Infusion of suicide-gene-engineered donor lymphocytes after family haploidentical haemopoietic stem-cell transplantation for leukaemia (the TK007 trial): a non-randomised phase I–II study

Ciceri, Fabio; Bonini, Chiara; Stanghellini, Maria Teresa Lupo; Bondanza, Attilio; Traversari, Catia; Salomoni, Monica; Turchetto, Lucia; Colombi, Scialini; Bernardi, Massimo; Peccatori, Jacopo; Pescarollo, Alessandra; Servida, Paolo; Magnani, Zulma; Perna, Serena; Valtolina, Veronica; Crippa, Fulvio; Callegaro, Luciano; Spoldi, Elena; Crocchiolo, Roberto; Fleischhauer, Katharina; Ponzoni, Maurilio; Vago, Luca; Rossini, Silvano; Santoro, Armando; Todisco, Elisabetta; Apperley, Jane F.; Olavarría, Eduardo; Slavin, Shimon; Weissinger, Eva M.; Ganser, Arnold; Stadler, Michael; Yannaki, Evangelia; Fassas, Αthanasios; Anagnostopoulos, Achilles; Bregni, Marco; Stampino, Corrado Gallo; Bruzzi, Paolo; Bordignon, Claudio

doi:10.1016/s1470-2045(09)70074-9

Cited by 445 publications

(357 citation statements)

References 42 publications

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“…Acute GvHD (grade I-IV) and chronic GvHD occurred in 10 and 1 patients, respectively, and were always controlled by the suicide gene induction. 46 This study confirmed the safety and potential benefit of the gene transfer technology, integrated with allo-HSCT, in improving survival of treated patients, as shown by the abrogation of late transplant-related mortality, extremely frequent after T cell-depleted haplo-SCT. 50 The following three major limitations have emerged in clinical trials with TK cells:…”

Section: The Adoptive Transfer Of Selected Antigen-specific Lymphocytsupporting

confidence: 76%

“…This has been shown to occur without interfering with the natural process of immune reconstitution promoted by the graft. 46 The first and, until now, the only suicide gene tested and validated in clinical trials, is the herpes simplex virus thymidine kinase (TK) gene that confers ganciclovir sensitivity to transduced cells. Clinical trials involving 4120 transplanted patients showed the safety of the TK-based gene therapy approach.…”

Section: The Adoptive Transfer Of Selected Antigen-specific Lymphocytmentioning

confidence: 99%

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Progress and prospects: graft-versus-host disease

et al. 2010

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Section: The Adoptive Transfer Of Selected Antigen-specific Lymphocytsupporting

confidence: 76%

Section: The Adoptive Transfer Of Selected Antigen-specific Lymphocytmentioning

confidence: 99%

Progress and prospects: graft-versus-host disease

et al. 2010

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“…13 Several clinical trials support the feasibility of this approach. [14][15][16][17][18] However, HSV-tk is a viral gene and may induce an unwanted immune response against functionally desirable T cells. Activation of the system also requires a clinically useful prodrug (like ganciclovir) to be administered for cell destruction.…”

Section: Introductionmentioning

confidence: 99%

Inducible caspase-9 suicide gene controls adverse effects from alloreplete T cells after haploidentical stem cell transplantation

Zhou

Dotti

Krance

et al. 2015

Blood

188

172

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• Alloreplete iC9-T cells can promote immune recovery posttransplant and protect patients against viral infections.• iC9-T cells can be eliminated from both peripheral blood and CNS by administration of AP1903 leading to a rapid resolution of GVHD.To test the feasibility of a single T-cell manipulation to eliminate alloreactivity while sparing antiviral and antitumor T cells, we infused 12 haploidentical hematopoietic stem cell transplant patients with increasing numbers of alloreplete haploidentical T cells expressing the inducible caspase 9 suicide gene (iC9-T cells). We determined whether the iC9-T cells produced immune reconstitution and if any resultant graft-versus-host disease (GVHD) could be controlled by administration of a chemical inducer of dimerization (CID; AP1903/ Rimiducid). All patients receiving >10 4 alloreplete iC9-T lymphocytes per kilogram achieved rapid reconstitution of immune responses toward 5 major pathogenic viruses and concomitant control of active infections. Four patients received a single AP1903 dose. CID infusion eliminated 85% to 95% of circulating CD3 1 CD19 1 T cells within 30 minutes, with no recurrence of GVHD within 90 days. In one patient, symptoms and signs of GVHDassociated cytokine release syndrome (CRS-hyperpyrexia, high levels of proinflammatory cytokines, and rash) resolved within 2 hours of AP1903 infusion. One patient with varicella zoster virus meningitis and acute GVHD had iC9-T cells present in the cerebrospinal fluid, which were reduced by >90% after CID. Notably, virus-specific T cells recovered even after AP1903 administration and continued to protect against infection. Hence, alloreplete iC9-T cells can reconstitute immunity posttransplant and administration of CID can eliminate them from both peripheral blood and the central nervous system (CNS), leading to rapid resolution of GVHD and CRS. The approach may therefore be useful for the rapid and effective treatment of toxicities associated with infusion of engineered T lymphocytes. This trial was registered at www.clinicaltrials.gov as #NCT01494103. (Blood. 2015;125(26):4103-4113)

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“…[4][5][6] A partial T-cell depletion can be provided by alternative selections, such as CD3/CD19 negative selection or selective depletion of alloreactive T-cells; 7 a T-cell content of 1 Â 10 5 /kg in the graft requires a post-transplant immune prophylaxis and translates into a significant risk of acute GVHD.…”

mentioning

confidence: 99%

Haploidentical transplantation in patients with acquired aplastic anemia

Ciceri¹,

Stanghellini²,

Korthof

2013

Bone Marrow Transplant

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on behalf of the SAA-WP EBMT Haploidentical SCT (haplo-SCT) has been considered a therapeutic option in patients with acquired severe aplastic anemia (SAA) failing at least one course of immune suppressive therapy with antithymocyte globulin and lacking an HLA-matched related or unrelated donor. The platforms of both ex vivo T-cell-depleted and unmanipulated grafts have been explored in children and adults. Overall, the primary objective of a stable haploidentical hematopoietic engraftment with a low rate of GVHD is unmet in a significant proportion of patients undergoing haplo-SCT for SAA. Haploidentical transplants for refractory SAA should be performed in a specialist center with major experience in hematopoietic SCT procedures and preferably performed within the framework of a local clinical protocol designed specifically to address the prevention of graft rejection and GVHD.

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Infusion of suicide-gene-engineered donor lymphocytes after family haploidentical haemopoietic stem-cell transplantation for leukaemia (the TK007 trial): a non-randomised phase I–II study

Cited by 445 publications

References 42 publications

Progress and prospects: graft-versus-host disease

Progress and prospects: graft-versus-host disease

Inducible caspase-9 suicide gene controls adverse effects from alloreplete T cells after haploidentical stem cell transplantation

Haploidentical transplantation in patients with acquired aplastic anemia

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