title: A fully human chimeric antigen receptor with potent activity against cancer cells but reduced risk for off-tumor toxicity.
abstract: Chimeric antigen receptors (CARs) can redirect T cells against antigen-expressing tumors in an HLA-independent manner. To date, various CARs have been constructed using mouse single chain antibody variable fragments (scFvs) of high affinity that are immunogenic in humans and have the potential to mediate "on-target" toxicity. Here, we developed and evaluated a fully human CAR comprised of the human C4 folate receptor-alpha (αFR)-specific scFv coupled to intracellular T cell signaling domains. Human T cells transduced to express the C4 CAR specifically secreted proinflammatory cytokine and exerted cytolytic functions when cultured with αFR-expressing tumors in vitro. Adoptive transfer of C4 CAR T cells mediated the regression of large, established human ovarian cancer in a xenogeneic mouse model. Relative to a murine MOv19 scFv-based αFR CAR, C4 CAR T cells mediated comparable cytotoxic tumor activity in vitro and in vivo but had lower affinity for αFR protein and exhibited reduced recognition of normal cells expressing low levels of αFR. Thus, T cells expressing a fully human CAR of intermediate affinity can efficiently kill antigen-expressing tumors in vitro and in vivo and may overcome issues of transgene immunogenicity and "on-target off-tumor" toxicity that plague trials utilizing CARs containing mouse-derived, high affinity scFvs.
authors.affiliation: Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: De-Gang
authors.initials: DG
authors.lastname: Song
authors.affiliation: Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Qunrui
authors.initials: Q
authors.lastname: Ye
authors.affiliation: Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Poussin
authors.affiliation: Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Figini
authors.affiliation: Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Department of Pathology and Laboratory Medicine, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Powell
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D002469:Cell Separation; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D058975:Folate Receptor 1 / Q000737:chemistry*; D057809:HEK293 Cells; D006680:HLA Antigens / Q000737:chemistry*; D006801:Humans; D016219:Immunotherapy, Adoptive; D007249:Inflammation; D016086:Lentivirus / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000628:therapy*; D017434:Protein Structure, Tertiary; D011946:Receptors, Antigen / Q000737:chemistry*; D015398:Signal Transduction; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000737:chemistry; D023041:Xenograft Model Antitumor Assays
chemical_list: D016207:Cytokines; D058975:Folate Receptor 1; D006680:HLA Antigens; D011946:Receptors, Antigen; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7
keywords: T cells; adoptive immunotherapy; chimeric antigen receptor; folate receptor alpha; ovarian cancer