Truncated form of human CD19 antigen as a suicide gene to control T-cell alloreactivity: ΔCD19

Abstract

Donor lymphocyte infusion (DLI) is employed to either treat or prevent relapse in patients with hematologic malignancies, as well as to accelerate recovery of adaptive immunity, after allogeneic hematopoietic stem cell transplantation (allo-HSCT). With the increased use of DLI, there is renewed interest in the development of approaches able to prevent graft-versus-host disease (GvHD) reaction. In this study, we describe a novel and effective safety switch represented by the truncated form of the human CD19 antigen (ΔCD19) used to transduce T lymphocytes (hΔCD19 Tcells). We demonstrated that the exposure of ΔCD19-T-cells to an anti-hCD19-hCD3 T-cell bispecific T-cell engager (BiTE) molecule (structurally identical to blinatumomab, an agent largely used in the treatment of B-cell acute lymphoblastic leukemia) resulted into a prompt elimination of hCD19+/CD3+ cells both in vitro and in an in vivo animal model of mice developing a xenograft reaction mimicking GvHD after infusion of in vitro-activated/expanded human T cells. Importantly, the administration of the anti-hCD19-hCD3 BiTE molecule in the animal model, from one hand led to the improvement of signs and symptoms of GvHD, as well as of the overall-survival of the mice, and from the other, after a drug washout, was associated with the resurge of ΔCD19-T-cells without reoccurrence of GvHD. Our study provides evidence that the ΔCD19 suicide gene used in combination with an anti-hCD19-hCD3 T-cell BiTE molecule could represent a valid and effective strategy to control GvHD occurring after the infusion of donor T lymphocytes.