Selective T‐cell depletion targeting <scp>CD</scp>45<scp>RA</scp> reduces viremia and enhances early T‐cell recovery compared with <scp>CD</scp>3‐targeted T‐cell depletion

Triplett, Brandon M.; Muller, Brad; Kang, Guolian; Liu, Ying; Cross, Shane J; Moen, Joseph; Cunningham, Lea; Janssen, William E.; Mamcarz, Ewelina; Shook, David; Srinivasan, Ashok; Choi, John K.; Hayden, Randall T.; Leung, Wing

doi:10.1111/tid.12823

Cited by 56 publications

(61 citation statements)

References 27 publications

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“…Nevertheless, the same group reported an increased incidence of graft rejection in the context of HHV-6 reactivation. A pre-emptive treatment based on ganciclovir or foscarnet was started in any patient showing erythematous rash and fever before the engraftment as a strategy to prevent HHV-6 reactivation [40]. We have considered the possibility of chromosomally integrated HHV-6, but it is a rare condition reported in less than 1% of control subjects in the United States and the United Kingdom [41] so it would hardly explain the high rates we observed.…”

Section: Discussionmentioning

confidence: 88%

Unexpected High Incidence of Human Herpesvirus-6 Encephalitis after Naive T Cell–Depleted Graft of Haploidentical Stem Cell Transplantation in Pediatric Patients

Sisinni

Gasior

Paz

et al. 2018

Biology of Blood and Marrow Transplantation

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The CD45RA T cell depletion (TCD) method has been used to deplete naive T cells, preventing graft-versus-host disease (GVHD) but preserving memory cells, providing immediate functional T cells with anti-infection, antileukemia, and antirejection effects. We describe a series of 25 consecutive high-risk patients with leukemia who received haploidentical hematopoietic stem cell transplantation (haplo-HSCT) with CD45RA TCD. Each patient received 2 cell products: 1 created by CD34 positive selection and the other through CD45RA depletion from the CD34 negative fraction by a CliniMACS device. CD45RA-depleted haplo-HSCT was well tolerated, with rapid engraftment and low risk of severe acute GVHD and chronic GVHD. Although this treatment achieved a good control of viral reactivations, such as cytomegalovirus and adenovirus, we observed an unexpectedly high rate of limbic encephalitis due to human herpesvirus-6 (HHV-6; 8 cases). Characteristically, the infection appeared early in almost all patients, just after the engraftment. Although no patient died from encephalitis, 1 patient showed neuropsychological sequelae, and another experienced secondary graft failure just after the HHV-6 reactivation.

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Section: Discussionmentioning

confidence: 88%

Unexpected High Incidence of Human Herpesvirus-6 Encephalitis after Naive T Cell–Depleted Graft of Haploidentical Stem Cell Transplantation in Pediatric Patients

Sisinni

Gasior

Paz

et al. 2018

Biology of Blood and Marrow Transplantation

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“…The study was conducted at 3 pediatric transplant centers, 1 Italian (Perugia) and 2 Spanish (Barcelona and Madrid) from January 1, 2015 to April 30, 2018 and included patients who received ex vivo manipulated haploidentical HSCT. The Italian cohort received ex vivo graft manipulation with CD34 + selection and regulatory T cell (Treg)/conventional T cell (Tcon) infusion (Treg/Tcon cohort) [21,22], whereas the Spanish cohort received CD45RA T cellÀD 1 8 X X depleted donor peripheral blood stem cells (CD45RA cohort) [23,24]. Table 1 shows patient demographic, disease, and transplant characteristics.…”

Section: Methodsmentioning

confidence: 99%

High Incidence of Early Human Herpesvirus-6 Infection in Children Undergoing Haploidentical Manipulated Stem Cell Transplantation for Hematologic Malignancies

Perruccio¹,

Sisinni

Pérez‐Martínez

et al. 2018

Biology of Blood and Marrow Transplantation

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Human herpesvirus-6 (HHV-6) infection is increasingly recognized among allogeneic hematopoietic stem cell transplantation (HSCT) recipients, with 30% at risk of reactivation in the haploidentical setting. It has been associated with encephalitis, acute graft-versus-host disease, and graft failure. Here we report 2 cohorts of pediatric haploidentical manipulated HSCT in which, despite many differences, HHV-6 reactivation and disease occurred with very high incidence compared with data reported in the literature and represented the main early post-transplant infectious complication compared with other viral, bacterial, or fungal infections. The 2 cohorts were recruited at the pediatric transplant centers of Perugia (n = 13), Barcelona (n = 10), and Madrid (n = 15). All patients received myeloablative conditioning regimens and 2 different types of ex vivo graft manipulation: CD34 selection and regulatory T cell/conventional T cell infusion in 13 patients and CD45RA T cell depletion in 25 patients. Antiviral prophylaxis was acyclovir in 33 and foscarnet in 5 patients. HHV-6 DNAemia was checked by quantitative or qualitative PCR. In vitro experiments demonstrated that donor CD4 T cells are the reservoir of HHV-6 and suggested a role of the graft composition in both transplant settings (rich in CD4 T cells) in the high rate of HHV-6 infections. All patients presented very early HHV-6 DNAemia after transplantation, and although viremic, 9 patients (24%) developed symptomatic limbic encephalitis. All patients responded to antiviral treatment, and none died of infection, although 2 experienced long-term neurologic sequelae (22%). Moreover, 6 patients presented organ involvement in absence of other causes: 1 hepatitis, 1 pneumonia, 2 gastroenteritis, and 2 multiorgan involvement(1 encephalitis, pneumonia, and gastritis; 1 pneumonia and enteritis). Incidences of other viral, bacterial, and fungal diseases were lower in both cohorts. In vitro, HHV-6 was found to infect only CD4 fraction of the graft. Co-culturing CD4 T cells with CD56 natural killer (NK) cells eliminated the virus, demonstrating the main role of NK cells in the antiviral immune response. All 38 pediatric patients undergoing these manipulated haploidentical HSCTs showed HHV-6 reactivation, and 14 of 38 developed HHV-6 disease with similar features in terms of timing, morbidity, response to treatment, and outcome. The graft composition in both transplant platforms, rich in CD4 T cells and poor in NK cells, seems to play a key role. HHV-6 DNAemia surveillance was useful to diagnose and treat preemptively HHV-6 infection.

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“…This fact is determinant and constitutes the basis of adoptive cell therapy of viral infections in immunosuppressed patients in the context of allogeneic hematopoietic stem cell transplantation (HSCT). In HSCT the infusion of CD45RA − memory T cells has considerably reduced the morbidity and mortality induced by viral reactivations such as cytomegalovirus (CMV) or Epstein Barr Virus (EBV) and, at the same time, has reduced the alloreactivity conferred by the naïve CD45RA + T cells 17–21 .…”

Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 specific memory T lymphocytes from COVID-19 convalescent donors: identification, biobanking and large-scale production for Adoptive Cell Therapy

Ferreras

Pascual-Miguel

Mestre-Durán

et al. 2020

Preprint

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SARS-CoV-2 is causing a second outbreak so the hope for its complete eradication is far from happening. In the absence of effective vaccines, it is mandatory to find effective treatments with low adverse effects able to treat hospitalized patients with COVID-19 disease. In this work, we determined the existence of SARS-CoV-2 specific T cells within the CD45RA- T memory cells from the blood of convalescent donors. Memory T cells can respond quickly to the infection and provide long-term immune protection to reduce the severity of the COVID-19 symptoms. Also, CD45RA- memory T cells confer protection from other pathogens the donors encountered in their life. This is vital to clear other secondary infections usually developed in hospitalized COVID-19 patients. SARS-CoV-2 specific memory T cells were found within all the CD45RA- subsets CD3+, CD4+, CD8+, and in the central memory and effector memory subpopulations. The procedure to obtain the cells is feasible, easy to implement for small scale manufacture, quick and cost-effective involving minimal manipulation, and without GMP condition requirements. This biobank of specific SARS-CoV-2 memory T cells would be immediately available off-the-shelf to treat moderate/severe cases of COVID-19 increasing the therapeutic options available for these patients.

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Selective T‐cell depletion targeting CD45RA reduces viremia and enhances early T‐cell recovery compared with CD3‐targeted T‐cell depletion

Abstract: CD45RA-depletion provided a large number of donor memory T cells to the recipients and was associated with enhanced early T-cell recovery and protection against viremia.

Cited by 56 publications

References 27 publications

Unexpected High Incidence of Human Herpesvirus-6 Encephalitis after Naive T Cell–Depleted Graft of Haploidentical Stem Cell Transplantation in Pediatric Patients

Unexpected High Incidence of Human Herpesvirus-6 Encephalitis after Naive T Cell–Depleted Graft of Haploidentical Stem Cell Transplantation in Pediatric Patients

High Incidence of Early Human Herpesvirus-6 Infection in Children Undergoing Haploidentical Manipulated Stem Cell Transplantation for Hematologic Malignancies

SARS-CoV-2 specific memory T lymphocytes from COVID-19 convalescent donors: identification, biobanking and large-scale production for Adoptive Cell Therapy

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