Genetic manipulation of tumor-specific cytotoxic T lymphocytes to restore responsiveness to IL-7

Juan F. Vera, Valentina Hoyos, Barbara Savoldo, Concetta Quintarelli, Greta M.P. Giordano Attianese, Ann M. Leen, Hao Liu, Aaron E. Foster, Helen E. Heslop, Cliona M. Rooney, Malcolm K. Brenner, Gianpietro Dotti

Research output: Contribution to journalArticle

69 Citations (Scopus)

Abstract

Adoptive transfer of antigen-specific cytotoxic T lymphocytes (CTLs) can induce objective clinical responses in patients with malignant diseases. The option of providing a proliferative and survival advantage to adoptively transferred CTLs remains a challenge to improve their efficacy. Host lymphodepletion and administration of recombinant interleukin-2 (IL-2) are currently used to improve CTL survival and expansion after adoptive transfer, but these approaches are frequently associated with significant side effects and may increase proliferation of T regulatory cells. IL-7 is a crucial homeostatic cytokine that has been safely administered as a recombinant protein. However, while IL-7 induces robust expansion of naive and memory T lymphocytes, the lack of expression of the IL-7 receptor α chain (IL-7Rα) by CTLs precludes their response to this cytokine. We found that CTLs can be genetically modified to re-express IL-7Rα, and that this manipulation restores the response of these cells to IL-7 without apparent modification of their antigen specificity or dependency, and without changing their response to other common γ (γc) chain cytokines. This approach may allow selective expansion of CTLs without the unwanted effects associated with IL-2.

Original languageEnglish (US)
Pages (from-to)880-888
Number of pages9
JournalMolecular Therapy
Volume17
Issue number5
DOIs
StatePublished - Mar 4 2009
Externally publishedYes

Fingerprint

Interleukin-7
Cytotoxic T-Lymphocytes
Interleukin-7 Receptors
Neoplasms
Adoptive Transfer
Cytokines
Interleukin-2
Antigens
Regulatory T-Lymphocytes
Recombinant Proteins
T-Lymphocytes
Survival

ASJC Scopus subject areas

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

Cite this

Vera, J. F., Hoyos, V., Savoldo, B., Quintarelli, C., Giordano Attianese, G. M. P., Leen, A. M., ... Dotti, G. (2009). Genetic manipulation of tumor-specific cytotoxic T lymphocytes to restore responsiveness to IL-7. Molecular Therapy, 17(5), 880-888. https://doi.org/10.1038/mt.2009.34

Genetic manipulation of tumor-specific cytotoxic T lymphocytes to restore responsiveness to IL-7. / Vera, Juan F.; Hoyos, Valentina; Savoldo, Barbara; Quintarelli, Concetta; Giordano Attianese, Greta M.P.; Leen, Ann M.; Liu, Hao; Foster, Aaron E.; Heslop, Helen E.; Rooney, Cliona M.; Brenner, Malcolm K.; Dotti, Gianpietro.

In: Molecular Therapy, Vol. 17, No. 5, 04.03.2009, p. 880-888.

Research output: Contribution to journalArticle

Vera, JF, Hoyos, V, Savoldo, B, Quintarelli, C, Giordano Attianese, GMP, Leen, AM, Liu, H, Foster, AE, Heslop, HE, Rooney, CM, Brenner, MK & Dotti, G 2009, 'Genetic manipulation of tumor-specific cytotoxic T lymphocytes to restore responsiveness to IL-7', Molecular Therapy, vol. 17, no. 5, pp. 880-888. https://doi.org/10.1038/mt.2009.34
Vera JF, Hoyos V, Savoldo B, Quintarelli C, Giordano Attianese GMP, Leen AM et al. Genetic manipulation of tumor-specific cytotoxic T lymphocytes to restore responsiveness to IL-7. Molecular Therapy. 2009 Mar 4;17(5):880-888. https://doi.org/10.1038/mt.2009.34
Vera, Juan F. ; Hoyos, Valentina ; Savoldo, Barbara ; Quintarelli, Concetta ; Giordano Attianese, Greta M.P. ; Leen, Ann M. ; Liu, Hao ; Foster, Aaron E. ; Heslop, Helen E. ; Rooney, Cliona M. ; Brenner, Malcolm K. ; Dotti, Gianpietro. / Genetic manipulation of tumor-specific cytotoxic T lymphocytes to restore responsiveness to IL-7. In: Molecular Therapy. 2009 ; Vol. 17, No. 5. pp. 880-888.
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