PURPOSE OF REVIEW: Preserving the beneficial effects of donor T cells against tumor and pathogens while avoiding noxious graft-versus-host disease (GvHD) is the 'holy grail' of allogeneic hematopoietic stem cell transplantation (HSCT). The suicide gene strategy allows the selective elimination of genetically modified donor T cells during GvHD. This review summarizes the results obtained in recent years in the clinical trials of suicide gene therapy using the paradigmatic herpes simplex virus thymidine kinase (TK) suicide gene. RECENT FINDINGS: T cells genetically modified to express the TK suicide gene, TK-cells, are safe and preserve most of their functional features; when infused into patients they are capable of conferring substantial protection against infections and tumor recurrence, and are promptly eliminated in the case of GvHD, with complete resolution of the adverse reaction in all treated cases. Unexpectedly, TK-cells also have the indirect effect of promoting patient thymopoiesis, contributing to the renewal of a host-tolerant immune repertoire. SUMMARY: Suicide gene therapy with TK-cells is a promising approach to overcome the risk of GvHD in allogeneic HSCT, especially from partially incompatible donors, and is currently under evaluation in a multicentric phase III clinical trial.
PURPOSE OF REVIEW: Preserving the beneficial effects of donor T cells against tumor and pathogens while avoiding noxious graft-versus-host disease (GvHD) is the 'holy grail' of allogeneic hematopoietic stem cell transplantation (HSCT). The suicide gene strategy allows the selective elimination of genetically modified donor T cells during GvHD. This review summarizes the results obtained in recent years in the clinical trials of suicide gene therapy using the paradigmatic herpes simplex virus thymidine kinase (TK) suicide gene. RECENT FINDINGS: T cells genetically modified to express the TK suicide gene, TK-cells, are safe and preserve most of their functional features; when infused into patients they are capable of conferring substantial protection against infections and tumor recurrence, and are promptly eliminated in the case of GvHD, with complete resolution of the adverse reaction in all treated cases. Unexpectedly, TK-cells also have the indirect effect of promoting patient thymopoiesis, contributing to the renewal of a host-tolerant immune repertoire. SUMMARY: Suicide gene therapy with TK-cells is a promising approach to overcome the risk of GvHD in allogeneic HSCT, especially from partially incompatible donors, and is currently under evaluation in a multicentric phase III clinical trial.
Authors: Linda G Eissenberg; Michael P Rettig; Julie K Ritchey; Julie L Prior; Sally W Schwarz; Jennifer Frye; Brian S White; Robert S Fulton; Armin Ghobadi; Matthew L Cooper; Daniel R Couriel; Muhammad Esa Seegulam; David Piwnica-Worms; Farrokh Dehdashti; Kenneth Cornetta; John F DiPersio Journal: Mol Ther Date: 2015-03-25 Impact factor: 11.454
Authors: Roy L Kao; Laurel C Truscott; Tzu-Ting Chiou; Wenting Tsai; Anna M Wu; Satiro N De Oliveira Journal: Hum Gene Ther Date: 2019-04 Impact factor: 5.695
Authors: Melissa N McCracken; Eric H Gschweng; Evan Nair-Gill; Jami McLaughlin; Aaron R Cooper; Mireille Riedinger; Donghui Cheng; Christopher Nosala; Donald B Kohn; Owen N Witte Journal: Proc Natl Acad Sci U S A Date: 2013-01-14 Impact factor: 11.205