Recipient BCL2 inhibition and NK cell ablation form part of a reduced intensity conditioning regime that improves allo-bone marrow transplantation outcomes

Yuhao Jiao, Joanne E. Davis, Jai Rautela, Emma M. Carrington, Mandy J. Ludford-Menting, Wilford Goh, Rebecca B. Delconte, Fernando Souza-Fonseca-Guimaraes, Rachel Koldej, Daniel Gray, David Huang, Ben T. Kile, Andrew M. Lew, David S. Ritchie, Nicholas D. Huntington

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Allogeneic hematopoietic stem cell transplantation (alloSCT) is used to treat over 15,000 patients with acute myeloid leukemia (AML) per year. Donor graft-versus-leukemia (GVL) effect can prevent AML relapse; however, alloSCT is limited by significant toxicity related to conditioning intensity, immunosuppression, opportunistic infections, and graft-versus-host disease (GVHD). Reducing the intensity of conditioning regimens prior to alloSCT has improved their tolerability, but does not alter the pattern of GVHD and has been associated with increased rates of graft rejection and relapse. Here, using a murine pre-clinical model, we describe a novel recipient conditioning approach combining reduced intensity conditioning with either genetic or pharmacological inhibition of NK cell numbers that permits efficient donor engraftment and promotes GVL without inducing GVHD. We show that NK cell-specific deletion of Bcl2 or Mcl1 in mice, or pharmacological inhibition of BCL2 impairs radio-resistant NK cell-mediated rejection of allogeneic engraftment and allows reduction of conditioning intensity below that associated with GVHD priming. The combination of reduced intensity conditioning and NK cell targeting in mice allowed successful donor T cell engraftment and protective immunity against AML while avoiding GVHD. These findings suggest that reduced conditioning in combination with targeted therapies against recipient NK cells may allow the delivery of effective alloSCT against AML while reducing the toxicities associated with more intensive conditioning including GVHD.

Original languageEnglish
Pages (from-to)1516-1530
Number of pages15
JournalCell Death and Differentiation
Volume26
DOIs
Publication statusPublished - 12 Nov 2018

Keywords

  • cancer
  • immunology

Cite this

Jiao, Yuhao ; Davis, Joanne E. ; Rautela, Jai ; Carrington, Emma M. ; Ludford-Menting, Mandy J. ; Goh, Wilford ; Delconte, Rebecca B. ; Souza-Fonseca-Guimaraes, Fernando ; Koldej, Rachel ; Gray, Daniel ; Huang, David ; Kile, Ben T. ; Lew, Andrew M. ; Ritchie, David S. ; Huntington, Nicholas D. / Recipient BCL2 inhibition and NK cell ablation form part of a reduced intensity conditioning regime that improves allo-bone marrow transplantation outcomes. In: Cell Death and Differentiation. 2018 ; Vol. 26. pp. 1516-1530.
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title = "Recipient BCL2 inhibition and NK cell ablation form part of a reduced intensity conditioning regime that improves allo-bone marrow transplantation outcomes",
abstract = "Allogeneic hematopoietic stem cell transplantation (alloSCT) is used to treat over 15,000 patients with acute myeloid leukemia (AML) per year. Donor graft-versus-leukemia (GVL) effect can prevent AML relapse; however, alloSCT is limited by significant toxicity related to conditioning intensity, immunosuppression, opportunistic infections, and graft-versus-host disease (GVHD). Reducing the intensity of conditioning regimens prior to alloSCT has improved their tolerability, but does not alter the pattern of GVHD and has been associated with increased rates of graft rejection and relapse. Here, using a murine pre-clinical model, we describe a novel recipient conditioning approach combining reduced intensity conditioning with either genetic or pharmacological inhibition of NK cell numbers that permits efficient donor engraftment and promotes GVL without inducing GVHD. We show that NK cell-specific deletion of Bcl2 or Mcl1 in mice, or pharmacological inhibition of BCL2 impairs radio-resistant NK cell-mediated rejection of allogeneic engraftment and allows reduction of conditioning intensity below that associated with GVHD priming. The combination of reduced intensity conditioning and NK cell targeting in mice allowed successful donor T cell engraftment and protective immunity against AML while avoiding GVHD. These findings suggest that reduced conditioning in combination with targeted therapies against recipient NK cells may allow the delivery of effective alloSCT against AML while reducing the toxicities associated with more intensive conditioning including GVHD.",
keywords = "cancer, immunology",
author = "Yuhao Jiao and Davis, {Joanne E.} and Jai Rautela and Carrington, {Emma M.} and Ludford-Menting, {Mandy J.} and Wilford Goh and Delconte, {Rebecca B.} and Fernando Souza-Fonseca-Guimaraes and Rachel Koldej and Daniel Gray and David Huang and Kile, {Ben T.} and Lew, {Andrew M.} and Ritchie, {David S.} and Huntington, {Nicholas D.}",
year = "2018",
month = "11",
day = "12",
doi = "10.1038/s41418-018-0228-y",
language = "English",
volume = "26",
pages = "1516--1530",
journal = "Cell Death and Differentiation",
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Jiao, Y, Davis, JE, Rautela, J, Carrington, EM, Ludford-Menting, MJ, Goh, W, Delconte, RB, Souza-Fonseca-Guimaraes, F, Koldej, R, Gray, D, Huang, D, Kile, BT, Lew, AM, Ritchie, DS & Huntington, ND 2018, 'Recipient BCL2 inhibition and NK cell ablation form part of a reduced intensity conditioning regime that improves allo-bone marrow transplantation outcomes' Cell Death and Differentiation, vol. 26, pp. 1516-1530. https://doi.org/10.1038/s41418-018-0228-y

Recipient BCL2 inhibition and NK cell ablation form part of a reduced intensity conditioning regime that improves allo-bone marrow transplantation outcomes. / Jiao, Yuhao; Davis, Joanne E.; Rautela, Jai; Carrington, Emma M.; Ludford-Menting, Mandy J.; Goh, Wilford; Delconte, Rebecca B.; Souza-Fonseca-Guimaraes, Fernando; Koldej, Rachel; Gray, Daniel; Huang, David; Kile, Ben T.; Lew, Andrew M.; Ritchie, David S.; Huntington, Nicholas D.

In: Cell Death and Differentiation, Vol. 26, 12.11.2018, p. 1516-1530.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Recipient BCL2 inhibition and NK cell ablation form part of a reduced intensity conditioning regime that improves allo-bone marrow transplantation outcomes

AU - Jiao, Yuhao

AU - Davis, Joanne E.

AU - Rautela, Jai

AU - Carrington, Emma M.

AU - Ludford-Menting, Mandy J.

AU - Goh, Wilford

AU - Delconte, Rebecca B.

AU - Souza-Fonseca-Guimaraes, Fernando

AU - Koldej, Rachel

AU - Gray, Daniel

AU - Huang, David

AU - Kile, Ben T.

AU - Lew, Andrew M.

AU - Ritchie, David S.

AU - Huntington, Nicholas D.

PY - 2018/11/12

Y1 - 2018/11/12

N2 - Allogeneic hematopoietic stem cell transplantation (alloSCT) is used to treat over 15,000 patients with acute myeloid leukemia (AML) per year. Donor graft-versus-leukemia (GVL) effect can prevent AML relapse; however, alloSCT is limited by significant toxicity related to conditioning intensity, immunosuppression, opportunistic infections, and graft-versus-host disease (GVHD). Reducing the intensity of conditioning regimens prior to alloSCT has improved their tolerability, but does not alter the pattern of GVHD and has been associated with increased rates of graft rejection and relapse. Here, using a murine pre-clinical model, we describe a novel recipient conditioning approach combining reduced intensity conditioning with either genetic or pharmacological inhibition of NK cell numbers that permits efficient donor engraftment and promotes GVL without inducing GVHD. We show that NK cell-specific deletion of Bcl2 or Mcl1 in mice, or pharmacological inhibition of BCL2 impairs radio-resistant NK cell-mediated rejection of allogeneic engraftment and allows reduction of conditioning intensity below that associated with GVHD priming. The combination of reduced intensity conditioning and NK cell targeting in mice allowed successful donor T cell engraftment and protective immunity against AML while avoiding GVHD. These findings suggest that reduced conditioning in combination with targeted therapies against recipient NK cells may allow the delivery of effective alloSCT against AML while reducing the toxicities associated with more intensive conditioning including GVHD.

AB - Allogeneic hematopoietic stem cell transplantation (alloSCT) is used to treat over 15,000 patients with acute myeloid leukemia (AML) per year. Donor graft-versus-leukemia (GVL) effect can prevent AML relapse; however, alloSCT is limited by significant toxicity related to conditioning intensity, immunosuppression, opportunistic infections, and graft-versus-host disease (GVHD). Reducing the intensity of conditioning regimens prior to alloSCT has improved their tolerability, but does not alter the pattern of GVHD and has been associated with increased rates of graft rejection and relapse. Here, using a murine pre-clinical model, we describe a novel recipient conditioning approach combining reduced intensity conditioning with either genetic or pharmacological inhibition of NK cell numbers that permits efficient donor engraftment and promotes GVL without inducing GVHD. We show that NK cell-specific deletion of Bcl2 or Mcl1 in mice, or pharmacological inhibition of BCL2 impairs radio-resistant NK cell-mediated rejection of allogeneic engraftment and allows reduction of conditioning intensity below that associated with GVHD priming. The combination of reduced intensity conditioning and NK cell targeting in mice allowed successful donor T cell engraftment and protective immunity against AML while avoiding GVHD. These findings suggest that reduced conditioning in combination with targeted therapies against recipient NK cells may allow the delivery of effective alloSCT against AML while reducing the toxicities associated with more intensive conditioning including GVHD.

KW - cancer

KW - immunology

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