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 journalArticlepeer-review

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
Pages (from-to)880-888
Number of pages9
JournalMolecular Therapy
Volume17
Issue number5
DOIs
Publication statusPublished - 2009

ASJC Scopus subject areas

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

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