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An Inducible Caspase 9 Safety Switch Can Halt Cell Therapy-Induced Autoimmune Disease¹

Moniek A. de Witte^2,*, Annelies Jorritsma^2,*, Erwin Swart^*, Karin C. Straathof, Karin de Punder, John B. A. G. Haanen^*, Cliona M. Rooney and Ton N. M. Schumacher^3,*

^* Division of Immunology and Division of Experimental Animal Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; and Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030

Transfer of either allogeneic or genetically modified T cells as a therapy for malignancies can be accompanied by T cell-mediated tissue destruction. The introduction of an efficient "safety switch" can potentially be used to control the survival of adoptively transferred cell populations and as such reduce the risk of severe graft-vs-host disease. In this study, we have tested the value of an inducible caspase 9-based safety switch to halt an ongoing immune attack in a murine model for cell therapy-induced type I diabetes. The data obtained in this model indicate that self-reactive T cells expressing this conditional safety switch show unimpaired lymphopenia- and vaccine-induced proliferation and effector function in vivo, but can be specifically and rapidly eliminated upon triggering. These data provide strong support for the evaluation of this conditional safety switch in clinical trials of adoptive cell therapy.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the European Union FP6 Program ATTACK and Koningin Wilhelmina Fonds Grant 2003-2860.

² M.A.d.W. and A.J. contributed equally to this work.

³ Address correspondence and reprint requests to Prof. Ton N. M. Schumacher, Division of Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands. E-mail address: t.schumacher{at}nki.nl

⁴ Abbreviations used in this paper: DLI, donor lymphocyte infusion; GvL, graft-vs-leukemia; GvHD, graft-vs-host disease; CR, chimeric receptor; TK, thymidine kinase; allo-SCT, allogeneic stem cell transplantation; CID, chemical inducer of dimerization; FKBP, FK506-binding protein; IRES, internal ribosomal entry site; iCaspase9, inducible caspase 9; ODN, oligodeoxynucleotide; IHC, immunohistochemistry; ACT, adoptive T cell therapy.