title: TALEN-Mediated Inactivation of PD-1 in Tumor-Reactive Lymphocytes Promotes Intratumoral T-cell Persistence and Rejection of Established Tumors.
abstract: Despite the promising efficacy of adoptive cell therapies (ACT) in melanoma, complete response rates remain relatively low and outcomes in other cancers are less impressive. The immunosuppressive nature of the tumor microenvironment and the expression of immune-inhibitory ligands, such as PD-L1/CD274 by the tumor and stroma are considered key factors limiting efficacy. The addition of checkpoint inhibitors (CPI) to ACT protocols bypasses some mechanisms of immunosuppression, but associated toxicities remain a significant concern. To overcome PD-L1-mediated immunosuppression and reduce CPI-associated toxicities, we used TALEN technology to render tumor-reactive T cells resistant to PD-1 signaling. Here, we demonstrate that inactivation of the PD-1 gene in melanoma-reactive CD8(+) T cells and in fibrosarcoma-reactive polyclonal T cells enhanced the persistence of PD-1 gene-modified T cells at the tumor site and increased tumor control. These results illustrate the feasibility and potency of approaches incorporating advanced gene-editing technologies into ACT protocols to silence immune checkpoints as a strategy to overcome locally active immune escape pathways. Cancer Res; 76(8); 2087-93. ©2016 AACR.
authors.affiliation: Cancer Immunology Unit, Research Department of Hematology, University College London Cancer Institute, London, United Kingdom.
authors.forename: Laurie
authors.initials: L
authors.lastname: Menger
authors.affiliation: Cancer Immunology Unit, Research Department of Hematology, University College London Cancer Institute, London, United Kingdom.
authors.forename: Anna
authors.initials: A
authors.lastname: Sledzinska
authors.affiliation: Cancer Immunology Unit, Research Department of Hematology, University College London Cancer Institute, London, United Kingdom.
authors.forename: Katharina
authors.initials: K
authors.lastname: Bergerhoff
authors.affiliation: Cancer Immunology Unit, Research Department of Hematology, University College London Cancer Institute, London, United Kingdom.
authors.forename: Frederick Arce
authors.initials: FA
authors.lastname: Vargas
authors.affiliation: Cellectis, Paris, France.
authors.forename: Julianne
authors.initials: J
authors.lastname: Smith
authors.affiliation: Cellectis, Paris, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Poirot
authors.affiliation: Cancer Immunology Unit, Research Department of Hematology, University College London Cancer Institute, London, United Kingdom.
authors.forename: Martin
authors.initials: M
authors.lastname: Pule
authors.affiliation: Cancer Immunology Unit, Research Department of Hematology, University College London Cancer Institute, London, United Kingdom. Bill Lyons Informatics Centre, University College London Cancer Institute, London, United Kingdom.
authors.forename: Javier
authors.initials: J
authors.lastname: Hererro
authors.affiliation: Cancer Immunology Unit, Research Department of Hematology, University College London Cancer Institute, London, United Kingdom. s.quezada@ucl.ac.uk Karl.Peggs@ucl.ac.uk.
authors.forename: Karl S
authors.initials: KS
authors.lastname: Peggs
authors.affiliation: Cancer Immunology Unit, Research Department of Hematology, University College London Cancer Institute, London, United Kingdom. s.quezada@ucl.ac.uk Karl.Peggs@ucl.ac.uk.
authors.forename: Sergio A
authors.initials: SA
authors.lastname: Quezada
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D005354:Fibrosarcoma / Q000276:immunology; D020868:Gene Silencing; D008213:Lymphocyte Activation; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008546:Melanoma, Experimental / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D014162:Transfection; D059016:Tumor Microenvironment / Q000276:immunology
chemical_list: C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor