title: Redirected antitumor activity of primary human lymphocytes transduced with a fully human anti-mesothelin chimeric receptor.
abstract: Cancer regression by gene-modified T cells bearing a chimeric antigen receptor (CAR) exodomain of mouse origin can be limited by the induction of transgene immunogenicity resulting in poor persistence and function in vivo. The development of functionally-active CAR of human origin can address this issue. Here, we constructed and evaluated fully human anti-mesothelin CARs comprised of a human mesothelin-specific single-chain antibody variable fragment (P4 scFv) coupled to T cell signaling domains. Primary human T cells expressing P4 CAR specifically produced proinflammatory cytokines, degranulated and exerted potent cytolytic functions when cultured with mesothelin-expressing tumors in vitro. P4 CAR T cells also mediated bystander killing of mesothelin-negative cancer cells during coculture. CAR reactivity was not abrogated by soluble tumor-secreted or recombinant mesothelin protein even at supraphysiological levels. Importantly, adoptive transfer of P4 CAR-expressing T cells mediated the regression of large, established tumor in the presence of soluble mesothelin in a xenogenic model of human ovarian cancer. Thus, primary human T cells expressing fully human anti-mesothelin CAR efficiently kill mesothelin-expressing tumors in vitro and in vivo and have the potential to overcome the issue of transgene immunogenicity that may limit CAR T cell trials that utilize scFvs of mouse origin.
authors: Department of Obstetrics and Gynecology, Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors: Evripidis
authors: E
authors: Lanitis
authors: Mathilde
authors: M
authors: Poussin
authors: Ian S
authors: IS
authors: Hagemann
authors: George
authors: G
authors: Coukos
authors: Raphael
authors: R
authors: Sandaltzopoulos
authors: Nathalie
authors: N
authors: Scholler
authors: Daniel J
authors: DJ
authors: Powell
mesh_terms: D000818:Animals; D024201:Bystander Effect / Q000276:immunology; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D000939:Epitopes / Q000276:immunology; D005260:Female; D058851:GPI-Linked Proteins / Q000276:immunology* / Q000378:metabolism; D023061:Gene Order; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D000090204:Mesothelin; D051379:Mice; D010051:Ovarian Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000276:immunology; D057127:Single-Chain Antibodies / Q000235:genetics* / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014161:Transduction, Genetic; D023041:Xenograft Model Antitumor Assays
chemical_list: D000939:Epitopes; D058851:GPI-Linked Proteins; C000715528:Msln protein, mouse; D011948:Receptors, Antigen, T-Cell; D057127:Single-Chain Antibodies; D000090204:Mesothelin