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

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.

Anti-PSMA CAR-Engineered NK-92 Cells: An Off-the-Shelf Cell Therapy for Prostate Cancer

“…Second, NK-92 cells can spontaneously kill tumors by recognizing diverse ligands via a variety of NK activating receptors. Among these, the NKG2D receptor is one of the major signaling pathways involved in cancer immunosurveillance [41][42][43][44]. As we demonstrated that CAR-and NKG2D-dependent activation pathways do not reciprocally interfere, it is conceivable that they can act in concert in engineered NK-92 cells to potentiate tumor destruction.…”

“…Hence, repeated infusions of irradiated NK-92 cells are required as a means to circumvent their limited survival, but the approach has drawbacks in terms of costs and patient compliance. In this regard, introducing a suicide gene into NK-92/CAR cells might represent a valid safety option alternative to irradiation, because it would likely allow a single administration of effectors that are subsequently amenable to being completely switched off after exerting their therapeutic activity or in the case of severe, unwanted toxicity [42][43][44][45][46][47].…”

Engineering for Success: Approaches to Improve Chimeric Antigen Receptor T Cell Therapy for Solid Tumors

“…Additionally, repeated doses of CID were able to eliminate a residual percentage of repopulating cells that express low levels of iC9 [ 144 ], indicating that repeated doses of CID to activate inducible genes are safe and functional. Other dimerizer systems take advantage of Fas [ 145 ] or other molecules in the apoptosis or necroptosis pathways, as reviewed elsewhere [ 146 ]. Lastly, expression of a cell surface antigen on engineered T cells such as truncated CD20 or EGFR allows the elimination of T cells with FDA-approved mAbs that induce complement activation and/or antibody-dependent cellular cytotoxicity (ADCC) [ 147 , 148 ].…”

Combinatorial suicide gene strategies for the safety of cell therapies

“…Its immunogenicity could preclude persistence and activity of the infused therapeutic cells. In the setting of donor lymphocyte infusion post allogeneic HSCT this still resulted in anti-tumor effect, likely due to the slow kinetic of cell's elimination (15). The requirement for ganciclovir may limit its use in patients with cytomegalovirus infection where this agent is a primary treatment option.…”

“…The DiC9 suicide gene is a chimeric protein composed of a drug-binding domain linked in frame with a component of the apoptotic pathway, allowing conditional dimerization and apoptosis of the transduced cells after administration of a nontherapeutic small molecule dimerizer, such as AP1903 or BB homodimerizer (15)(16)(17)(18)(19). Straathof et al (19) and Tey et al (20) validated the DiC9 construct for T cell applications, demonstrating optimal transduction efficiency, expansion, and elimination of DiC9 T cells with strong expression of the transgene (19)(20)(21).…”