Serial Activation of the Inducible Caspase 9 Safety Switch After Human Stem Cell Transplantation

Abstract

Activation of the inducible caspase 9 (iC9) safety gene by a dimerizing drug (chemical inducer of dimerization (CID) AP1903) effectively resolves the symptoms and signs of graft-versus-host disease (GvHD) in haploidentical stem cell transplant (HSCT) recipients. However, after CID treatment, 1% of iC9-T cells remain and can regrow over time; although these resurgent T cells do not cause recurrent GvHD, it remains unclear whether repeat CID treatments are a safe and feasible way to further deplete residual gene-modified T cells should any other adverse effects associated with them occur. Here, we report a patient who received an infusion of haploidentical iC9-T cells after HSCT and subsequently received three treatments with AP1903. There was a mild (grade 2) and transient pancytopenia following each AP1903 administration but no non-hematological toxicity. Ninety five percent of circulating iC9-T cells (CD3(+)CD19(+)) were eliminated after the first AP1903 treatment. Three months later, the residual cells had expanded more than eightfold and had a lower level of iC9 expression. Each repeated AP1903 administration eliminated a diminishing percentage of the residual repopulating cells, but elimination could be enhanced by T-cell activation. These data support the safety and efficiency of repeated CID treatments for persistent or recurring toxicity from T-cell therapies.

Adoptive Immunotherapy Using PRAME-Specific T Cells in Medulloblastoma

“…(48,49) Indeed, iC9 activation alone has been shown to produce rapid and sustained control of graft-versus-host disease caused by donor-derived iC9-T cells in recipients of allogeneic stem cell transplantation. (48)(49)(50)(51) To the best of our knowledge, no data were available on the possibility to use iC9 suicide gene system also to control the presence of genetically modified cells in the brain compartment. In the present work, we have proved that the systemic administration of the dimerizing drug AP1903 in a MB orthotopic mouse model led to both BLI reduction in the total mouse body, including brain, and the lack of hCD3+ T cells in mouse cerebellum.…”

“…The cytotoxic specificity of T cells was evaluated using a standard 4-hour 51 Cr-release assay. Target cells were incubated in medium alone or in 1% Triton X-100…”

“…(Sigma-Aldrich, UK) to determine spontaneous and maximum 51 Cr release, respectively. iC9-SLL Statistical analysis.…”

“…We evaluated the cytotoxic activity of iC9-SLL TCR T cells using standard 6-hour 51 Cr release assays against the HLA-A*02+ PRAME+ MB DAOY cell line and a negative control, namely the HLA-A*02neg.ve PRAME+ RS4;11 cell line (Supplemental Figure 8). We demonstrated that iC9-SLL TCR T cells produced significantly greater lysis of the HLA-A*02+ PRAME+ MB cell line DAOY (43.3%±17.7% specific lysis at the E:T ratio of 20:1) than that observed with CNT T cells (11.3%±6,1%; p=0.004; Supplemental Figure 8B).…”

Current status of ex vivo gene therapy for hematological disorders: a review of clinical trials in Japan around the world

“…Alloreplete haploidentical T cells expressing the inducible caspase 9 suicide gene could reconstitute immunity posttransplant, and administration of CID could eliminate these cells from both peripheral blood and the central nervous system (CNS), leading to rapid resolution of GVHD and GVHD-associated cytokine release syndrome [75]. The safety and efficiency of repeated CID treatments for persistent or recurring toxicity from T-cell therapies have also been demonstrated [76]. This approach was considered to be useful for the rapid and effective treatment of toxicities associated with infusion of engineered T lymphocytes [75,76].…”