Analysis of transgene-specific immune responses that limit the in vivo persistence of adoptively transferred HSV-TK-modified donor T cells after allogeneic hematopoietic cell transplantation
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Analysis of transgene-specific immune responses that limit the in vivo persistence of adoptively transferred HSV-TK-modified donor T cells after allogeneic hematopoietic cell transplantation. / Berger, Carolina; Flowers, Mary E; Warren, Edus H; Riddell, Stanley R.
In: BLOOD, Vol. 107, No. 6, 15.03.2006, p. 2294-302.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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T1 - Analysis of transgene-specific immune responses that limit the in vivo persistence of adoptively transferred HSV-TK-modified donor T cells after allogeneic hematopoietic cell transplantation
AU - Berger, Carolina
AU - Flowers, Mary E
AU - Warren, Edus H
AU - Riddell, Stanley R
PY - 2006/3/15
Y1 - 2006/3/15
N2 - The introduction of an inducible suicide gene such as the herpes simplex virus thymidine kinase (HSV-TK) might allow exploitation of the antitumor activity of donor T cells after allogeneic hematopoietic cell transplantation (HCT) without graft versus host disease. However, HSV-TK is foreign, and immune responses to gene-modified T cells could lead to their premature elimination. We show that after the infusion of HSV-TK-modified donor T cells to HCT recipients, CD8+ and CD4+ T-cell responses to HSV-TK are rapidly induced and coincide with the disappearance of transferred cells. Cytokine flow cytometry using an overlapping panel of HSV-TK peptides allowed rapid detection and quantitation of HSV-TK-specific T cells in the blood and identified multiple immunogenic epitopes. Repeated infusion of modified T cells boosted the induced HSV-TK-specific T cells, which persisted as memory cells. These studies demonstrate the need for nonimmunogenic suicide genes and identify a strategy for detection of CD4+ and CD8+ T-cell responses to transgene products that should be generally applicable to monitoring patients on gene therapy trials. The potency of gene-modified T cells to elicit robust and durable immune responses imply this approach might be used for vaccination to elicit T-cell responses to viral or tumor antigens.
AB - The introduction of an inducible suicide gene such as the herpes simplex virus thymidine kinase (HSV-TK) might allow exploitation of the antitumor activity of donor T cells after allogeneic hematopoietic cell transplantation (HCT) without graft versus host disease. However, HSV-TK is foreign, and immune responses to gene-modified T cells could lead to their premature elimination. We show that after the infusion of HSV-TK-modified donor T cells to HCT recipients, CD8+ and CD4+ T-cell responses to HSV-TK are rapidly induced and coincide with the disappearance of transferred cells. Cytokine flow cytometry using an overlapping panel of HSV-TK peptides allowed rapid detection and quantitation of HSV-TK-specific T cells in the blood and identified multiple immunogenic epitopes. Repeated infusion of modified T cells boosted the induced HSV-TK-specific T cells, which persisted as memory cells. These studies demonstrate the need for nonimmunogenic suicide genes and identify a strategy for detection of CD4+ and CD8+ T-cell responses to transgene products that should be generally applicable to monitoring patients on gene therapy trials. The potency of gene-modified T cells to elicit robust and durable immune responses imply this approach might be used for vaccination to elicit T-cell responses to viral or tumor antigens.
KW - Adoptive Transfer/methods
KW - Adult
KW - Antibody Formation
KW - CD4-Positive T-Lymphocytes/immunology
KW - CD8-Positive T-Lymphocytes/immunology
KW - Genes, Transgenic, Suicide
KW - Hematopoietic Stem Cell Transplantation
KW - Humans
KW - Immunologic Memory
KW - Lymphocyte Count
KW - Simplexvirus
KW - T-Lymphocytes/immunology
KW - Thymidine Kinase/administration & dosage
KW - Transgenes
KW - Transplantation, Homologous
U2 - 10.1182/blood-2005-08-3503
DO - 10.1182/blood-2005-08-3503
M3 - SCORING: Journal article
C2 - 16282341
VL - 107
SP - 2294
EP - 2302
JO - BLOOD
JF - BLOOD
SN - 0006-4971
IS - 6
ER -