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.
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.
Berger
Carolina
C
Fred Hutchinson Cancer Research Center, Clinical Research Division, Seattle, Washington 98109, USA. cberger@fhcrc.org
Flowers
Mary E
ME
Warren
Edus H
EH
Riddell
Stanley R
SR
D019264:Adoptive Transfer / Q000379:methods*; D000328:Adult; D000917:Antibody Formation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D041722:Genes, Transgenic, Suicide; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007156:Immunologic Memory; D018655:Lymphocyte Count; D018139:Simplexvirus; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation*; D013937:Thymidine Kinase / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D019076:Transgenes; D014184:Transplantation, Homologous
D013937:Thymidine Kinase