Interleukin-7 mediates selective expansion of tumor-redirected cytotoxic T lymphocytes (CTLs) without enhancement of regulatory T-cell inhibition.

ABSTRACT: The antitumor activity of chimeric antigen receptor (CAR)-redirected CTLs should be enhanced if it were possible to increase their proliferation and function after adoptive transfer without concomitantly increasing the proliferation and function of regulatory T cells (Treg). Here, we explored whether the lack of IL-7R? in Treg can be exploited by the targeted manipulation of the interleukin-7 (IL-7) cytokine-cytokine receptor axis in CAR-engrafted Epstein-Barr Virus-specific CTLs (EBV-CTLs) to selectively augment their growth and antitumor activity even in the presence of Treg.We generated a bicistronic retroviral vector encoding a GD2-specific CAR and the IL-7R? subunit, expressed the genes in EBV-CTLs, and assessed their capacity to control tumor growth in the presence of Treg in vitro and in vivo when exposed to either interleukin-2 (IL-2) or IL-7 in a neuroblastoma xenograft.We found that IL-7, in sharp contrast with IL-2, supports the proliferation and antitumor activity of IL-7R?.CAR-GD2(+) EBV-CTLs both in vitro and in vivo even in the presence of fully functional Treg.IL-7 selectively favors the survival, proliferation, and effector function of IL-7R?-transgenic/CAR-redirected EBV-CTLs in the presence of Treg both in vitro and in vivo. Thus, IL-7 can have a significant impact in sustaining expansion and persistence of adoptively CAR-redirected CTLs.

SUBMITTER: Perna SK 

PROVIDER: S-EPMC4113428 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature