Graft-versus-leukemia effect of HLA-haploidentical central-memory t-cells expanded with leukemic APCs and modified with a suicide gene

Monica Casucci, Serena Kimi Perna, Laura Falcone, Barbara Camisa, Zulma Magnani, Massimo Bernardi, Alessandro Crotta, Cristina Tresoldi, Katharina Fleischhauer, Maurilio Ponzoni, Silvia Gregori, Federico Caligaris Cappio, Fabio Ciceri, Claudio Bordignon, Alessandro Cignetti, Attilio Bondanza, Chiara Bonini

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Allogeneic hematopoietic stem cell transplantation (HSCT) from a human leukocyte antigen (HLA)-haploidentical family donor (haplo-HSCT) is a readily available and potentially curative option for high-risk leukemia. In haplo-HSCT, alloreactivity plays a major role in the graft-versus-leukemia (GVL) effect, which, however, is frequently followed by relapse due to emerging leukemic cell variants that have lost the unshared HLA haplotype as a mechanism of immune escape. We report that stimulation of HLA-haploidentical donor T lymphocytes with leukemic antigen-presenting cells (L-APCs) expands a population of leukemia-reactive T cells, which, besides alloreactivity to unshared HLAs, contain leukemia-associated specificities restricted by shared HLAs. According to a preferential central-memory (T CM) phenotype and to high interleukin (IL)-7Rα expression, these T cells persist in vivo and sustain a major GVL effect in a clinically relevant xenograft model. Moreover, we demonstrate that modifying L-APC-expanded T cells to express the herpes simplex virus thymidine kinase (HSV-tk) suicide gene enables their elimination with the prodrug ganciclovir (GCV), therefore providing a safety switch in case of graft-versus-host disease (GVHD). These results warrant the clinical investigation of L-APC-expanded T cells modified with a suicide gene in the setting of haplo-HSCT.

Original languageEnglish
Pages (from-to)466-475
Number of pages10
JournalMolecular Therapy
Volume21
Issue number2
DOIs
Publication statusPublished - Feb 2013

Fingerprint

Hematopoietic Stem Cell Transplantation
HLA Antigens
Suicide
Leukemia
Antigen-Presenting Cells
T-Lymphocytes
Transplants
Genes
T-Cell Leukemia
Ganciclovir
Thymidine Kinase
Interleukins
Prodrugs
Graft vs Host Disease
Simplexvirus
Heterografts
Haplotypes
Phenotype
Safety
Recurrence

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine
  • Genetics
  • Drug Discovery
  • Pharmacology

Cite this

Graft-versus-leukemia effect of HLA-haploidentical central-memory t-cells expanded with leukemic APCs and modified with a suicide gene. / Casucci, Monica; Perna, Serena Kimi; Falcone, Laura; Camisa, Barbara; Magnani, Zulma; Bernardi, Massimo; Crotta, Alessandro; Tresoldi, Cristina; Fleischhauer, Katharina; Ponzoni, Maurilio; Gregori, Silvia; Caligaris Cappio, Federico; Ciceri, Fabio; Bordignon, Claudio; Cignetti, Alessandro; Bondanza, Attilio; Bonini, Chiara.

In: Molecular Therapy, Vol. 21, No. 2, 02.2013, p. 466-475.

Research output: Contribution to journalArticle

Casucci, M, Perna, SK, Falcone, L, Camisa, B, Magnani, Z, Bernardi, M, Crotta, A, Tresoldi, C, Fleischhauer, K, Ponzoni, M, Gregori, S, Caligaris Cappio, F, Ciceri, F, Bordignon, C, Cignetti, A, Bondanza, A & Bonini, C 2013, 'Graft-versus-leukemia effect of HLA-haploidentical central-memory t-cells expanded with leukemic APCs and modified with a suicide gene', Molecular Therapy, vol. 21, no. 2, pp. 466-475. https://doi.org/10.1038/mt.2012.227
Casucci, Monica ; Perna, Serena Kimi ; Falcone, Laura ; Camisa, Barbara ; Magnani, Zulma ; Bernardi, Massimo ; Crotta, Alessandro ; Tresoldi, Cristina ; Fleischhauer, Katharina ; Ponzoni, Maurilio ; Gregori, Silvia ; Caligaris Cappio, Federico ; Ciceri, Fabio ; Bordignon, Claudio ; Cignetti, Alessandro ; Bondanza, Attilio ; Bonini, Chiara. / Graft-versus-leukemia effect of HLA-haploidentical central-memory t-cells expanded with leukemic APCs and modified with a suicide gene. In: Molecular Therapy. 2013 ; Vol. 21, No. 2. pp. 466-475.
@article{d7a5941d29d94635adac0e4defeba1a3,
title = "Graft-versus-leukemia effect of HLA-haploidentical central-memory t-cells expanded with leukemic APCs and modified with a suicide gene",
abstract = "Allogeneic hematopoietic stem cell transplantation (HSCT) from a human leukocyte antigen (HLA)-haploidentical family donor (haplo-HSCT) is a readily available and potentially curative option for high-risk leukemia. In haplo-HSCT, alloreactivity plays a major role in the graft-versus-leukemia (GVL) effect, which, however, is frequently followed by relapse due to emerging leukemic cell variants that have lost the unshared HLA haplotype as a mechanism of immune escape. We report that stimulation of HLA-haploidentical donor T lymphocytes with leukemic antigen-presenting cells (L-APCs) expands a population of leukemia-reactive T cells, which, besides alloreactivity to unshared HLAs, contain leukemia-associated specificities restricted by shared HLAs. According to a preferential central-memory (T CM) phenotype and to high interleukin (IL)-7Rα expression, these T cells persist in vivo and sustain a major GVL effect in a clinically relevant xenograft model. Moreover, we demonstrate that modifying L-APC-expanded T cells to express the herpes simplex virus thymidine kinase (HSV-tk) suicide gene enables their elimination with the prodrug ganciclovir (GCV), therefore providing a safety switch in case of graft-versus-host disease (GVHD). These results warrant the clinical investigation of L-APC-expanded T cells modified with a suicide gene in the setting of haplo-HSCT.",
author = "Monica Casucci and Perna, {Serena Kimi} and Laura Falcone and Barbara Camisa and Zulma Magnani and Massimo Bernardi and Alessandro Crotta and Cristina Tresoldi and Katharina Fleischhauer and Maurilio Ponzoni and Silvia Gregori and {Caligaris Cappio}, Federico and Fabio Ciceri and Claudio Bordignon and Alessandro Cignetti and Attilio Bondanza and Chiara Bonini",
year = "2013",
month = "2",
doi = "10.1038/mt.2012.227",
language = "English",
volume = "21",
pages = "466--475",
journal = "Molecular Therapy",
issn = "1525-0016",
publisher = "Nature Publishing Group",
number = "2",

}

TY - JOUR

T1 - Graft-versus-leukemia effect of HLA-haploidentical central-memory t-cells expanded with leukemic APCs and modified with a suicide gene

AU - Casucci, Monica

AU - Perna, Serena Kimi

AU - Falcone, Laura

AU - Camisa, Barbara

AU - Magnani, Zulma

AU - Bernardi, Massimo

AU - Crotta, Alessandro

AU - Tresoldi, Cristina

AU - Fleischhauer, Katharina

AU - Ponzoni, Maurilio

AU - Gregori, Silvia

AU - Caligaris Cappio, Federico

AU - Ciceri, Fabio

AU - Bordignon, Claudio

AU - Cignetti, Alessandro

AU - Bondanza, Attilio

AU - Bonini, Chiara

PY - 2013/2

Y1 - 2013/2

N2 - Allogeneic hematopoietic stem cell transplantation (HSCT) from a human leukocyte antigen (HLA)-haploidentical family donor (haplo-HSCT) is a readily available and potentially curative option for high-risk leukemia. In haplo-HSCT, alloreactivity plays a major role in the graft-versus-leukemia (GVL) effect, which, however, is frequently followed by relapse due to emerging leukemic cell variants that have lost the unshared HLA haplotype as a mechanism of immune escape. We report that stimulation of HLA-haploidentical donor T lymphocytes with leukemic antigen-presenting cells (L-APCs) expands a population of leukemia-reactive T cells, which, besides alloreactivity to unshared HLAs, contain leukemia-associated specificities restricted by shared HLAs. According to a preferential central-memory (T CM) phenotype and to high interleukin (IL)-7Rα expression, these T cells persist in vivo and sustain a major GVL effect in a clinically relevant xenograft model. Moreover, we demonstrate that modifying L-APC-expanded T cells to express the herpes simplex virus thymidine kinase (HSV-tk) suicide gene enables their elimination with the prodrug ganciclovir (GCV), therefore providing a safety switch in case of graft-versus-host disease (GVHD). These results warrant the clinical investigation of L-APC-expanded T cells modified with a suicide gene in the setting of haplo-HSCT.

AB - Allogeneic hematopoietic stem cell transplantation (HSCT) from a human leukocyte antigen (HLA)-haploidentical family donor (haplo-HSCT) is a readily available and potentially curative option for high-risk leukemia. In haplo-HSCT, alloreactivity plays a major role in the graft-versus-leukemia (GVL) effect, which, however, is frequently followed by relapse due to emerging leukemic cell variants that have lost the unshared HLA haplotype as a mechanism of immune escape. We report that stimulation of HLA-haploidentical donor T lymphocytes with leukemic antigen-presenting cells (L-APCs) expands a population of leukemia-reactive T cells, which, besides alloreactivity to unshared HLAs, contain leukemia-associated specificities restricted by shared HLAs. According to a preferential central-memory (T CM) phenotype and to high interleukin (IL)-7Rα expression, these T cells persist in vivo and sustain a major GVL effect in a clinically relevant xenograft model. Moreover, we demonstrate that modifying L-APC-expanded T cells to express the herpes simplex virus thymidine kinase (HSV-tk) suicide gene enables their elimination with the prodrug ganciclovir (GCV), therefore providing a safety switch in case of graft-versus-host disease (GVHD). These results warrant the clinical investigation of L-APC-expanded T cells modified with a suicide gene in the setting of haplo-HSCT.

UR - http://www.scopus.com/inward/record.url?scp=84873341771&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84873341771&partnerID=8YFLogxK

U2 - 10.1038/mt.2012.227

DO - 10.1038/mt.2012.227

M3 - Article

C2 - 23299798

AN - SCOPUS:84873341771

VL - 21

SP - 466

EP - 475

JO - Molecular Therapy

JF - Molecular Therapy

SN - 1525-0016

IS - 2

ER -