Umbilical cord blood-derived T regulatory cells to prevent GVHD: Kinetics, toxicity profile, and clinical effect

Claudio G. Brunstein; Jeffrey S. Miller; David H. McKenna; Keli L. Hippen; Todd E. DeFor; Darin Sumstad; Julie Curtsinger; Michael R. Verneris; Margaret L. MacMillan; Bruce L. Levine; James L. Riley; Carl H. June; Chap Le; Daniel J. Weisdorf; Philip B. McGlave; Bruce R. Blazar; John E. Wagner

doi:10.1182/blood-2015-06-653667

Umbilical cord blood-derived T regulatory cells to prevent GVHD: Kinetics, toxicity profile, and clinical effect

Claudio G. Brunstein, Jeffrey S. Miller, David H. McKenna, Keli L. Hippen, Todd E. DeFor, Darin Sumstad, Julie Curtsinger, Michael R. Verneris, Margaret L. MacMillan, Bruce L. Levine, James L. Riley, Carl H. June, Chap Le, Daniel J. Weisdorf, Philip B. McGlave, Bruce R. Blazar, John E. Wagner

Research output: Contribution to journal › Article › peer-review

307 Scopus citations

Abstract

We studied the safety and clinical outcomes of patients treated with umbilical cord blood (UCB)-derived regulatory T cells (Tregs) that expanded in cultures stimulated with K562 cells modified to express the high-affinity Fc receptor (CD64) and CD86, the natural ligand of CD28 (KT64/86). Eleven patients were treated with Treg doses from 3-100 × 10⁶ Treg/kg. The median proportion of CD4⁺FoxP3⁺CD127^- in the infused product was 87% (range, 78%-95%), and we observed no dose-limiting infusional adverse events. Clinical outcomes were compared with contemporary controls (n 5 22) who received the same conditioning regimen with sirolimus and mycophenolate mofetil immune suppression. The incidence of grade II-IV acute graft-versus-host disease (GVHD) at 100 days was 9% (95% confidence interval [CI], 0-25) vs 45% (95% CI, 24-67) in controls (P 5 .05). Chronic GVHD at 1 year was zero in Tregs and 14% in controls. Hematopoietic recovery and chimerism, cumulative density of infections, nonrelapse mortality, relapse, and diseasefree survival were similar in the Treg recipients and controls. KT64/86-expanded UCB Tregs were safe and resulted in low risk of acute GVHD.

Original language	English (US)
Pages (from-to)	1044-1051
Number of pages	8
Journal	Blood
Volume	127
Issue number	8
DOIs	https://doi.org/10.1182/blood-2015-06-653667
State	Published - Feb 25 2016

Bibliographical note

Funding Information:
The authors acknowledge Stefanie Hage and Jill L. Aughey from the University of Minnesota Clinical Trials Office for research nurse and regulatory support during the execution of this clinical trial; Diane Kadidlo and Fran Rabe from the University of Minnesota Medical Center Cell Therapy Laboratory andMolecular & Cellular Therapeutics for their assistance with cell therapy development and production; The Saint Louis Cord Blood Bank for kindly providing the UCB units for Treg manufacture; and the faculty, advanced practice providers, unit and clinic nurses, pharmacists, and social workers of the Blood and Marrow Transplant Program who cared for the patients at the University of Minnesota Medical Center. This work was supported in part by National Institutes of Health (NIH) National Cancer Institute grants P30 CA77598, P01 CA65493 (C.G.B., J.S.M.,D.H.M., P.B.M., B.R.B., J.E.W.), and R01 CA105216 (C.H.J.), Leukemia and Lymphoma Society Scholar in Clinical Research Award grant CDP-2417-11 (C.G.B.), the Children''s Cancer Research Fund (J.E.W., T.E.D.), NIH National Heart, Lung, and Blood Institute grant R01 HL11879 (B.R.B.), and contract HHSN268201000008C (J.S.M., D.H.M., K.L.H., J.C., J.E.W.), and Leukemia and Lymphoma Translational Research grant R6029-07 (B.R.B.).

Publisher Copyright:
© 2016 by The American Society of Hematology.

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Brunstein, C. G., Miller, J. S., McKenna, D. H., Hippen, K. L., DeFor, T. E., Sumstad, D., Curtsinger, J., Verneris, M. R., MacMillan, M. L., Levine, B. L., Riley, J. L., June, C. H., Le, C., Weisdorf, D. J., McGlave, P. B., Blazar, B. R., & Wagner, J. E. (2016). Umbilical cord blood-derived T regulatory cells to prevent GVHD: Kinetics, toxicity profile, and clinical effect. Blood, 127(8), 1044-1051. https://doi.org/10.1182/blood-2015-06-653667

Brunstein, CG, Miller, JS , McKenna, DH , Hippen, KL , DeFor, TE, Sumstad, D, Curtsinger, J, Verneris, MR, MacMillan, ML, Levine, BL, Riley, JL, June, CH, Le, C, Weisdorf, DJ, McGlave, PB, Blazar, BR & Wagner, JE 2016, 'Umbilical cord blood-derived T regulatory cells to prevent GVHD: Kinetics, toxicity profile, and clinical effect', Blood, vol. 127, no. 8, pp. 1044-1051. https://doi.org/10.1182/blood-2015-06-653667

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title = "Umbilical cord blood-derived T regulatory cells to prevent GVHD: Kinetics, toxicity profile, and clinical effect",

abstract = "We studied the safety and clinical outcomes of patients treated with umbilical cord blood (UCB)-derived regulatory T cells (Tregs) that expanded in cultures stimulated with K562 cells modified to express the high-affinity Fc receptor (CD64) and CD86, the natural ligand of CD28 (KT64/86). Eleven patients were treated with Treg doses from 3-100 × 106 Treg/kg. The median proportion of CD4+FoxP3+CD127- in the infused product was 87% (range, 78%-95%), and we observed no dose-limiting infusional adverse events. Clinical outcomes were compared with contemporary controls (n 5 22) who received the same conditioning regimen with sirolimus and mycophenolate mofetil immune suppression. The incidence of grade II-IV acute graft-versus-host disease (GVHD) at 100 days was 9% (95% confidence interval [CI], 0-25) vs 45% (95% CI, 24-67) in controls (P 5 .05). Chronic GVHD at 1 year was zero in Tregs and 14% in controls. Hematopoietic recovery and chimerism, cumulative density of infections, nonrelapse mortality, relapse, and diseasefree survival were similar in the Treg recipients and controls. KT64/86-expanded UCB Tregs were safe and resulted in low risk of acute GVHD.",

author = "Brunstein, {Claudio G.} and Miller, {Jeffrey S.} and McKenna, {David H.} and Hippen, {Keli L.} and DeFor, {Todd E.} and Darin Sumstad and Julie Curtsinger and Verneris, {Michael R.} and MacMillan, {Margaret L.} and Levine, {Bruce L.} and Riley, {James L.} and June, {Carl H.} and Chap Le and Weisdorf, {Daniel J.} and McGlave, {Philip B.} and Blazar, {Bruce R.} and Wagner, {John E.}",

note = "Funding Information: The authors acknowledge Stefanie Hage and Jill L. Aughey from the University of Minnesota Clinical Trials Office for research nurse and regulatory support during the execution of this clinical trial; Diane Kadidlo and Fran Rabe from the University of Minnesota Medical Center Cell Therapy Laboratory andMolecular & Cellular Therapeutics for their assistance with cell therapy development and production; The Saint Louis Cord Blood Bank for kindly providing the UCB units for Treg manufacture; and the faculty, advanced practice providers, unit and clinic nurses, pharmacists, and social workers of the Blood and Marrow Transplant Program who cared for the patients at the University of Minnesota Medical Center. This work was supported in part by National Institutes of Health (NIH) National Cancer Institute grants P30 CA77598, P01 CA65493 (C.G.B., J.S.M.,D.H.M., P.B.M., B.R.B., J.E.W.), and R01 CA105216 (C.H.J.), Leukemia and Lymphoma Society Scholar in Clinical Research Award grant CDP-2417-11 (C.G.B.), the Children''s Cancer Research Fund (J.E.W., T.E.D.), NIH National Heart, Lung, and Blood Institute grant R01 HL11879 (B.R.B.), and contract HHSN268201000008C (J.S.M., D.H.M., K.L.H., J.C., J.E.W.), and Leukemia and Lymphoma Translational Research grant R6029-07 (B.R.B.). Publisher Copyright: {\textcopyright} 2016 by The American Society of Hematology.",

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AU - Hippen, Keli L.

AU - DeFor, Todd E.

AU - Sumstad, Darin

AU - Curtsinger, Julie

AU - Verneris, Michael R.

AU - MacMillan, Margaret L.

AU - Levine, Bruce L.

AU - Riley, James L.

AU - June, Carl H.

AU - Le, Chap

AU - Weisdorf, Daniel J.

AU - McGlave, Philip B.

AU - Blazar, Bruce R.

AU - Wagner, John E.

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Umbilical cord blood-derived T regulatory cells to prevent GVHD: Kinetics, toxicity profile, and clinical effect

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