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 Citations (Scopus)

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

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T-cells
Cytotoxic T-Lymphocytes
HLA Antigens
Bone Marrow
Dogs
Green Fluorescent Proteins
Graft vs Host Disease
T-Lymphocytes
Grafts
Kanamycin Kinase
Stem cells
Whole-Body Irradiation
Hematopoietic Stem Cell Transplantation
Homologous Transplantation
Blood
Genes
Immunosuppression
Suicide
Transplantation (surgical)
In Situ Hybridization

ASJC Scopus subject areas

  • Hematology

Cite this

Georges, G. E., Storb, R., Bruno, B., Brodie, S. J., Thompson, J. D., Taranova, A. G., ... 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

Engraftment of DLA-haploidentical marrow with ex vivo expanded, retrovirally transduced cytotoxic T lymphocytes. / Georges, George E.; Storb, Rainer; Bruno, Benedetto; Brodie, Scott J.; Thompson, Jennifer D.; Taranova, Anna G.; Maciej Zaucha, J.; Little, Marie Térèse; Zellmer, Eustacia; Moore, Peter F; Gooley, Theodore; Sale, George; Kiem, Hans Peter; Sandmaier, Brenda M.; Lyons, Russette M.; Nash, Richard A.

In: Blood, Vol. 98, No. 12, 01.12.2001, p. 3447-3455.

Research output: Contribution to journalArticle

Georges, GE, Storb, R, Bruno, B, Brodie, SJ, Thompson, JD, Taranova, AG, Maciej Zaucha, J, Little, MT, Zellmer, E, Moore, PF, Gooley, T, Sale, G, Kiem, HP, Sandmaier, BM, Lyons, RM & Nash, RA 2001, 'Engraftment of DLA-haploidentical marrow with ex vivo expanded, retrovirally transduced cytotoxic T lymphocytes', Blood, vol. 98, no. 12, pp. 3447-3455. https://doi.org/10.1182/blood.V98.12.3447
Georges GE, Storb R, Bruno B, Brodie SJ, Thompson JD, Taranova AG et al. Engraftment of DLA-haploidentical marrow with ex vivo expanded, retrovirally transduced cytotoxic T lymphocytes. Blood. 2001 Dec 1;98(12):3447-3455. https://doi.org/10.1182/blood.V98.12.3447
Georges, George E. ; Storb, Rainer ; Bruno, Benedetto ; Brodie, Scott J. ; Thompson, Jennifer D. ; Taranova, Anna G. ; Maciej Zaucha, J. ; Little, Marie Térèse ; Zellmer, Eustacia ; Moore, Peter F ; Gooley, Theodore ; Sale, George ; Kiem, Hans Peter ; Sandmaier, Brenda M. ; Lyons, Russette M. ; Nash, Richard A. / Engraftment of DLA-haploidentical marrow with ex vivo expanded, retrovirally transduced cytotoxic T lymphocytes. In: Blood. 2001 ; Vol. 98, No. 12. pp. 3447-3455.
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AU - Brodie, Scott J.

AU - Thompson, Jennifer D.

AU - Taranova, Anna G.

AU - Maciej Zaucha, J.

AU - Little, Marie Térèse

AU - Zellmer, Eustacia

AU - Moore, Peter F

AU - Gooley, Theodore

AU - Sale, George

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