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DOI: 10.1055/s-2005-872521
© Georg Thieme Verlag Stuttgart · New York
Adoptive Cellular Immunotherapy with CD19-Specific T Cells
Adoptive zelluläre Immuntherapie mit CD19-spezifischen T-ZellenPublikationsverlauf
Publikationsdatum:
24. November 2005 (online)
![](https://www.thieme-connect.de/media/klinpaed/200506/lookinside/thumbnails/10.1055-s-2005-872521-1.jpg)
Abstract
Background: No effective therapeutic modalities exist for the treatment of relapsed high risk acute lymphoblastic leukemia (ALL). Adoptive cellular immunotherapy by transfusion of polyclonal donor lymphocytes is not always effective and is limited by cellular cross-reactivity with normal tissues, leading to development of clinical graft-versus-host disease (GVHD). Method: To develop an immunotherapeutic strategy for targeted elimination of residual leukemic blasts, human T cells were gene-modified to express CD19-specific chimeric receptors. Results: Gene-modified T cells specifically lyse CD19-expressing lymphatic blast cells, however, they show a limited proliferative response to stimulation with CD19. Integration of the signal transduction domain of the costimulatory molecule CD28 enhances the proliferative properties of the gene-modified T cells. Conclusions: Adoptive transfer of gene-modified virus-specific T cells may provide a useful strategy for prevention and early treatment of ALL relapses following allogeneic stem cell transplantation.
Zusammenfassung
Hintergrund: Für Rezidive der Hochrisikoformen akuter lymphoblastischer Leukämien (ALL) des Kindesalters nach allogener Stammzelltransplantation gibt es bisher keine effektiven Therapieoptionen. Eine adoptive zelluläre Immuntherapie durch Transfusion polyklonaler Spenderlymphozyten hat sich in vielen Fällen als nicht ausreichend wirksam erwiesen und ist limitiert durch die Kreuzreaktivität der Zellen mit gesunden Geweben, die in der Mehrzahl der Fälle zur Entwicklung einer Graft- versus Host-Erkrankung (GVHD) führt. Methode: Mit dem Ziel der Entwicklung einer immuntherapeutischen Strategie zur gezielten Eliminierung residualer leukämischer Blasten wurden humane T-Lymphozyten durch genetische Modifikation mit Spezifität für das B-Zell-Antigen CD19 ausgestattet. Ergebnisse: CD19ζ-transduzierte T-Zellen können CD19-exprimierende lymphatische Blasten spezifisch lysieren, zeigen jedoch eine limitierte proliferative Antwort auf Stimulation mit CD19. Die Integration der Signaltransduktionsdomäne des kostimulatorischen Moleküls CD28 verstärkt die proliferativen Eigenschaften der genmodifizieren T-Zellen. Schlussfolgerung: Der adoptive Transfer genetisch modifizierter virusspezifischer T-Zellen könnte eine sinnvolle Strategie zur ALL-Rezidivprophylaxe im Anschluss an eine allogene Stammzelltransplantation darstellen.
Key words
Immunotherapy - ALL - T cells - CD19
Schlüsselwörter
Immuntherapie - ALL - T-Zellen - CD19
References
- 1 Kolb H J, Schattenberg A, Goldman J M, Hertenstein B, Jacobsen N, Arcese W, Ljungman P, Ferrant A, Verdonck L, Niederwieser D, Vanrhee F, Mittermueller J, Dewitte T, Holler E, Ansari H. Graft-Versus-Leukemia Effect of Donor Lymphocyte Transfusions in Marrow Grafted Patients. Blood. 1995; 86 2041-2050
- 2 Borgmann A, Stackelberg A, Hartmann R, Ebell W, Klingebiel T, Peters C, Henze G. Unrelated donor stem cell transplantation compared with chemotherapy for children with acute lymphoblastic leukemia in a second remission: a matched-pair analysis. Blood. 2003; 101 3835-3839
- 3 Bader P, Kreyenberg H, Hoelle W, Dueckers G, Handgretinger R, Lang P, Kremens B, Dilloo D, Sykora K W, Schrappe M, Niemeyer C, Stackelberg A, Gruhn B, Henze G, Greil J, Niethammer D, Dietz K, Beck J F, Klingebiel T. Increasing mixed chimerism is an important prognostic factor for unfavorable outcome in children with acute lymphoblastic leukemia after allogeneic stem-cell transplantation: Possible role for pre-emptive immunotherapy?. J Clin Oncol. 2004; 22 1696-1705
- 4 Kolb H J, Mittermuller J, Clemm C, Holler E, Ledderose G, Brehm G, Heim M, Wilmanns W. Donor Leukocyte Transfusions for Treatment of Recurrent Chronic Myelogenous Leukemia in Marrow Transplant Patients. Blood. 1990; 76 2462-2465
- 5 Cardoso A A, Veiga J P, Ghia P, Afonso H M, Haining W N, Sallan S E, Nadler L M. Adoptive T-cell therapy for B-cell acute lymphoblastic leukemia: preclinical studies. Blood. 1999; 94 3531-3540
- 6 Eshhar Z, Waks T, Gross G, Schindler D G. Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the gamma or zeta subunits of the immunoglobulin and T-cell receptors. Proc Natl Acad Sci USA. 1993; 90 720-724
- 7 Uckun F M, Burkhardt A L, Jarvis L, Jun X, Stealey B, Dibirdik I, Myers D E, Tuel-Ahlgren L, Bolen J B. Signal transduction through the CD19 receptor during discrete developmental stages of human B-cell ontogeny. J Biol Chem. 1993; 268 21172-21184
- 8 Fearon D T, Carroll M C. Regulation of B lymphocyte responses to foreign and self-antigens by the CD19/CD21 complex. Annu Rev Immunol. 2000; 18 393-422
- 9 Rickert R C, Rajewsky K, Roes J. Impairment of T-Cell-Dependent B-Cell Responses and B-1 Cell-Development in Cd19-Deficient Mice. Nature. 1995; 376 352-355
- 10 Uckun F M, Evans W E, Forsyth C J, Waddick K G, Ahlgren L T, Chelstrom L M, Burkhardt A, Bolen J, Myers D E. Biotherapy of B-cell precursor leukemia by targeting genistein to CD19- associated tyrosine kinases. Science. 1995; 267 886-891
- 11 Lang P, Barbin K, Feuchtinger T, Greil J, Peipp M, Zunino S J, Pfeiffer M, Handgretinger R, Niethammer D, Fey G H. Chimeric CD19 antibody mediates cytotoxic activity against leukemic blasts with effector cells from pediatric patients who received T-cell-depleted allografts. Blood. 2004; 103 3982-3985
- 12 Nicholson I C, Lenton K A, Little D J, Decorso T, Lee F T, Scott A M, Zola H, Hohmann A W. Construction and characterisation of a functional CD19 specific single chain Fv fragment for immunotherapy of B lineage leukaemia and lymphoma. Mol Immunol. 1997; 34 1157-1165
- 13 Rossig C, Pscherer S, Baer A, Altvater B, Pule M, Rooney C M, Brenner M K, Juergens H, Vormoor J. Target antigen expression on a professional antigen-presenting cell induces superior proliferative anti-tumor T cell responses via chimeric T cell receptors. J Immunother. 2005; in print
- 14 Riviere 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. 1995; 92 6733-6737
- 15 Henze G, Borgmann A, Stackelberg A, Baumgarten E, Uchanska-Ziegler B, Ziegler A, Wittig B. Immunotherapy of acute lymphoblastic leukemia by vaccination with autologous leukemic cells transfected with a cDNA expression plasmid coding for an allogeneic HLA class I antigen combined with interleukin-2 treatment. Journal of Molecular Medicine Jmm. 1998; 76 215-221
- 16 Rousseau R, Biagi E, Yvon E, Mei Z Y, Inman S, Rill D, Heslop H, Popat U, Gee A, Krance R, Carrum G, Alcoser P, Rodgers S, Kuehnle I, Margolin J, Brenner M. Treatment of high-risk acute leukemia with an autologous vaccine expressing transgenic IL-2 and CD40L. Blood. 2002; 100 867 A-868 A
- 17 Walker R E, Bechtel C M, Natarajan V, Baseler M, Hege K M, Metcalf J A, Stevens R, Hazen A, Blaese R M, Chen C C, Leitman S F, Palensky J, Wittes J, Davey R T, Falloon J, Polis M A, Kovacs J A, Broad D F, Levine B L, Roberts M R, Masur H, Lane H C. Long-term in vivo survival of receptor-modified syngeneic T cells in patients with human immunodeficiency virus infection. Blood. 2000; 96 467-474
- 18 Eshhar Z, Waks T, Bendavid A, Schindler D G. Functional expression of chimeric receptor genes in human T cells. J Immunol Methods. 2001; 248 67-76
- 19 Heemskerk M HM, Hoogeboom M, Hagedoorn R, Willemze R, Falkenburg J HF. Redirection of CMV-specific T-cells towards anti-leukaemic reactivity using T-cell receptor gene transfer. Bone Marrow Transplant. 2004; 33 S 21
- 20 Kershaw M H, Westwood J A, Hwu P. Dual-specific T cells combine proliferation and antitumor activity. Nature Biotechnology. 2002; 20 1221-1227
- 21 Rossig C, Bollard C M, Nuchtern J G, Rooney C M, Brenner M K. Epstein-Barr virus-specific human T lymphocytes expressing antitumor chimeric T-cell receptors: potential for improved immunotherapy. Blood. 2002; 99 2009-2016
- 22 Kimby E. Tolerability and safety of rituximab (MabThera(®)). Cancer Treatment Reviews. 2005; [Epub ahead of print]
Dr. med. Claudia Rössig
Universitätsklinikum Münster · Klinik und Poliklinik für Kinderheilkunde ·
Pädiatrische Hämatologie/Onkologie
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