Improving the safety of T-Cell therapies using an inducible caspase-9 gene

Abstract

Adoptive transfer of T cells can be an effective anti-cancer treatment. However, uncontrolled or unpredictable immediate or persistent toxicities are a source of concern. The ability to conditionally eliminate aberrant cells in vivo therefore is becoming a critical step for the successful translation of this approach to the clinic. We review the evolution of safety systems, focusing on a suicide switch that can be expressed stably and efficiently in human T cells without impairing phenotype, function or antigen specificity. This system is based on the fusion of human caspase 9 to a modified human FK-binding protein, allowing conditional dimerization in the presence of an otherwise bioinert small molecule drug. When exposed to the synthetic dimerizing drug, the inducible caspase 9 (iC9) becomes activated and leads to the rapid apoptosis of cells expressing this construct. We have demonstrated the clinical feasibility and efficacy of this approach after haploidentical hematopoietic stem cell transplant (haplo-HSCT). Here we review the benefits and limitations of the approach.

Advances in cellular and humoral immunotherapy – implications for the treatment of poor risk childhood, adolescent, and young adult B‐cell non‐Hodgkin lymphoma

“…They are working to understand the mechanisms of the neurotoxicity (Taraseviciute et al , ). Genetic engineering can decrease the inflammatory responses produced or can place a suicide gene into the construct for turning off the activation in cases of severe CRS or neurotoxicity (Zhou & Brenner, ). The depletion of normal B‐cell populations requires regular infusion of gamma globulin to prevent infections.…”

Debate: Transplant is Still Necessary in the Era of Targeted Cellular Therapy for ALL

“…4,16,22 Durability of response is dependent on persistence of the CAR T cells and prevention of immune escape. Across studies, approximately one-third to one-half of the relapses are CD19 negative, and cases of switch to a myeloid phenotype have also been reported.…”

Specific Adoptive Cellular Immunotherapy in Allogeneic Stem Cell Transplantation

“…Currently, 1 clinical trial (NCT03114670) is recruiting patients for the treatment of recurred AML after allo-HSCT with a CD123-CAR coupled with truncated epidermal growth factor receptor (EGFR-t) expression for depletion of CAR-engineered T cells in the case of severe adverse effects [74,75]. The inducible caspase-9 (iCas9) system [76], the reversible CAR platform (UniCAR) [77], and the transcription activator-like effector nuclease (TALEN) technology [78] represent additional safety mechanisms currently investigated. CAR constructs containing such safety systems may be more easily used if antigens are targeted that are expressed more widely also in healthy cells harboring functions which cannot be easily replaced artificially (e.g., CD33) [79,80].…”