Virus Specific Immune Responses after Human Neoadjuvant Adenovirus-mediated Suicide Gene Therapy for Prostate Cancer

Linden, Richard R.M van der; Haagmans, Bart L.; Mongiat-Artus, Pierre; Doornum, G J van; Kraaij, Robert; Kadmon, Dov; Aguilar-Córdova, Estuardo; Osterhaus, A. D. M. E.; Kwast, Theodorus H. van der; Bangma, Chris H.

doi:10.1016/j.eururo.2005.02.013

Cited by 31 publications

(23 citation statements)

References 22 publications

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“…This approach resulted in abrogation of the adverse effects while sparing the anti-viral activity of the infused T cell product [38,39]. Subsequent studies and clinical trials have supported the effectiveness of this approach, which is now in a Phase III clinical trial [55–60]. …”

Section: Evolution Of Safety Switchesmentioning

confidence: 99%

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

Zhou

Brenner

2016

Experimental Hematology

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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.

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Section: Evolution Of Safety Switchesmentioning

confidence: 99%

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

Zhou

Brenner

2016

Experimental Hematology

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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

183

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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“…A number of phase I/II trials have been conducted. The results, though ambiguous, advocate the usage of this approach not individually but together with radiation therapy because ganciclovir can act as a radiation sensitizer as well (Hassan et al, 2000;van der Linden et al, 2005).…”

Section: Gene Therapymentioning

confidence: 83%

Multidimensional approaches in dealing with prostate cancer

Ali

2008

Gene

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Virus Specific Immune Responses after Human Neoadjuvant Adenovirus-mediated Suicide Gene Therapy for Prostate Cancer

Cited by 31 publications

References 22 publications

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

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

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

Multidimensional approaches in dealing with prostate cancer

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