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In vitro comparison of three different chimeric receptor-modified effector T-cell populations for leukemia cell therapy.
Pizzitola, Irene; Agostoni, Valentina; Cribioli, Elisabetta; Pule, Martin; Rousseau, Raphael; Finney, Helene; Lawson, Alastair; Biondi, Andrea; Biagi, Ettore; Marin, Virna.
Afiliação
  • Pizzitola I; Centro Ricerca M. Tettamanti, Clinica Pediatrica, Ospedale San Gerardo, Università Milano-Bicocca, Monza, Italy.
J Immunother ; 34(6): 469-79, 2011.
Article em En | MEDLINE | ID: mdl-21654519
ABSTRACT
The identification of the optimal T-cell effector subtype is a crucial issue for adoptive cell therapy with chimeric receptor-modified T cells. The ideal T cell population must be able to home toward tumor site, exert prolonged antitumoral activity, and display minimal toxicity against normal tissues. Therefore, we characterized the in vitro antitumoral properties of three effector T-cell populations Epstein-Barr virus-specific cytotoxic T lymphocytes (EBV-CTLs), cytokine-induced killer (CIK) cells, and γ9δ2 T (GDT) cells, after transduction with a chimeric receptor specific for the CD33 antigen, broadly expressed on acute myeloid leukemia cells. EBV-CTLs, CIK, and GDT cells were generated and transduced with high efficiency with a retroviral vector coding for an anti-CD33-ζ chimeric receptor without alterations of their native phenotype. Anti-CD33-ζ chimeric receptor-redirected T cells displayed analogous in vitro chemotactic activity toward CXCL12. In addition, anti-CD33-ζ chimeric receptor-expressing EBV-CTLs, CIK, and GDT cells showed potent and similar cytotoxicity against several CD33⁺ leukemic targets both in short-term 4-hours-5¹chromium-release assays (mean killing vs primary leukemic cells at effectortarget ratio of 51; 50%, 61%, and 50% for EBV-CTLs, CIK, and GDT cells, respectively) and in long-term assays, where they were cocultured with leukemic cells for 6 days on stromal mesenchymal cells (mean survival of primary leukemic cells at effectortarget ratio of 1100; 18%, 16%, and 29% for EBV-CTLs, CIK, and GDT cells, respectively). Moreover, all effector cells acquired consistent capability to proliferate in vitro after contact with CD33⁺ cells and to release high and comparable levels of immunostimulatory cytokines, while secreting similar low amount of immunoregulatory cytokines as the unmanipulated counterpart. Our results indicate that expression of an anti-CD33-ζ chimeric receptor potently and similarly increase the antileukemic functions of different effector T-cell subtypes, underlying the impossibility to identify a more potent T-cell population through in vitro analysis, and consistently with recent observations that have emerged from clinical trials with chimeric receptor-modified T cells, suggesting the need to perform such type of studies in the human setting.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Receptores de Antígenos de Linfócitos T / Linfócitos T / Leucemia / Quimerismo / Terapia Baseada em Transplante de Células e Tecidos Limite: Child / Humans Idioma: En Revista: J Immunother Ano de publicação: 2011 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Receptores de Antígenos de Linfócitos T / Linfócitos T / Leucemia / Quimerismo / Terapia Baseada em Transplante de Células e Tecidos Limite: Child / Humans Idioma: En Revista: J Immunother Ano de publicação: 2011 Tipo de documento: Article