Engraftment of DLA-haploidentical marrow with ex vivo expanded, retrovirally transduced cytotoxic T lymphocytes

George E. Georges, Rainer Storb, Benedetto Bruno, Scott J. Brodie, Jennifer D. Thompson, Anna G. Taranova, J. Maciej Zaucha, Marie Térèse Little, Eustacia Zellmer, Peter F Moore, Theodore Gooley, George Sale, Hans Peter Kiem, Brenda M. Sandmaier, Russette M. Lyons, Richard A. Nash

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Genetically modified donor T cells with an inducible "suicide" gene have the potential to improve the safety and availability of allogeneic hematopoietic stem cell transplantation by enhancing engraftment and permitting control of graft-versus-host disease (GVHD). However, several clinical studies of gene-modified T cells have shown limited to no in vivo function of the ex vivo expanded T cells. Using the well-established dog model of allogeneic marrow transplantation, the question was asked if retrovirally transduced, donor derived, ex vivo expanded cytotoxic T lymphocytes (CTLs) that are recipient specific could enhance engraftment of dog leukocyte antigen (DLA)-haploidentical marrow following a single dose of 9.2 Gy total body irradiation and no postgrafting immunosuppression. In this setting, only 4 of 11 control recipients of DLA-haploidentical marrow without added CTLs engrafted. CTLs did not enhance engraftment of CD34 + selected peripheral blood stem cells. However, recipient-specific CTLs enhanced engraftment of DLA-haploidentical marrow in 9 of 11 evaluable recipients (P = .049). All dogs that engrafted developed multiorgan GVHD. To facilitate in vivo tracking, 8 dogs received CTLs transduced with a retroviral vector encoding green fluorescent protein (GFP) and neomycin phosphotransferase (neo). Recipients that engrafted had sharp increases in the numbers of circulating GFP + CTLs on days +5 to +6 after transplantation. GFP + CTLs isolated from blood were capable of recipient-specific lysis. At necropsy, up to 7.1% of CD3 + cells in tissues were GFP + and polymerase chain reaction in situ hybridization for neo showed infiltration of transduced CTLs in GVHD-affected organs. These results show that ex vivo expanded, transduced T cells maintained in vivo function and enhanced marrow engraftment.

Original languageEnglish (US)
Pages (from-to)3447-3455
Number of pages9
JournalBlood
Volume98
Issue number12
DOIs
StatePublished - Dec 1 2001

ASJC Scopus subject areas

  • Hematology

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    Georges, G. E., Storb, R., Bruno, B., Brodie, S. J., Thompson, J. D., Taranova, A. G., Maciej Zaucha, J., Little, M. T., Zellmer, E., Moore, P. F., Gooley, T., Sale, G., Kiem, H. P., Sandmaier, B. M., Lyons, R. M., & Nash, R. A. (2001). Engraftment of DLA-haploidentical marrow with ex vivo expanded, retrovirally transduced cytotoxic T lymphocytes. Blood, 98(12), 3447-3455. https://doi.org/10.1182/blood.V98.12.3447