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• W2213092085 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. 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. Although adoptive cellular immunotherapy can be an effective therapeutic strategy to treat human malignancies, the adverse effects may be both severe and prolonged. After allogeneic stem cell transplantation, for example, adoptive transfer of T cells to accelerate immune reconstitution and antiviral immunity can produce progressive and fatal acute and chronic graft-versus-host disease (GvHD), while transfer of tumor-directed T cells can lead to a fatal cytokine release syndrome or to on-target/off-tumor or off-target events that may be both rapid in onset and fatal in outcome.1Cieri N Mastaglio S Oliveira G Casucci M Bondanza A Bonini C Adoptive immunotherapy with genetically modified lymphocytes in allogeneic stem cell transplantation.Immunol Rev. 2014; 257: 165-180Crossref PubMed Scopus (41) Google Scholar,2Amrolia PJ Muccioli-Casadei G Huls H Adams S Durett A Gee A et al.Adoptive immunotherapy with allodepleted donor T-cells improves immune reconstitution after haploidentical stem cell transplantation.Blood. 2006; 108: 1797-1808Crossref PubMed Scopus (205) Google Scholar,3Morgan RA Yang JC Kitano M Dudley ME Laurencot CM Rosenberg SA Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2.Mol Ther. 2010; 18: 843-851Abstract Full Text Full Text PDF PubMed Scopus (1746) Google Scholar,4Brentjens RJ Davila ML Riviere I Park J Wang X Cowell LG et al.CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia.Sci Transl Med. 2013; 5: 177ra38Crossref PubMed Scopus (1499) Google Scholar,5Kochenderfer JN Dudley ME Feldman SA Wilson WH Spaner DE Maric I et al.B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells.Blood. 2012; 119: 2709-2720Crossref PubMed Scopus (1142) Google Scholar,6Lee DW Kochenderfer JN Stetler-Stevenson M Cui YK Delbrook C Feldman SA et al.T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial.Lancet. 2015; 385: 517-528Abstract Full Text Full Text PDF PubMed Scopus (2053) Google Scholar,7Morgan RA Chinnasamy N Abate-Daga D Gros A Robbins PF Zheng Z et al.Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy.J Immunother. 2013; 36: 133-151Crossref PubMed Scopus (796) Google Scholar As a consequence, there is increasing interest in developing safety or suicide systems that can address this panoply of adverse events by rapidly, reliably, and fully eliminating the T cells producing the unwanted events. The herpes simplex virus thymidine kinase (HSV-tk) suicide gene system has previously been used as a safety system since it allows T cells to be ablated by the administration of prodrugs such as ganciclovir. However, activation of HSV-TK by ganciclovir is relatively slow, and administration of ganciclovir to treat cytomegalovirus (CMV) infections would result in unwanted destruction of HSV-TK expressing cells. We have previously described an approach based on the expression of an inducible human caspase 9 transgene (iC9), which is dimerized and hence activated by the administration of an otherwise bioinert small molecule drug, AP1903.8Spencer DM Wandless TJ Schreiber SL Crabtree GR Controlling signal transduction with synthetic ligands.Science. 1993; 262: 1019-1024Crossref PubMed Scopus (691) Google Scholar,9Fan L Freeman KW Khan T Pham E Spencer DM Improved artificial death switches based on caspases and FADD.Hum Gene Ther. 1999; 10: 2273-2285Crossref PubMed Scopus (99) Google Scholar,10Straathof KC Pulè MA Yotnda P Dotti G Vanin EF Brenner MK et al.An inducible caspase 9 safety switch for T-cell therapy.Blood. 2005; 105: 4247-4254Crossref PubMed Scopus (498) Google Scholar Since no monoclonal antibody is available to detect iC9, we monitored the infused iC9-T cells in vivo by generating a retroviral vector encoding iC9 in combination with a truncated CD19 linked by a 2A sequence to use as a selectable and trackable marker. Our preclinical and clinical analyses have shown close concordance between changes in levels of CD3+CD19+ expression and iC9 transgene expression.11Tey SK Dotti G Rooney CM Heslop HE Brenner MK Inducible caspase 9 suicide gene to improve the safety of allodepleted T cells after haploidentical stem cell transplantation.Biol Blood Marrow Transplant. 2007; 13: 913-924Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar,12Ramos CA Asgari Z Liu E Yvon E Heslop HE Rooney CM et al.An inducible caspase 9 suicide gene to improve the safety of mesenchymal stromal cell therapies.Stem Cells. 2010; 28: 1107-1115Crossref PubMed Scopus (72) Google Scholar,13Di Stasi A Tey SK Dotti G Fujita Y Kennedy-Nasser A Martinez C et al.Inducible apoptosis as a safety switch for adoptive cell therapy.N Engl J Med. 2011; 365: 1673-1683Crossref PubMed Scopus (1041) Google Scholar This iC9 safety switch is human derived, has limited immunogenicity, and allows patients to receive ganciclovir and related drugs to treat viral infections without T-cell damage. Activation of iC9 eradicates up to 99% of iC9-expressing T cells (iC9-T cells) in vitro and in vivo within 2 hours of a single dose of the chemical inducer of dimerization (CID AP1903), and even a single dose of dimerizing drug to activate the iC9 transgene can produce sufficient in vivo allodepletion of GvHD-inducing T cells.11Tey SK Dotti G Rooney CM Heslop HE Brenner MK Inducible caspase 9 suicide gene to improve the safety of allodepleted T cells after haploidentical stem cell transplantation.Biol Blood Marrow Transplant. 2007; 13: 913-924Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar,13Di Stasi A Tey SK Dotti G Fujita Y Kennedy-Nasser A Martinez C et al.Inducible apoptosis as a safety switch for adoptive cell therapy.N Engl J Med. 2011; 365: 1673-1683Crossref PubMed Scopus (1041) Google Scholar,14Zhou X Di Stasi A Tey SK Krance RA Martinez C Leung KS et al.Long-term outcome after haploidentical stem cell transplant and infusion of T cells expressing the inducible caspase 9 safety transgene.Blood. 2014; 123: 3895-3905Crossref PubMed Scopus (129) Google Scholar,15Zhou X Dotti G Krance RA Martinez CA Naik S Kamble RT et al.Inducible caspase-9 suicide gene controls adverse effects from alloreplete T cells after haploidentical stem cell transplantation.Blood. 2015; 125: 4103-4113Crossref PubMed Scopus (153) Google Scholar Although a single dose of dimerizing drug can effectively control GvHD, we observed that the small remaining fraction of iC9-T cells can subsequently expand and repopulate patients. Although such resurgence does not lead to a recurrence of GvHD, it currently remains unclear whether we could continue to deplete cells in vivo should other adverse effects associated with adoptive transfer of T cells occur, and it is unknown whether multiple doses of CID could have unanticipated toxicity. Here, we evaluated the feasibility and safety of multiple treatments with dimerizing drug in vivo in a patient who received three doses of the drug. The patient was an 8-year-old male who received a haploidentical stem cell transplant (HSCT) with CD34+ selected stem cells from his mother to treat acquired hemophagocytic lymphohistiocytosis with central nervous system involvement. Prior to HSCT, he had received long-term steroid treatment for his primary disease, and his early post-transplant course was complicated by reactivation of multiple viruses (CMV, human herpesvirus 6 (HHV6), adenovirus (AdV), BK virus (BKV), and Epstein–Barr virus (EBV)), persistent transaminitis, and steroid-induced hypertension and hyperglycemia. He was enrolled on the DOTTI (Administration of haploidentical DOnor T cells Transduced with the Inducible caspase-9 suicide gene) study in which patients received escalating doses of iC9-T cells post HSCT in order augment immune reconstitution.15Zhou X Dotti G Krance RA Martinez CA Naik S Kamble RT et al.Inducible caspase-9 suicide gene controls adverse effects from alloreplete T cells after haploidentical stem cell transplantation.Blood. 2015; 125: 4103-4113Crossref PubMed Scopus (153) Google Scholar On day 47 post HSCT, he received 1 × 106 iC9-T cells/kg. He had no immediate adverse effects from the T-cell infusions, and within 1–10 weeks, reactivations of CMV, HHV6, AdV, and BKV were successfully controlled as judged by polymerase chain reaction (PCR) analyses for viral DNA in blood (Table 1).Table 1Viral reactivations and infections after iC9-T-cell infusionTime to iC9-T-cell infusionAdV (copies/ml)CMV (copies/ml)HHV6 (copies/ml)BKV (copies/ml)EBV (copies/μg DNA)Pre-infusion3,000228012,3000Week 101,8021,30011,6000Week 201,537<18811,3000Week 30318029,0000Week 400051,1000Week 5000107,0000Week 600<18869,5000Week 7000N/A0Week 800026,8000Week 90004,500454Week 1000004,267Week 11000025,918bPatient received Rituximab.Week 120000754Month 3 (AP1903 #1)0000105bPatient received Rituximab.Month 3.500<188076Month 400000Month 4.50742aReactivation of CMV that was rapidly controlled without further treatment.000Month 50<50000Month 6 (AP1903 #2/#3)00000Month 70265019,7000Month 809306,6000AdV, adenovirus; BKV, BK virus; CmV, cytomegalovirus; Epstein-Barr virus; HHV6, human herpesvirus 6.a Reactivation of CMV that was rapidly controlled without further treatment.b Patient received Rituximab. Open table in a new tab AdV, adenovirus; BKV, BK virus; CmV, cytomegalovirus; Epstein-Barr virus; HHV6, human herpesvirus 6. Three months after administration of iC9-T cells, however, the patient was admitted with gastritis. A gastric biopsy was positive by PCR for EBV, HHV6, and HHV7, but there was no histological evidence of GvHD. As his EBV load in blood was also elevated, he was treated with Rituximab (Table 1). During this admission, he developed a skin rash, and biopsy was consistent with GvHD (grade 2). He was given a single dose of iC9 dimerizer drug AP1903 (#1), and his rash had completely resolved within 24 hours. Over the next 4–6 weeks, his gastritis also resolved. However, 3 weeks later, his hepatic transaminases became elevated although bilirubin and alkaline phosphatase remained normal. Circulating iC9-T cells (detected as the CD3+CD19+ population) remained below pre-dimerizer drug levels (220/µl: Figure 1: #1), but the possibility that the infused T cells may have contributed to a possible flare of acute GvHD was nonetheless considered. He therefore received two additional doses of the dimerizing drug (Figure 1: #2, #3) at intervals of 48 hours. Retreatment had no effect on his transaminitis, which was also unresponsive to intensive subsequent immunosuppression. A repeat liver biopsy 5 weeks later showed macrovesicular steatosis compatible with drug therapy and parenteral nutrition to which his transaminitis was attributed since he had no evidence of acute or chronic GvHD. Unfortunately, in association with prolonged steroid therapy, the patient then developed pulmonary zygomycetes from which he died 2 months later. After the initial dose of dimerizing drug (dose #1; 3 months after the initial iC9-T–cell infusion), circulating CD3+CD19+ T cells decreased from 532/µl to 28/µlL within 2 hours (Figure 1a,b). Residual CD3+CD19+ T cells expanded over the next 3 months (Figure 1a), and on administration of the second dose of dimerizing drug (#2), the circulating CD3+CD19+ T cells decreased from 220/µl to 78/µl; there was no substantive change in CD3+CD19+ T cells after the third dose of AP1903, 48 hours later (Figure 1c). There were no non-hematological toxicities associated with administration of any of the doses of AP1903. However, following each dose, there was a transient decrease of peripheral blood cell counts in all lineages. Figure 2 shows the effects of the dimerizer on nontransduced (CD3+CD19−) T cells after each treatment with the dimerizing drug; counts returned to pretreatment levels within 72 hours (Figure 2b,c). The drug had similar effects on B lymphocytes and natural killer (NK) cells (see Supplementary Figure S1) and on neutrophils and platelets (see Supplementary Figure S2). Overall, we observed a transient hematological toxicity that was limited to grade 2. A subpopulation of iC9+ T cells may persist after exposure to the dimerizing drug because the surviving cells express lower levels of the transgene. We therefore examined the level of iC9-ΔCD19 expression in the T-cell population before and after each dimerizer treatment. Figure 3a shows the absolute number of CD3+CD19+ T cells detected in peripheral blood before each dimerizer treatment. Immediately prior to the first exposure to dimerizing drug, the mean fluorescence intensity (MFI) of CD19 in iC9-T cells was 12,200 (Figure 3b left panel). The recovering iC9+ cells, however, had a lower MFI, so that immediately prior to the second treatment, the value was 4,419. The cells surviving from the second treatment had still lower median expression, so that immediately prior to treatment 3 the MFI was just 2,605 (Figure 3b left panel). Of note, immediately following dimerizer treatment, the MFI of surviving cells was always less than 3,000, irrespective of the number of prior drug exposures (Figure 3b right panel), meaning that the highest expressing fraction of cells (>3,000 MFI) is removed at each drug exposure. Consistent with selective removal of the highest expressing cells, the iC9 transgene copy number detected before and after each dimerizer treatment by quantitative PCR (Q-PCR) showed a 90% decline after the first dimerizer treatment (from 11.5 to 1.1, normalized by β-actin), but limited further decline after exposure #2 and no discernible additional fall after exposure #3 (see Supplementary Figure S3). Hence, differences in the proportion of cells eliminated after each dose relate to a progressive destruction of the most highly transduced and most highly expressing cells. Although iC9 selectively eliminated the most highly expressing and most highly transduced T cells, the susceptibility to dimerizing drug may be further influenced by the activation status of the T cells. Transgene expression derived from retroviral integrants is highly dependent on the state of T-cell activation;16Pollok KE Hanenberg H Noblitt TW Schroeder WL Kato I Emanuel D et al.High-efficiency gene transfer into normal and adenosine deaminase-deficient T lymphocytes is mediated by transduction on recombinant fibronectin fragments.J Virol. 1998; 72: 4882-4892PubMed Google Scholar,17Quinn ER Lum LG Trevor KT T cell activation modulates retrovirus-mediated gene expression.Hum Gene Ther. 1998; 9: 1457-1467Crossref PubMed Scopus (39) Google Scholar,18Cattoglio C Maruggi G Bartholomae C Malani N Pellin D Cocchiarella F et al.High-definition mapping of retroviral integration sites defines the fate of allogeneic T cells after donor lymphocyte infusion.PLoS One. 2010; 5: e15688Crossref PubMed Scopus (39) Google Scholar during GvHD, for example, alloreactive cells are the most activated, express the highest level of iC9, and therefore are the most readily eliminated.10Straathof KC Pulè MA Yotnda P Dotti G Vanin EF Brenner MK et al.An inducible caspase 9 safety switch for T-cell therapy.Blood. 2005; 105: 4247-4254Crossref PubMed Scopus (498) Google Scholar To determine whether the reduced iC9-CD19 expression observed during subsequent exposure to dimerizing drug also correlated with the level of activation of the residual transduced T cells, we measured CD25 positivity in the T-cell population (Figure 4). All CD8+CD19+CD25+ T cells were eliminated after the first dimerizer treatment (18/µl and 0/µl, pre and post treatment, respectively) and, in contrast to the bulk population of T cells, had not returned in the 3 months prior to the second treatment (Figure 4a). Similarly, more than 90% of the CD4+CD19+CD25+ T-cell population was eliminated after the first dimerizer treatment (48/µl to 4/µl, pre and post treatment, respectively) and had minimal re-expansion during the next 3 months (10/µl and 7/µl, pre and post treatment, respectively) (Figure 4b). To further assess whether the reduced in vivo destruction of T cells after subsequent doses of the dimerizing agent predominantly reflected the lack of associated in vivo (allo)activation by GvHD, we collected T cells from the patient after his GvHD had been treated with dimerizing drug. These T cells were then exposed in vitro to CD3/CD28 monoclonal antibodies to simulate T-cell receptor (TCR) activation and co-stimulation. At 48–72 hours, CD3/CD28 reactivated CD3+CD19+ cells had significantly higher transgene expression than nonreactivated cells, with their CD19 MFI increasing from 4,603 to 30,720 (CD19+), while their CD3 MFI was unchanged (Figure 5a). Following exposure to CD3/CD28, we treated these cells with CID, and the percentage of CD3+CD19+ cells surviving exposure to CID was reduced by half, from 18 to 8% (Figure 5b). Killing of CD3+CD19− T cells following CID exposure was unaffected by prior anti-CD3/anti-CD28 activation (Figure 5c). To evaluate whether resistance arose from functional mutations in the iC9 protein, we sequenced the iC9 transgene obtained after amplification of the DNA extracted from total peripheral blood mononuclear cells (PBMCs) collected at different time points before and after AP1903 treatments. We sequenced multiple individual clones derived from the subcloned PCR products. Nonsense mutations causing a premature stop codon in the iC9 transgene were detected in 2 out of 10 and 1 out of 10 subcloned PCR products in the DNA extracted from PBMCs collected 30 minutes and 4 days after the third administration of AP1903, respectively (Figure 6). Hence, sporadic mutations could contribute to the low responses but they are neither the sole nor the primary mechanism for dimerizer resistance. Rapid control or elimination of cells expressing a therapeutic transgene may be required to overcome both short- and long-term toxicities.19Lamers CH Sleijfer S van Steenbergen S van Elzakker P van Krimpen B Groot C et al.Treatment of metastatic renal cell carcinoma with CAIX CAR-engineered T cells: clinical evaluation and management of on-target toxicity.Mol Ther. 2013; 21: 904-912Abstract Full Text Full Text PDF PubMed Scopus (488) Google Scholar,20Kalos M Levine BL Porter DL Katz S Grupp SA Bagg A et al.T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia.Sci Transl Med. 2011; 3: 95ra73Crossref PubMed Scopus (1795) Google Scholar,21Brentjens RJ Rivière I Park JH Davila ML Wang X Stefanski J et al.Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias.Blood. 2011; 118: 4817-4828Crossref PubMed Scopus (994) Google Scholar,22Ertl HC Zaia J Rosenberg SA June CH Dotti G Kahn J et al.Considerations for the clinical application of chimeric antigen receptor T cells: observations from a recombinant DNA Advisory Committee Symposium.Cancer Res. 2011; 71: 3175-3181Crossref PubMed Scopus (68) Google Scholar We have previously shown that the iC9 safety system can be activated by a single dose of 0.4 mg/kg AP1903, and iC9 activation can effectively and sustainably remove alloreactive T cells causing GvHD after haplo-HSCT. The system can immediately control the symptoms and signs of a systemic inflammatory response associated with T-cell activation.14Zhou X Di Stasi A Tey SK Krance RA Martinez C Leung KS et al.Long-term outcome after haploidentical stem cell transplant and infusion of T cells expressing the inducible caspase 9 safety transgene.Blood. 2014; 123: 3895-3905Crossref PubMed Scopus (129) Google Scholar,15Zhou X Dotti G Krance RA Martinez CA Naik S Kamble RT et al.Inducible caspase-9 suicide gene controls adverse effects from alloreplete T cells after haploidentical stem cell transplantation.Blood. 2015; 125: 4103-4113Crossref PubMed Scopus (153) Google Scholar,23Arber C Abhyankar H Heslop HE Brenner MK Liu H Dotti G et al.The immunogenicity of virus-derived 2A sequences in immunocompetent individuals.Gene Ther. 2013; 20: 958-962Crossref PubMed Scopus (27) Google Scholar In the current report, we show that additional dimerizer treatments can eliminate up to 85% of the iC9-resistant T cells that survive after the first dose of dimerizer drug. In circumstances where persistence or regrowth of adoptively transferred T cells may be problematic, the administration of multiple doses of dimerizing drug appears to be safe and to induce further T-cell depletion. A number of safety concerns are associated with adoptive T-cell therapies. Adverse effects include the acute toxicities of GvHD after transfer of allogeneic T cells2Amrolia PJ Muccioli-Casadei G Huls H Adams S Durett A Gee A et al.Adoptive immunotherapy with allodepleted donor T-cells improves immune reconstitution after haploidentical stem cell transplantation.Blood. 2006; 108: 1797-1808Crossref PubMed Scopus (205) Google Scholar,12Ramos CA Asgari Z Liu E Yvon E Heslop HE Rooney CM et al.An inducible caspase 9 suicide gene to improve the safety of mesenchymal stromal cell therapies.Stem Cells. 2010; 28: 1107-1115Crossref PubMed Scopus (72) Google Scholar,15Zhou X Dotti G Krance RA Martinez CA Naik S Kamble RT et al.Inducible caspase-9 suicide gene controls adverse effects from alloreplete T cells after haploidentical stem cell transplantation.Blood. 2015; 125: 4103-4113Crossref PubMed Scopus (153) Google Scholar and a cytokine release syndrome (or systemic inflammatory response) when adoptively transferred T cells become highly activated and expand in vivo, producing pro-inflammatory cytokines and inducing the release of additional inflammatory mediators from monocytes and other cells.4Brentjens RJ Davila ML Riviere I Park J Wang X Cowell LG et al.CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia.Sci Transl Med. 2013; 5: 177ra38Crossref PubMed Scopus (1499) Google Scholar,24Grupp SA Kalos M Barrett D Aplenc R Porter DL Rheingold SR et al.Chimeric antigen receptor-modified T cells for acute lymphoid leukemia.N Engl J Med. 2013; 368: 1509-1518Crossref PubMed Scopus (2495) Google Scholar,25Davila ML Riviere I Wang X Bartido S Park J Curran K et al.Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia.Sci Transl Med. 2014; 6: 224ra25Crossref PubMed Scopus (1758) Google Scholar,26Porter DL Levine BL Kalos M Bagg A June CH Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia.N Engl J Med. 2011; 365: 725-733Crossref PubMed Scopus (2622) Google Scholar In addition to these complications, there may be off-target damage to unrelated cells. For instance, fatal neurologic and cardiac toxicities can be caused by the cross-reactivity of high-affinity MAGE-A3 TCR with unrecognized expression of epitopes, even unrelated peptides in off-target organs or tissues.7Morgan RA Chinnasamy N Abate-Daga D Gros A Robbins PF Zheng Z et al.Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy.J Immunother. 2013; 36: 133-151Crossref PubMed Scopus (796) Google Scholar,27Linette GP Stadtmauer EA Maus MV Rapoport AP Levine BL Emery L et al.Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma.Blood. 2013; 122: 863-871Crossref PubMed Scopus (763) Google Scholar,28Cameron BJ Gerry AB Dukes J Harper JV Kannan V Bianchi FC et al.Identification of a Titin-derived HLA-A1-presented peptide as a cross-reactive target for engineered MAGE A3-directed T cells.Sci Transl Med. 2013; 5: 197ra103Crossref PubMed Scopus (447) Google Scholar Finally, there may be on-target but off-tumor organ toxicities such as the hypogammaglobulinemia that follows the prolonged depletion of normal CD19+ B cells by long-lived CD19-CAR T cells intended to kill CD19+ malignancies.20Kalos M Levine BL Porter DL Katz S Grupp SA Bagg A et al.T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia.Sci Transl Med. 2011; 3: 95ra73Crossref PubMed Scopus (1795) Google Scholar We have previously shown that a single dose of dimerizing drug produces sufficient iC9 activation to rapidly deplete adoptively transferred haploidentical donor T cells and to rapidly and completely resolve the symptoms and signs of GvHD. Importantly, this single-dose regimen is sufficient to permanently abrogate the GvHD even though a small number of remaining (in vivo dimerizer-resistant) T cells subsequently expand and repopulate the host, likely because these cells have been depleted of their alloreactive component. In other applications of adoptive T-cell therapy, however, resurgent T cells might again produce the adverse effects initially observed, including the elimination of CD19+ normal B cells by CD19-CAR T cells. The outcome we report here is the first to show that such resistant and then resurgent T cells nonetheless continue to be vulnerable to killing by re-exposure to additional doses of the dimerizing drug in vivo, although the level of killing is lower than on initial exposure (85 versus 95%). One concern over repeated administration of dimerizing drug is that there may be unexpected toxicities. Although no evidence of treatment-related serious adverse events was reported in large animal models exposed either to a higher dosage of dimerizing drug for 30 days consecutively or to long-term administration of the agent,29Richard RE De Claro RA Yan J Chien S Von Recum H Morris J et al.Differences in F36VMpl-based in vivo selection among large animal models.Mol Ther. 2004; 10: 730-740Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar,30Okazuka K Beard BC Emery DW Schwarzwaelder K Spector MR Sale GE et al.Long-term regulation of genetically modified primary hematopoietic cells in dogs.Mol Ther. 2011; 19: 1287-1294Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar there are no phase 1 data to show that multidose administration is safe in humans.31Iuliucci JD Oliver SD Morley S Ward C Ward J Dalgarno D et al.Intravenous safety and pharmacokinetics of a novel dimerizer drug, AP1903, in healthy volunteers.J Clin Pharmacol. 2001; 41: 870-879Crossref PubMed Scopus (90) Google Scholar Our patient had evidence of liver toxicity after the first dose of AP1903, but we think this was likely not associated with CID administration since the onset was delayed and did not worsen with subsequent drug treatments. Moreover, no such toxicity was reported in a phase 1 study of single-dose administration of the dimerizing drug even when a higher dose was infused (1.0 mg/kg versus 0.4 mg/kg); of note, none of the seven other patients treated with the agent had hepatotxicity attributable to drug administration.12Ramos CA Asgari Z Liu E Yvon E Heslop HE Rooney CM et al.An" @default.
• W2213092085 created "2016-06-24" @default.
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• W2213092085 date "2016-04-01" @default.
• W2213092085 modified "2023-10-18" @default.
• W2213092085 title "Serial Activation of the Inducible Caspase 9 Safety Switch After Human Stem Cell Transplantation" @default.
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