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• W2103020736 abstract "We previously reported that the infusion of ex vivo expanded umbilical cord blood (UCB)-derived natural regulatory T cells (nTregs) infused immediately after UCB transplantation was associated with a reduced incidence of acute graft-versus-host disease (GVHD) relative to historical control subjects [1Brunstein C.G. Miller J.S. Cao Q. et al.Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics.Blood. 2011; 117: 1061-1070Crossref PubMed Scopus (820) Google Scholar]. We did not observe an increased incidence of opportunistic infections or relapse, suggesting the transient nature of nTreg provided sufficient immune suppression to control GVHD without long-term deleterious effects. However, we hypothesized that early side effects might be heightened and could be evaluated at specific time points, such as when adoptively transferred nTregs were detectable in the peripheral blood of patient. All but 1 patient, receiving an nTreg dose of 10 × 106/kg on day +1 and 3 × 106/kg on day 15, have been reported [1Brunstein C.G. Miller J.S. Cao Q. et al.Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics.Blood. 2011; 117: 1061-1070Crossref PubMed Scopus (820) Google Scholar]. Patient eligibility, conditioning regimen and immune suppression, and supportive care were reported [1Brunstein C.G. Miller J.S. Cao Q. et al.Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics.Blood. 2011; 117: 1061-1070Crossref PubMed Scopus (820) Google Scholar]. In this analysis, the historical control subjects consisted of a 65-patient subset of the 108 reported [1Brunstein C.G. Miller J.S. Cao Q. et al.Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics.Blood. 2011; 117: 1061-1070Crossref PubMed Scopus (820) Google Scholar] who had post-UCB transplantation T cell subset phenotype data available using standard procedures. In contrast to prior analyses that compared the cumulative incidence of opportunistic, in this analysis we studied infection density that accounts for multiple infections in an individual patient. We calculated infection density per 1000 patient-days within 180 days by dividing the total number of infections within the time period by total patient-day multiplied by 1000 [2Lin D.Y. Non-parametric inference for cumulative incidence functions in competing risks studies.Stat Med. 1997; 16: 901-910Crossref PubMed Scopus (367) Google Scholar]. In our initial report, we demonstrated that adoptively transferred nTregs were present in the peripheral blood of patients up to 14 days after the infusion of fresh and up to 4 days after the infusion of cryopreserved product [1Brunstein C.G. Miller J.S. Cao Q. et al.Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics.Blood. 2011; 117: 1061-1070Crossref PubMed Scopus (820) Google Scholar]. Notably, in the current study we found in this early period (days 0 to +30) that nTregs are present, there was significantly higher cumulative density of OI in Treg (18.06 infections per 1000 patient-days) as compared with historical control subjects (7.71 infections per 1000 patient-days) patients (univariate RR, 5.35, P = .02) (Figure 1A). These were essentially viral reactivations with no effect on the risk of fungal infections. Thus, it is possible that Treg can increase the risk of infection during the period of time they are detectable. This contrasts with our initial report in which we found no difference in the risk OIs as assessed by the cumulative incidence. In contrast to the first 30 days, between days +31 and +180 there was similar OI density in the two groups (7.22/1000 versus 4.22/1000; univariate RR, 0.58, P = .07) (Figure 1A). Notably, the higher risk of early infection did not affect nonrelapse mortality (18% [95% confidence interval [CI], 2% to 34%] versus 10% [95% CI, 2% to 17%], P = .34) or progression-free survival (33% [95% CI, 16% to 52%] versus 35% [95% CI, 24% to 47%], P = .93), as compared with historical control subjects. The viral infections observed in nTreg patients through day +30 were human herpesvirus-6 viremia (HHV6, n = 9), cytomegalovirus (n = 2) viremia, and 1 case of parainfluenza upper respiratory infection. The corresponding viral infections observed in historical control subjects through day +30 were HHV-6 viremia (n = 6), cytomegalovirus reactivation (n = 8), adenovirus gastroenteritis (n = 4), polyoma virus in the urine (n = 4), enterovirus gastroenteritis (n = 1), and upper airway respiratory syncytial virus (n = 1). Three of 9 HHV-6 viremia episodes in the Treg group and 2 of 6 in the historical control group were treated with foscarnet. In our institution, we observed 69% incidence reactivation of HHV-6 by 6 weeks after UCB transplantation, overall [3Betts B.C. Young J.A. Ustun C. et al.Human herpesvirus 6 infection after hematopoietic cell transplantation: is routine surveillance necessary?.Biol Blood Marrow Transplant. 2011; 17: 1562-1568Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar]. Thus, although a high rate of HHV-6 infections in the first month is not unexpected, the higher density of this infection in the first month as compared with similarly treated patients could be the result of the Treg infusion. However, patients in a phase I clinical trial are monitored more closely than patients receiving the standard of care, and we cannot rule out that our higher infection density is the result of an observation bias and/or the limited number of Treg recipients. A potential benefit of not developing GVHD is the ability to taper immune suppression sooner, leading to potentially faster reconstitution of immune reconstitution. However, we did not observe a significant difference between nTreg patients versus historical control subjects. At day +180, the median absolute number of peripheral blood CD19+ cells was 179/μL (range, 0 to 1160) versus 282/μL (range, 1 to 1632) (P = .54), CD3+/CD8+ was 58/μL (range, 14 to 645) versus 72/μL (range, 8 to 848) (P = .46), and CD3+/CD4+ cells was 255/μL (range, 6 to 527) versus 219/μL (range, 27 to 1179) (P = .48) for nTreg versus historical control subjects, respectively (Figure 1B-D). In contrast, data on the adoptive transfer of nTregs in combination with T effector cells in haploidentical related donor transplantation showed that antigen-specific T cell immunity was observed sooner than in historical control subjects [4Di Ianni M. Falzetti F. Carotti A. et al.Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation.Blood. 2011; 117: 3921-3928Crossref PubMed Scopus (816) Google Scholar]. This may be secondary to biological differences between donor types because cord blood recipients may take longer to achieve adequate numbers of virus-specific T cells [5McGoldrick S.M. Bleakley M.E. Guerrero A. et al.Cytomegalovirus-specific T cells are primed early after cord blood transplant but fail to control virus in vivo.Blood. 2013; 121: 2796-2803Crossref PubMed Scopus (31) Google Scholar]. Clearly, longer follow-up and more detailed analysis are required for better understanding of lymphocyte subsets reconstitution. In summary, there is potentially a higher viral infection risk within 30 days of UCB-derived nTregs infusion due to suppression of the immune response; however, there was no adverse effect on the longer term outcomes, including later risk of OIs. Although observation bias is a possibility, our data suggesting higher density of viral infections argues for close observation in studies of the adoptive transfer of nTregs to reduce GVHD in allogeneic hematopoietic cell transplantation and in solid organ transplantation. Financial disclosure: Supported in part by grants from the National Cancer Institute (P01 CA65493 to C.G.B., J.S.M., D.H.M., P.B.M., B.R.B., and J.E.W.), Leukemia and Lymphoma Society Scholar in Clinical Research Award (2417-11 to C.G.B.), the Children's Cancer Research Fund (to J.E.W. and T.E.D. and R01 CA105216 to C.H.J.), National Heart, Lung and Blood Institute (N01 HB037164 to J.S.M., D.H.M., and J.E.W. and HHSN268201000008C to J.S.M., D.H.M., K.L.H., J.C., and J.E.W.), Leukemia and Lymphoma Translational Research (R6029-07 to B.R.B.), and National Marrow Donor Program (13396 AM#2 to B.R.B. and J.E.W.)." @default.
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• W2103020736 title "Adoptive Transfer of Umbilical Cord Blood-Derived Regulatory T Cells and Early Viral Reactivation" @default.
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