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

Serena K. Perna, Daria Pagliara, Aruna Mahendravada, Hao Liu, Malcolm K. Brenner, Barbara Savoldo, Gianpietro Dotti

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

Purpose: 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-7Ra 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. Experimental Design: We generated a bicistronic retroviral vector encoding a GD2-specific CAR and the IL-7Rα 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. Results: Wefound that IL-7, in sharp contrast with IL-2, supports the proliferation and antitumor activity of IL-7Rα.CAR-GD2+ EBV-CTLs both in vitro and in vivo even in the presence of fully functional Treg. Conclusions: IL-7 selectively favors the survival, proliferation, and effector function of IL-7Rα-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. Clin Cancer Res; 20(1); 131-9.

Original languageEnglish (US)
Pages (from-to)131-139
Number of pages9
JournalClinical Cancer Research
Volume20
Issue number1
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

Fingerprint

Interleukin-7
Antigen Receptors
Cytotoxic T-Lymphocytes
Regulatory T-Lymphocytes
Human Herpesvirus 4
Neoplasms
Interleukin-2
Cytokine Receptors
Adoptive Transfer
Growth
Neuroblastoma
Heterografts
Research Design
Cytokines
Genes
In Vitro Techniques

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Interleukin-7 mediates selective expansion of tumor-redirected cytotoxic T lymphocytes (CTLs) without enhancement of regulatory T-cell inhibition. / Perna, Serena K.; Pagliara, Daria; Mahendravada, Aruna; Liu, Hao; Brenner, Malcolm K.; Savoldo, Barbara; Dotti, Gianpietro.

In: Clinical Cancer Research, Vol. 20, No. 1, 01.01.2014, p. 131-139.

Research output: Contribution to journalArticle

Perna, Serena K. ; Pagliara, Daria ; Mahendravada, Aruna ; Liu, Hao ; Brenner, Malcolm K. ; Savoldo, Barbara ; Dotti, Gianpietro. / Interleukin-7 mediates selective expansion of tumor-redirected cytotoxic T lymphocytes (CTLs) without enhancement of regulatory T-cell inhibition. In: Clinical Cancer Research. 2014 ; Vol. 20, No. 1. pp. 131-139.
@article{3691e053cf20423494ab5cf37d92acd3,
title = "Interleukin-7 mediates selective expansion of tumor-redirected cytotoxic T lymphocytes (CTLs) without enhancement of regulatory T-cell inhibition",
abstract = "Purpose: 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-7Ra 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. Experimental Design: We generated a bicistronic retroviral vector encoding a GD2-specific CAR and the IL-7Rα 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. Results: Wefound that IL-7, in sharp contrast with IL-2, supports the proliferation and antitumor activity of IL-7Rα.CAR-GD2+ EBV-CTLs both in vitro and in vivo even in the presence of fully functional Treg. Conclusions: IL-7 selectively favors the survival, proliferation, and effector function of IL-7Rα-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. Clin Cancer Res; 20(1); 131-9.",
author = "Perna, {Serena K.} and Daria Pagliara and Aruna Mahendravada and Hao Liu and Brenner, {Malcolm K.} and Barbara Savoldo and Gianpietro Dotti",
year = "2014",
month = "1",
day = "1",
doi = "10.1158/1078-0432.CCR-13-1016",
language = "English (US)",
volume = "20",
pages = "131--139",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "1",

}

TY - JOUR

T1 - Interleukin-7 mediates selective expansion of tumor-redirected cytotoxic T lymphocytes (CTLs) without enhancement of regulatory T-cell inhibition

AU - Perna, Serena K.

AU - Pagliara, Daria

AU - Mahendravada, Aruna

AU - Liu, Hao

AU - Brenner, Malcolm K.

AU - Savoldo, Barbara

AU - Dotti, Gianpietro

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Purpose: 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-7Ra 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. Experimental Design: We generated a bicistronic retroviral vector encoding a GD2-specific CAR and the IL-7Rα 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. Results: Wefound that IL-7, in sharp contrast with IL-2, supports the proliferation and antitumor activity of IL-7Rα.CAR-GD2+ EBV-CTLs both in vitro and in vivo even in the presence of fully functional Treg. Conclusions: IL-7 selectively favors the survival, proliferation, and effector function of IL-7Rα-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. Clin Cancer Res; 20(1); 131-9.

AB - Purpose: 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-7Ra 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. Experimental Design: We generated a bicistronic retroviral vector encoding a GD2-specific CAR and the IL-7Rα 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. Results: Wefound that IL-7, in sharp contrast with IL-2, supports the proliferation and antitumor activity of IL-7Rα.CAR-GD2+ EBV-CTLs both in vitro and in vivo even in the presence of fully functional Treg. Conclusions: IL-7 selectively favors the survival, proliferation, and effector function of IL-7Rα-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. Clin Cancer Res; 20(1); 131-9.

UR - http://www.scopus.com/inward/record.url?scp=84892165951&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84892165951&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-13-1016

DO - 10.1158/1078-0432.CCR-13-1016

M3 - Article

VL - 20

SP - 131

EP - 139

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 1

ER -