Redirecting T cells to glypican-3 with 4-1BB zeta chimeric antigen receptors results in Th1 polarization and potent antitumor activity

Wenpeng Li, Linjie Guo, Purva Rathi, Ekaterina Marinova, Xiuhua Gao, Meng Feng Wu, Hao Liu, Gianpietro Dotti, Stephen Gottschalk, Leonid S. Metelitsa, Andras Heczey

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

T cells engineered to express CD19-specific chimeric antigen receptors (CARs) have shown breakthrough clinical successes in patients with B-cell lymphoid malignancies. However, similar therapeutic efficacy of CAR T cells in solid tumors is yet to be achieved. In this study we systematically evaluated a series of CAR constructs targeting glypican-3 (GPC3), which is selectively expressed on several solid tumors. We compared GPC3-specific CARs that encoded CD3σ (Gz) alone or with costimulatory domains derived from CD28 (G28z), 4-1BB (GBBz), or CD28 and 4-1BB (G28BBz). All GPC3-CARs rendered T cells highly cytotoxic to GPC3-positive hepatocellular carcinoma, hepatoblastoma, and malignant rhabdoid tumor cell lines in vitro. GBBz induced the preferential production of Th1 cytokines (interferon γ/granulocyte macrophage colony-stimulating factor) while G28z preferentially induced Th2 cytokines (interleukin-4/interleukin-10). Inclusion of 4-1BB in G28BBz could only partially ameliorate the Th2-polarizing effect of CD28. 4-1BB induced superior expansion of CAR T cells in vitro and in vivo. T cells expressing GPC3-CARs incorporating CD28, 4-1BB, or both induced sustained tumor regressions in two xenogeneic tumor models. Thus, GBBz CAR endows T cells with superior proliferative potential, potent antitumor activity, and a Th1-biased cytokine profile, justifying further clinical development of GBBz CAR for immunotherapy of GPC3-positive solid tumors.

Original languageEnglish (US)
Pages (from-to)437-448
Number of pages12
JournalHuman Gene Therapy
Volume28
Issue number5
DOIs
StatePublished - May 1 2017
Externally publishedYes

Fingerprint

Glypicans
Antigen Receptors
T-Cell Antigen Receptor
T-Lymphocytes
Neoplasms
Cytokines
Rhabdoid Tumor
Hepatoblastoma
Granulocyte-Macrophage Colony-Stimulating Factor
Tumor Cell Line
Interleukin-4
Interleukin-10
Immunotherapy
Interferons
Hepatocellular Carcinoma
B-Lymphocytes

Keywords

  • chimeric antigen receptor
  • glypican-3
  • hepatoblastoma
  • hepatocellular carcinoma
  • immunotherapy
  • rhabdoid tumor
  • T-cell therapy

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

Redirecting T cells to glypican-3 with 4-1BB zeta chimeric antigen receptors results in Th1 polarization and potent antitumor activity. / Li, Wenpeng; Guo, Linjie; Rathi, Purva; Marinova, Ekaterina; Gao, Xiuhua; Wu, Meng Feng; Liu, Hao; Dotti, Gianpietro; Gottschalk, Stephen; Metelitsa, Leonid S.; Heczey, Andras.

In: Human Gene Therapy, Vol. 28, No. 5, 01.05.2017, p. 437-448.

Research output: Contribution to journalArticle

Li, W, Guo, L, Rathi, P, Marinova, E, Gao, X, Wu, MF, Liu, H, Dotti, G, Gottschalk, S, Metelitsa, LS & Heczey, A 2017, 'Redirecting T cells to glypican-3 with 4-1BB zeta chimeric antigen receptors results in Th1 polarization and potent antitumor activity', Human Gene Therapy, vol. 28, no. 5, pp. 437-448. https://doi.org/10.1089/hum.2016.025
Li, Wenpeng ; Guo, Linjie ; Rathi, Purva ; Marinova, Ekaterina ; Gao, Xiuhua ; Wu, Meng Feng ; Liu, Hao ; Dotti, Gianpietro ; Gottschalk, Stephen ; Metelitsa, Leonid S. ; Heczey, Andras. / Redirecting T cells to glypican-3 with 4-1BB zeta chimeric antigen receptors results in Th1 polarization and potent antitumor activity. In: Human Gene Therapy. 2017 ; Vol. 28, No. 5. pp. 437-448.
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abstract = "T cells engineered to express CD19-specific chimeric antigen receptors (CARs) have shown breakthrough clinical successes in patients with B-cell lymphoid malignancies. However, similar therapeutic efficacy of CAR T cells in solid tumors is yet to be achieved. In this study we systematically evaluated a series of CAR constructs targeting glypican-3 (GPC3), which is selectively expressed on several solid tumors. We compared GPC3-specific CARs that encoded CD3σ (Gz) alone or with costimulatory domains derived from CD28 (G28z), 4-1BB (GBBz), or CD28 and 4-1BB (G28BBz). All GPC3-CARs rendered T cells highly cytotoxic to GPC3-positive hepatocellular carcinoma, hepatoblastoma, and malignant rhabdoid tumor cell lines in vitro. GBBz induced the preferential production of Th1 cytokines (interferon γ/granulocyte macrophage colony-stimulating factor) while G28z preferentially induced Th2 cytokines (interleukin-4/interleukin-10). Inclusion of 4-1BB in G28BBz could only partially ameliorate the Th2-polarizing effect of CD28. 4-1BB induced superior expansion of CAR T cells in vitro and in vivo. T cells expressing GPC3-CARs incorporating CD28, 4-1BB, or both induced sustained tumor regressions in two xenogeneic tumor models. Thus, GBBz CAR endows T cells with superior proliferative potential, potent antitumor activity, and a Th1-biased cytokine profile, justifying further clinical development of GBBz CAR for immunotherapy of GPC3-positive solid tumors.",
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AU - Wu, Meng Feng

AU - Liu, Hao

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AU - Heczey, Andras

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