title: Redirecting T Cells to Glypican-3 with 4-1BB Zeta Chimeric Antigen Receptors Results in Th1 Polarization and Potent Antitumor Activity.
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 CD3ζ (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.
authors.affiliation: 1 Texas Children's Cancer Center, Texas Children's Hospital, Houston, Texas.|2 Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, and Baylor College of Medicine, Houston, Texas.|3 Department of Pediatrics, Houston, Texas.
authors.forename: Wenpeng
authors.initials: W
authors.lastname: Li
authors.affiliation: 1 Texas Children's Cancer Center, Texas Children's Hospital, Houston, Texas.|2 Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, and Baylor College of Medicine, Houston, Texas.|3 Department of Pediatrics, Houston, Texas.
authors.forename: Linjie
authors.initials: L
authors.lastname: Guo
authors.affiliation: 4 Biostatistics Shared Resource, Dan L Duncan Comprehensive Cancer Center, Houston, Texas.
authors.forename: Purva
authors.initials: P
authors.lastname: Rathi
authors.affiliation: 1 Texas Children's Cancer Center, Texas Children's Hospital, Houston, Texas.|2 Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, and Baylor College of Medicine, Houston, Texas.|3 Department of Pediatrics, Houston, Texas.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Marinova
authors.affiliation: 1 Texas Children's Cancer Center, Texas Children's Hospital, Houston, Texas.|2 Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, and Baylor College of Medicine, Houston, Texas.|3 Department of Pediatrics, Houston, Texas.
authors.forename: Xiuhua
authors.initials: X
authors.lastname: Gao
authors.affiliation: 4 Biostatistics Shared Resource, Dan L Duncan Comprehensive Cancer Center, Houston, Texas.
authors.forename: Meng-Feng
authors.initials: MF
authors.lastname: Wu
authors.affiliation: 4 Biostatistics Shared Resource, Dan L Duncan Comprehensive Cancer Center, Houston, Texas.
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.affiliation: 5 Department of Microbiology and Immunology, University of North Carolina , Chapel Hill, North Carolina.
authors.forename: Gianpietro
authors.initials: G
authors.lastname: Dotti
authors.affiliation: 1 Texas Children's Cancer Center, Texas Children's Hospital, Houston, Texas.|2 Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, and Baylor College of Medicine, Houston, Texas.|3 Department of Pediatrics, Houston, Texas.|6 Department of Pathology and Immunology; Baylor College of Medicine, Houston, Texas.
authors.forename: Stephen
authors.initials: S
authors.lastname: Gottschalk
authors.affiliation: 1 Texas Children's Cancer Center, Texas Children's Hospital, Houston, Texas.|2 Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, and Baylor College of Medicine, Houston, Texas.|3 Department of Pediatrics, Houston, Texas.|6 Department of Pathology and Immunology; Baylor College of Medicine, Houston, Texas.
authors.forename: Leonid S
authors.initials: LS
authors.lastname: Metelitsa
authors.affiliation: 1 Texas Children's Cancer Center, Texas Children's Hospital, Houston, Texas.|2 Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, and Baylor College of Medicine, Houston, Texas.|3 Department of Pediatrics, Houston, Texas.|4 Biostatistics Shared Resource, Dan L Duncan Comprehensive Cancer Center, Houston, Texas.
authors.forename: Andras
authors.initials: A
authors.lastname: Heczey
mesh_terms: D000818:Animals; D018941:Antigens, CD19 / Q000235:genetics / Q000627:therapeutic use; D018106:CD28 Antigens / Q000235:genetics* / Q000627:therapeutic use; D016764:Cell Polarity / Q000276:immunology; D053673:Glypicans / Q000235:genetics* / Q000627:therapeutic use; D006801:Humans; D007167:Immunotherapy; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D051379:Mice; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000276:immunology / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000235:genetics* / Q000276:immunology / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D018941:Antigens, CD19; D018106:CD28 Antigens; D053673:Glypicans; D011948:Receptors, Antigen, T-Cell; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9
keywords: T-cell therapy; chimeric antigen receptor; glypican-3; hepatoblastoma; hepatocellular carcinoma; immunotherapy; rhabdoid tumor