Exploiting Cell Death Pathways for Inducible Cell Elimination to Modulate Graft-versus-Host-Disease.

Corey Falcon,Mustafa Al-Obaidi,Antonio Di Stasi

doi:10.3390/biomedicines5020030

Corey Falcon, Mustafa Al-Obaidi + Show 1 more

Open Access

https://doi.org/10.3390/biomedicines5020030

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Journal: Biomedicines	Publication Date: Jun 14, 2017
Citations: 5	License type: CC BY 4.0

Affiliation: University of Alabama at Birmingham

Abstract

Hematopoietic stem cell transplantation is a potent form of immunotherapy, potentially life-saving for many malignant hematologic diseases. However, donor lymphocytes infused with the graft while exerting a graft versus malignancy effect can also cause potentially fatal graft versus host disease (GVHD). Our group has previously validated the inducible caspase-9 suicide gene in the haploidentical stem cell transplant setting, which proved successful in reversing signs and symptoms of GVHD within hours, using a non-therapeutic dimerizing agent. Cellular death pathways such as apoptosis and necroptosis are important processes in maintaining healthy cellular homeostasis within the human body. Here, we review two of the most widely investigated cell death pathways active in T-cells (apoptosis and necroptosis), as well as the emerging strategies that can be exploited for the safety of T-cell therapies. Furthermore, such strategies could be exploited for the safety of other cellular therapeutics as well.

Highlights

Effector T-cells are key players of adaptive cellular immune responses, protecting the host from infectious pathogens, cancer, and other cells foreign to the body
The infusion of ∆iC9 suicide gene modified T-cells after allo-HSCT has resulted in effective control of GVHD, and, the number of patients treated far is low, it has the potential of reducing GVHD-related morbidity and mortality
The infusion of suicide gene modified T-cells after allo-HSCT has resulted in effective control of GVHD, which can substantially reduce GVHD-related non-relapse morbidity and mortality

Summary

Introduction

Effector T-cells are key players of adaptive cellular immune responses, protecting the host from infectious pathogens, cancer, and other cells foreign to the body. 5, 30 of DNA polymerase to chain termination and cell death [9], the ∆iC9 suicide gene activates the apoptotic pathway in gene modified cells after administration of an otherwise inert agent inducible of setting, the herpes-simplex-thymidine-kinase (HSV-TK) suicide gene [5] and the inducible caspase-9 dimerization. ΔiC9 donor lymphocytes avoided the use of immunosuppressive therapy [6,7,8], with potentially less prevention/treatment of GVHD Such strategies could be exported to other T-cell therapies as well as off-target effects on immune response and eventual organ damage. Review will summarize the molecular pathways of programmed cell death and the in vitro and in vivo investigations of suicide gene strategies for the safety of T-cell therapies with a focus on

Pathways of Programmed

Exploiting Apoptotic Pathways to Prevent or Treat Graft-versus-Host-Disease

Apoptosis by Ligand-Mediated Dimerization for Graft-versus-Host-Disease

Caspase-Independent Cell Death in T-Cells

Findings

Conclusions