title: Genetic manipulation of tumor-specific cytotoxic T lymphocytes to restore responsiveness to IL-7.
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 alpha chain (IL-7Ralpha) by CTLs precludes their response to this cytokine. We found that CTLs can be genetically modified to re-express IL-7Ralpha, 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 gamma (gammac) chain cytokines. This approach may allow selective expansion of CTLs without the unwanted effects associated with IL-2.
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, The Methodist Hospital, Houston, Texas 77030, USA.
authors.forename: Juan F
authors.initials: JF
authors.lastname: Vera
authors.forename: Valentina
authors.initials: V
authors.lastname: Hoyos
authors.forename: Barbara
authors.initials: B
authors.lastname: Savoldo
authors.forename: Concetta
authors.initials: C
authors.lastname: Quintarelli
authors.forename: Greta M P
authors.initials: GM
authors.lastname: Giordano Attianese
authors.forename: Ann M
authors.initials: AM
authors.lastname: Leen
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.forename: Aaron E
authors.initials: AE
authors.lastname: Foster
authors.forename: Helen E
authors.initials: HE
authors.lastname: Heslop
authors.forename: Cliona M
authors.initials: CM
authors.lastname: Rooney
authors.forename: Malcolm K
authors.initials: MK
authors.lastname: Brenner
authors.forename: Gianpietro
authors.initials: G
authors.lastname: Dotti
mesh_terms: D000818:Animals; D002460:Cell Line; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007376:Interleukin-2 / Q000276:immunology; D015851:Interleukin-7 / Q000276:immunology*; D051379:Mice; D016513:Mice, SCID; D051381:Rats; D017207:Rats, Sprague-Dawley; D020395:Receptors, Interleukin-7 / Q000235:genetics / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism*
chemical_list: D007376:Interleukin-2; D015851:Interleukin-7; D020395:Receptors, Interleukin-7; C415350:interleukin-7 receptor, alpha chain