S , 1974, Transplantation.

[20]  J. Falkenburg,et al.  Minor histocompatibility antigen-specific T cells with multiple distinct specificities can be isolated by direct cloning of IFNγ-secreting T cells from patients with relapsed leukemia responding to donor lymphocyte infusion , 2005, Leukemia.