Multicenter phase 1/2 application of adenovirus-specific T cells in high-risk pediatric patients after allogeneic stem cell transplantation

Ip, Winnie; Silva, Juliana M.F.; Gaspar, H. Bobby; Mitra, Arindam; Patel, Shreenal; Rao, Kanchan; Chiesa, Robert; Amrolia, Persis; Gilmour, Kimberly; Ahsan, Gul; Slatter, Mary; Gennery, Andrew R.; Wynn, Robert; Veys, Paul; Qasim, Waseem

doi:10.1016/j.jcyt.2018.03.040

Cited by 20 publications

(14 citation statements)

References 22 publications

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“…In summary, we reported on a boy that received HAdV‐reactive T cells from a haploidentical stem cell donor that had been manufactured under GMP conditions using the CCS with overlapping peptide pools. The patient showed no infusion‐related toxicity and a decrease of viral load suggesting feasibility and effectiveness as similarly described in many recent studies (summary in Table ) . In addition, we could detect the immune response by ELISpot demonstrating an induction of penton‐ and hexon‐specific T cells in the patient after transfer.…”

Section: Discussionsupporting

confidence: 78%

“…decrease of viral load suggesting feasibility and effectiveness as similarly described in many recent studies (summary in Table 2). 7,9,[13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] In addition, we could detect the immune response by ELISpot demonstrating an induction of penton-and hexon-specific T cells in the patient after transfer. Diligent monitoring of GvHD and anti-HAdV immune response enabled personally tailored immunosuppressive and antiviral therapy and led to control of both GvHD and HAdV infection in this patient.…”

Section: Ta B L E 2 (Continued)mentioning

confidence: 94%

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Transfer of Hexon‐ and Penton‐selected adenovirus‐specific T cells for refractory adenovirus infection after haploidentical stem cell transplantation

Schultze-Florey

Tischer-Zimmermann

Heuft

et al. 2019

Transplant Infectious Dis

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Adenovirus (HAdV) infections confer a high risk of morbidity and mortality for immunocompromised patients after stem cell transplantation (SCT). Treatment with standard antiviral drugs is of limited efficacy and associated with a high rate of adverse effects. HAdV‐specific T cells are crucial for sustained viral elimination and the efficacy of adoptive T‐cell therapy with donor‐derived HAdV‐specific T cells has been reported by several investigators. Here, we report our experience with the transfer of HAdV‐specific T cells specific for penton, which was recently identified as an immunodominant target of T cells, and hexon in a 14‐year‐old boy after T‐cell‐depleted haploidentical SCT for myelodysplastic syndrome (MDS). He developed severe HAdV‐associated enteritis complicated by acute graft‐versus‐host disease (GvHD). The patient received ten infusions of allogeneic HAdV‐specific T cells manufactured from the haploidentical stem cell donor using the CliniMacs Interferon‐γ (IFN‐γ) cytokine capture and immunomagnetic selection. Initially, T cells were generated against the immunodominant target hexon and in subsequent transfers dual antigen‐specific T cells against hexon and penton were applied. T‐cell transfers were scheduled individually tailored to current immunosuppressive treatment. Each transfer was followed by reduction of HAdV load in peripheral blood and clinical improvement. Importantly, T‐cell responses to both penton and hexon pools emerged in patient blood after repetitive transfers. Unfortunately, the patient experienced bacterial sepsis, and in this context, severe GvHD requiring intensive immunosuppression followed by secondary progression of HAdV infection. The patient succumbed to multiorgan failure 283 days after SCT. This case demonstrates the feasibility of HAdV‐specific T‐cell transfer even in the presence of immunosuppressive treatment. Targeting of multiple immunodominant viral proteins may prove valuable in patients with complicated HAdV infections.

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Section: Discussionsupporting

confidence: 78%

Section: Ta B L E 2 (Continued)mentioning

confidence: 94%

Transfer of Hexon‐ and Penton‐selected adenovirus‐specific T cells for refractory adenovirus infection after haploidentical stem cell transplantation

Schultze-Florey

Tischer-Zimmermann

Heuft

et al. 2019

Transplant Infectious Dis

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“…With these premises, two phase I/II clinical trials have been conducted on HSCT recipients ( 75 , 131 ). In the former, IFN-gamma immunomagnetic selected anti-ADV T-lymphocytes from HSCT donor or third party haploidentical donor were administered after short term ex-vivo expansion to patients with refractory ADV infection.…”

Section: Management Of Viral Infections After Hsctmentioning

confidence: 99%

“…All of the eight patients receiving ADV-specific cells as pre-emptive therapy achieved viral clearance. Grade II GVHD occurred in 1/8 patients ( 131 ).…”

Section: Management Of Viral Infections After Hsctmentioning

confidence: 99%

Viral Infections in HSCT: Detection, Monitoring, Clinical Management, and Immunologic Implications

et al. 2021

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In spite of an increasing array of investigations, the relationships between viral infections and allogeneic hematopoietic stem cell transplantation (HSCT) are still controversial, and almost exclusively regard DNA viruses. Viral infections per se account for a considerable risk of morbidity and mortality among HSCT recipients, and available antiviral agents have proven to be of limited effectiveness. Therefore, an optimal management of viral infection represents a key point in HSCT strategies. On the other hand, viruses bear the potential of shaping immunologic recovery after HSCT, possibly interfering with control of the underlying disease and graft-versus-host disease (GvHD), and eventually with HSCT outcome. Moreover, preliminary data are available about the possible role of some virome components as markers of immunologic recovery after HSCT. Lastly, HSCT may exert an immunotherapeutic effect against some viral infections, notably HIV and HTLV-1, and has been considered as an eradicating approach in these indications.

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“…The transfer of engineered virus-specific T cells has increasingly been used to treat life-threatening CMV [65], EBV [66], and ADV infections [67] after stem cell transplantation. The safety and efficacy of broad-spectrum T cells as treatment for ADV, EBV, CMV, and BKPyV infections after stem cell transplantation was published by Papadopoulou et al [68].…”

Section: Therapy With Virus-specific T Cellsmentioning

confidence: 99%

Virus-specific T cells in pediatric renal transplantation

Ahlenstiel-Grunow

Pape

2020

Pediatr Nephrol

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After pediatric kidney transplantation, immunosuppressive therapy causes an increased risk of severe viral complications, especially from cytomegalovirus (CMV), BK polyomavirus (BKPyV) or Epstein-Barr virus (EBV), and less frequent from adenovirus (ADV). However, suitable predictive markers for the individual outcome of viral infections are missing and the therapeutic management remains a challenge to the success of pediatric kidney transplantation. Virus-specific T cells are known for controlling viral replication and there is growing evidence that virus-specific T cells may serve as a prognostic marker to identify patients at risk for viral complications. This review provides an overview of the usability of virus-specific T cells for improving diagnostic and therapeutic management of viral infections with reference to the necessity of antiviral prophylaxis, timing of pre-emptive therapy, and dosing of immunosuppressive medication after pediatric kidney transplantation. Several studies demonstrated that high levels of virus-specific T cells are associated with decrease of virus load and favorable outcome, whereas lack of virus-specific T cells coincided with virus-induced complications. Accordingly, the additional monitoring of virus-specific T cells aims to personalize the management of antiviral therapy, identify overimmunosuppression, and avoid unnecessary therapeutic interventions. Prospective randomized trials in pediatric kidney recipients comparing standard antiviral and immunosuppressive regimens with T cell-guided therapeutic interventions are needed, before monitoring of virus-specific T cells is implemented in the routine care of pediatric kidney graft recipients.

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Multicenter phase 1/2 application of adenovirus-specific T cells in high-risk pediatric patients after allogeneic stem cell transplantation

Abstract: The study demonstrates the safety and feasibility of pre-emptively manufacturing peptide pulsed ADV-specific cells for high-risk pediatric patients after transplantation and provides early evidence of clinical efficacy.

Cited by 20 publications

References 22 publications

Transfer of Hexon‐ and Penton‐selected adenovirus‐specific T cells for refractory adenovirus infection after haploidentical stem cell transplantation

Transfer of Hexon‐ and Penton‐selected adenovirus‐specific T cells for refractory adenovirus infection after haploidentical stem cell transplantation

Viral Infections in HSCT: Detection, Monitoring, Clinical Management, and Immunologic Implications

Virus-specific T cells in pediatric renal transplantation

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