Generation of donor-derived Wilms tumor antigen 1–specific cytotoxic T lymphocytes with potent anti-leukemia activity for somatic cell therapy in children given haploidentical stem cell transplantation: a feasibility pre-clinical study

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Abstract

Background: The Wilms tumor antigen 1 (WT1) is over-expressed in a vast majority of adult and childhood acute leukemia and myelodysplastic syndromes, being lowly or transiently expressed in normal tissues and hematopoietic stem cells (HSCs). A number of HLA-restricted WT1 epitopes are immunogenic, allowing the in vitro induction of WT1-specific cytotoxic T lymphocytes (CTLs) from patients and healthy donors. Aim: The aim of the study was to investigate the feasibility of producing WT1-specific CTLs suitable for somatic cell therapy to prevent or treat relapse in children with acute myeloid or lymphoblastic leukemia given haploidentical HSC transplantation (haplo-HSCT). Methods: For WT1-specific CTL production, donor-derived either peripheral blood mononuclear cells (PBMCs) or CD8+ lymphocytes were stimulated with WT1 peptide-loaded donor dendritic cells in the presence of interleukin (IL)-7 and IL-12. Effector cells were re-stimulated once with irradiated donor PBMCs pulsed with WT1-peptides, and then expanded in an antigen-independent way. Results: WT1-specific CTLs, displaying high-level cytotoxicity against patients’ leukemia blasts and negligible activity against patients’ non-malignant cells, were obtained from both PBMCs and CD8+ lymphocytes. WT1-specific CTLs obtained from PBMCs showed a better expansion capacity and better anti-leukemia activity than those obtained from CD8+ lymphocytes, even though the difference was not statistically significant. In CTLs derived from PBMCs, both CD8+ and CD4+ subpopulations displayed strong anti-leukemia cytotoxic activity. Discussion: Results of this pre-clinical study pave the way to a somatic cell therapy approach aimed at preventing or treating relapse in children given haplo-HSCT for WT1-positive leukemia.

Original languageEnglish
JournalCytotherapy
DOIs
Publication statusPublished - Jan 1 2019

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Wilms Tumor
Stem Cell Transplantation
Cytotoxic T-Lymphocytes
Neoplasm Antigens
Cell- and Tissue-Based Therapy
Leukemia
Tissue Donors
Blood Cells
Lymphocytes
Clinical Studies
Recurrence
Interleukin-7
Peptides
Hematopoietic Stem Cell Transplantation
Myelodysplastic Syndromes
Interleukin-12
Hematopoietic Stem Cells
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Acute Myeloid Leukemia
Dendritic Cells

Keywords

  • acute leukemia
  • allogeneic hematopoietic stem cell transplantation
  • anti-tumor immunotherapy
  • cytotoxic T lymphocytes
  • somatic cell therapy
  • Wilms tumor antigen 1

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology
  • Genetics(clinical)
  • Cell Biology
  • Transplantation
  • Cancer Research

Cite this

@article{12cf29450e46404d92333ca34ac11d4a,
title = "Generation of donor-derived Wilms tumor antigen 1–specific cytotoxic T lymphocytes with potent anti-leukemia activity for somatic cell therapy in children given haploidentical stem cell transplantation: a feasibility pre-clinical study",
abstract = "Background: The Wilms tumor antigen 1 (WT1) is over-expressed in a vast majority of adult and childhood acute leukemia and myelodysplastic syndromes, being lowly or transiently expressed in normal tissues and hematopoietic stem cells (HSCs). A number of HLA-restricted WT1 epitopes are immunogenic, allowing the in vitro induction of WT1-specific cytotoxic T lymphocytes (CTLs) from patients and healthy donors. Aim: The aim of the study was to investigate the feasibility of producing WT1-specific CTLs suitable for somatic cell therapy to prevent or treat relapse in children with acute myeloid or lymphoblastic leukemia given haploidentical HSC transplantation (haplo-HSCT). Methods: For WT1-specific CTL production, donor-derived either peripheral blood mononuclear cells (PBMCs) or CD8+ lymphocytes were stimulated with WT1 peptide-loaded donor dendritic cells in the presence of interleukin (IL)-7 and IL-12. Effector cells were re-stimulated once with irradiated donor PBMCs pulsed with WT1-peptides, and then expanded in an antigen-independent way. Results: WT1-specific CTLs, displaying high-level cytotoxicity against patients’ leukemia blasts and negligible activity against patients’ non-malignant cells, were obtained from both PBMCs and CD8+ lymphocytes. WT1-specific CTLs obtained from PBMCs showed a better expansion capacity and better anti-leukemia activity than those obtained from CD8+ lymphocytes, even though the difference was not statistically significant. In CTLs derived from PBMCs, both CD8+ and CD4+ subpopulations displayed strong anti-leukemia cytotoxic activity. Discussion: Results of this pre-clinical study pave the way to a somatic cell therapy approach aimed at preventing or treating relapse in children given haplo-HSCT for WT1-positive leukemia.",
keywords = "acute leukemia, allogeneic hematopoietic stem cell transplantation, anti-tumor immunotherapy, cytotoxic T lymphocytes, somatic cell therapy, Wilms tumor antigen 1",
author = "FEDERICA FERULLI and MATTEO TANZI and ILARIA TURIN and ENRICA MONTINI and VITTORIO ROSTI and GLORIA ACQUAFREDDA and DANIELA LISINI and FRANCESCA COMPAGNO and STELLA BOGHEN and AMELIA LICARI and GIANLUIGI MARSEGLIA and M. ZECCA and DANIELA MONTAGNA",
year = "2019",
month = "1",
day = "1",
doi = "10.1016/j.jcyt.2019.06.007",
language = "English",
journal = "Cytotherapy",
issn = "1465-3249",
publisher = "Informa Healthcare",

}

TY - JOUR

T1 - Generation of donor-derived Wilms tumor antigen 1–specific cytotoxic T lymphocytes with potent anti-leukemia activity for somatic cell therapy in children given haploidentical stem cell transplantation

T2 - a feasibility pre-clinical study

AU - FERULLI, FEDERICA

AU - TANZI, MATTEO

AU - TURIN, ILARIA

AU - MONTINI, ENRICA

AU - ROSTI, VITTORIO

AU - ACQUAFREDDA, GLORIA

AU - LISINI, DANIELA

AU - COMPAGNO, FRANCESCA

AU - BOGHEN, STELLA

AU - LICARI, AMELIA

AU - MARSEGLIA, GIANLUIGI

AU - ZECCA, M.

AU - MONTAGNA, DANIELA

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Background: The Wilms tumor antigen 1 (WT1) is over-expressed in a vast majority of adult and childhood acute leukemia and myelodysplastic syndromes, being lowly or transiently expressed in normal tissues and hematopoietic stem cells (HSCs). A number of HLA-restricted WT1 epitopes are immunogenic, allowing the in vitro induction of WT1-specific cytotoxic T lymphocytes (CTLs) from patients and healthy donors. Aim: The aim of the study was to investigate the feasibility of producing WT1-specific CTLs suitable for somatic cell therapy to prevent or treat relapse in children with acute myeloid or lymphoblastic leukemia given haploidentical HSC transplantation (haplo-HSCT). Methods: For WT1-specific CTL production, donor-derived either peripheral blood mononuclear cells (PBMCs) or CD8+ lymphocytes were stimulated with WT1 peptide-loaded donor dendritic cells in the presence of interleukin (IL)-7 and IL-12. Effector cells were re-stimulated once with irradiated donor PBMCs pulsed with WT1-peptides, and then expanded in an antigen-independent way. Results: WT1-specific CTLs, displaying high-level cytotoxicity against patients’ leukemia blasts and negligible activity against patients’ non-malignant cells, were obtained from both PBMCs and CD8+ lymphocytes. WT1-specific CTLs obtained from PBMCs showed a better expansion capacity and better anti-leukemia activity than those obtained from CD8+ lymphocytes, even though the difference was not statistically significant. In CTLs derived from PBMCs, both CD8+ and CD4+ subpopulations displayed strong anti-leukemia cytotoxic activity. Discussion: Results of this pre-clinical study pave the way to a somatic cell therapy approach aimed at preventing or treating relapse in children given haplo-HSCT for WT1-positive leukemia.

AB - Background: The Wilms tumor antigen 1 (WT1) is over-expressed in a vast majority of adult and childhood acute leukemia and myelodysplastic syndromes, being lowly or transiently expressed in normal tissues and hematopoietic stem cells (HSCs). A number of HLA-restricted WT1 epitopes are immunogenic, allowing the in vitro induction of WT1-specific cytotoxic T lymphocytes (CTLs) from patients and healthy donors. Aim: The aim of the study was to investigate the feasibility of producing WT1-specific CTLs suitable for somatic cell therapy to prevent or treat relapse in children with acute myeloid or lymphoblastic leukemia given haploidentical HSC transplantation (haplo-HSCT). Methods: For WT1-specific CTL production, donor-derived either peripheral blood mononuclear cells (PBMCs) or CD8+ lymphocytes were stimulated with WT1 peptide-loaded donor dendritic cells in the presence of interleukin (IL)-7 and IL-12. Effector cells were re-stimulated once with irradiated donor PBMCs pulsed with WT1-peptides, and then expanded in an antigen-independent way. Results: WT1-specific CTLs, displaying high-level cytotoxicity against patients’ leukemia blasts and negligible activity against patients’ non-malignant cells, were obtained from both PBMCs and CD8+ lymphocytes. WT1-specific CTLs obtained from PBMCs showed a better expansion capacity and better anti-leukemia activity than those obtained from CD8+ lymphocytes, even though the difference was not statistically significant. In CTLs derived from PBMCs, both CD8+ and CD4+ subpopulations displayed strong anti-leukemia cytotoxic activity. Discussion: Results of this pre-clinical study pave the way to a somatic cell therapy approach aimed at preventing or treating relapse in children given haplo-HSCT for WT1-positive leukemia.

KW - acute leukemia

KW - allogeneic hematopoietic stem cell transplantation

KW - anti-tumor immunotherapy

KW - cytotoxic T lymphocytes

KW - somatic cell therapy

KW - Wilms tumor antigen 1

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U2 - 10.1016/j.jcyt.2019.06.007

DO - 10.1016/j.jcyt.2019.06.007

M3 - Article

AN - SCOPUS:85068256016

JO - Cytotherapy

JF - Cytotherapy

SN - 1465-3249

ER -