Cytotoxic T lymphocytes directed to the preferentially expressed antigen of melanoma (PRAME) target chronic myeloid leukemia

Concetta Quintarelli, Gianpietro Dotti, Biagio De Angelis, Valentina Hoyos, Martha Mims, Luigia Luciano, Helen E. Heslop, Cliona M. Rooney, Fabrizio Pane, Barbara Savoldo

Research output: Contribution to journalArticle

Abstract

The cancer testis antigen (CTA) preferentially expressed antigen of melanoma (PRAME) is overexpressed in many hematologic malignancies, including chronic myeloid leukemia (CML). The sensitivity of CML to donor lymphocyte infusion after allogeneic stem cell transplantation suggests this tumor can be highly susceptible to cellular immunotherapy targeted to tumor associated antigens. We therefore tested whether functional PRAME-specific cytotoxic T lymphocytes (PRAME CTLs) could be generated and expanded from healthy donors and CML patients, or whether the limited immunogenicity of this CTA coupled with tumor-associated anergy would preclude this approach. Using optimized culture conditions and HLA-A*02-restricted PRAME-peptides, we have consistently generated PRAME CTLs from 8/9 healthy donors and 5/6 CML patients. These CTLs released IFN7 in response to PRAME peptides (between 113 ± 8 and 795 ± 23 spot forming cells/10 5 T cells) and lysed PRAME peptideloaded cells (45 ± 19% at an effector: target [E:T] ratio of 20:1) in a MHC-restricted fashion. Importantly, these CTLs recognized and had cytotoxic activity against HLA-A*02 +/PRAME + tumor cell lines, and could recognize and respond to primary CML cells. PRAME CTLs were generated almost exclusively from the naive T-cell compartment, and clonal analysis showed these cells could have high αβTCR-peptide avidity. PRAME CTLs or vaccines may thus be of value for patients with CML.

Original languageEnglish
Pages (from-to)1876-1885
Number of pages10
JournalBlood
Volume112
Issue number5
DOIs
Publication statusPublished - Sep 1 2008

Fingerprint

Melanoma-Specific Antigens
T-cells
Cytotoxic T-Lymphocytes
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Tumors
HLA-A Antigens
Testicular Neoplasms
Tissue Donors
Antigens
Peptides
T-Lymphocytes
Lymphocytes
Stem Cell Transplantation
Neoplasm Antigens
Hematologic Neoplasms
Myeloid Cells
Stem cells
Tumor Cell Line
Immunotherapy
Neoplasms

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Cytotoxic T lymphocytes directed to the preferentially expressed antigen of melanoma (PRAME) target chronic myeloid leukemia. / Quintarelli, Concetta; Dotti, Gianpietro; De Angelis, Biagio; Hoyos, Valentina; Mims, Martha; Luciano, Luigia; Heslop, Helen E.; Rooney, Cliona M.; Pane, Fabrizio; Savoldo, Barbara.

In: Blood, Vol. 112, No. 5, 01.09.2008, p. 1876-1885.

Research output: Contribution to journalArticle

Quintarelli, Concetta ; Dotti, Gianpietro ; De Angelis, Biagio ; Hoyos, Valentina ; Mims, Martha ; Luciano, Luigia ; Heslop, Helen E. ; Rooney, Cliona M. ; Pane, Fabrizio ; Savoldo, Barbara. / Cytotoxic T lymphocytes directed to the preferentially expressed antigen of melanoma (PRAME) target chronic myeloid leukemia. In: Blood. 2008 ; Vol. 112, No. 5. pp. 1876-1885.
@article{d9bde18d36b04157bbd5e13d9f6b8fba,
title = "Cytotoxic T lymphocytes directed to the preferentially expressed antigen of melanoma (PRAME) target chronic myeloid leukemia",
abstract = "The cancer testis antigen (CTA) preferentially expressed antigen of melanoma (PRAME) is overexpressed in many hematologic malignancies, including chronic myeloid leukemia (CML). The sensitivity of CML to donor lymphocyte infusion after allogeneic stem cell transplantation suggests this tumor can be highly susceptible to cellular immunotherapy targeted to tumor associated antigens. We therefore tested whether functional PRAME-specific cytotoxic T lymphocytes (PRAME CTLs) could be generated and expanded from healthy donors and CML patients, or whether the limited immunogenicity of this CTA coupled with tumor-associated anergy would preclude this approach. Using optimized culture conditions and HLA-A*02-restricted PRAME-peptides, we have consistently generated PRAME CTLs from 8/9 healthy donors and 5/6 CML patients. These CTLs released IFN7 in response to PRAME peptides (between 113 ± 8 and 795 ± 23 spot forming cells/10 5 T cells) and lysed PRAME peptideloaded cells (45 ± 19{\%} at an effector: target [E:T] ratio of 20:1) in a MHC-restricted fashion. Importantly, these CTLs recognized and had cytotoxic activity against HLA-A*02 +/PRAME + tumor cell lines, and could recognize and respond to primary CML cells. PRAME CTLs were generated almost exclusively from the naive T-cell compartment, and clonal analysis showed these cells could have high αβTCR-peptide avidity. PRAME CTLs or vaccines may thus be of value for patients with CML.",
author = "Concetta Quintarelli and Gianpietro Dotti and {De Angelis}, Biagio and Valentina Hoyos and Martha Mims and Luigia Luciano and Heslop, {Helen E.} and Rooney, {Cliona M.} and Fabrizio Pane and Barbara Savoldo",
year = "2008",
month = "9",
day = "1",
doi = "10.1182/blood-2008-04-150045",
language = "English",
volume = "112",
pages = "1876--1885",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "5",

}

TY - JOUR

T1 - Cytotoxic T lymphocytes directed to the preferentially expressed antigen of melanoma (PRAME) target chronic myeloid leukemia

AU - Quintarelli, Concetta

AU - Dotti, Gianpietro

AU - De Angelis, Biagio

AU - Hoyos, Valentina

AU - Mims, Martha

AU - Luciano, Luigia

AU - Heslop, Helen E.

AU - Rooney, Cliona M.

AU - Pane, Fabrizio

AU - Savoldo, Barbara

PY - 2008/9/1

Y1 - 2008/9/1

N2 - The cancer testis antigen (CTA) preferentially expressed antigen of melanoma (PRAME) is overexpressed in many hematologic malignancies, including chronic myeloid leukemia (CML). The sensitivity of CML to donor lymphocyte infusion after allogeneic stem cell transplantation suggests this tumor can be highly susceptible to cellular immunotherapy targeted to tumor associated antigens. We therefore tested whether functional PRAME-specific cytotoxic T lymphocytes (PRAME CTLs) could be generated and expanded from healthy donors and CML patients, or whether the limited immunogenicity of this CTA coupled with tumor-associated anergy would preclude this approach. Using optimized culture conditions and HLA-A*02-restricted PRAME-peptides, we have consistently generated PRAME CTLs from 8/9 healthy donors and 5/6 CML patients. These CTLs released IFN7 in response to PRAME peptides (between 113 ± 8 and 795 ± 23 spot forming cells/10 5 T cells) and lysed PRAME peptideloaded cells (45 ± 19% at an effector: target [E:T] ratio of 20:1) in a MHC-restricted fashion. Importantly, these CTLs recognized and had cytotoxic activity against HLA-A*02 +/PRAME + tumor cell lines, and could recognize and respond to primary CML cells. PRAME CTLs were generated almost exclusively from the naive T-cell compartment, and clonal analysis showed these cells could have high αβTCR-peptide avidity. PRAME CTLs or vaccines may thus be of value for patients with CML.

AB - The cancer testis antigen (CTA) preferentially expressed antigen of melanoma (PRAME) is overexpressed in many hematologic malignancies, including chronic myeloid leukemia (CML). The sensitivity of CML to donor lymphocyte infusion after allogeneic stem cell transplantation suggests this tumor can be highly susceptible to cellular immunotherapy targeted to tumor associated antigens. We therefore tested whether functional PRAME-specific cytotoxic T lymphocytes (PRAME CTLs) could be generated and expanded from healthy donors and CML patients, or whether the limited immunogenicity of this CTA coupled with tumor-associated anergy would preclude this approach. Using optimized culture conditions and HLA-A*02-restricted PRAME-peptides, we have consistently generated PRAME CTLs from 8/9 healthy donors and 5/6 CML patients. These CTLs released IFN7 in response to PRAME peptides (between 113 ± 8 and 795 ± 23 spot forming cells/10 5 T cells) and lysed PRAME peptideloaded cells (45 ± 19% at an effector: target [E:T] ratio of 20:1) in a MHC-restricted fashion. Importantly, these CTLs recognized and had cytotoxic activity against HLA-A*02 +/PRAME + tumor cell lines, and could recognize and respond to primary CML cells. PRAME CTLs were generated almost exclusively from the naive T-cell compartment, and clonal analysis showed these cells could have high αβTCR-peptide avidity. PRAME CTLs or vaccines may thus be of value for patients with CML.

UR - http://www.scopus.com/inward/record.url?scp=52649135956&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=52649135956&partnerID=8YFLogxK

U2 - 10.1182/blood-2008-04-150045

DO - 10.1182/blood-2008-04-150045

M3 - Article

C2 - 18591381

AN - SCOPUS:52649135956

VL - 112

SP - 1876

EP - 1885

JO - Blood

JF - Blood

SN - 0006-4971

IS - 5

ER -