Adoptive Cellular Immunotherapy with CD19-Specific T Cells

 

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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.

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Dr. med. Claudia Rössig

Universitätsklinikum Münster · Klinik und Poliklinik für Kinderheilkunde ·
Pädiatrische Hämatologie/Onkologie

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