title: Immune responses to transgene and retroviral vector in patients treated with ex vivo-engineered T cells.
abstract: Adoptive transfer of immune effector cells that are gene modified by retroviral transduction to express tumor-specific receptors constitutes an attractive approach to treat cancer. In patients with metastatic renal cell carcinoma, we performed a study with autologous T cells genetically retargeted with a chimeric antibody receptor (CAR) directed toward carbonic anhydrase IX (CAIX), an antigen highly expressed in renal cell carcinoma. In the majority of patients, we observed distinct humoral and/or cellular anti-CAIX-CAR T-cell immune responses in combination with a limited peripheral persistence of transferred CAIX-CAR T cells in the majority of patients. Humoral immune responses were anti-idiotypic in nature and neutralized CAIX-CAR-mediated T-cell function. Cellular anti-CAIX-CAR immune responses were directed to the complementarity-determining and framework regions of the CAR variable domains. In addition, 2 patients developed immunity directed against presumed retroviral vector epitopes. Here, we document the novel feature that therapeutic cells, which were ex vivo engineered by means of transduction with a minimal γ-retroviral vector, do express immunogenic vector-encoded epitopes, which might compromise persistence of these cells. These observations may constitute a critical concern for clinical ex vivo γ-retroviral gene transduction in general and CAR-retargeted T-cell therapy in particular, and underscore the need to attenuate the immunogenicity of both transgene and vector.
authors.affiliation: Department of Medical Oncology, Erasmus University Medical Center-Daniel den Hoed Cancer Center, Rotterdam, The Netherlands. c.lamers@erasmusmc.nl
authors.forename: Cor H J
authors.initials: CH
authors.lastname: Lamers
authors.forename: Ralph
authors.initials: R
authors.lastname: Willemsen
authors.forename: Pascal
authors.initials: P
authors.lastname: van Elzakker
authors.forename: Sabine
authors.initials: S
authors.lastname: van Steenbergen-Langeveld
authors.forename: Marieke
authors.initials: M
authors.lastname: Broertjes
authors.forename: Jeannette
authors.initials: J
authors.lastname: Oosterwijk-Wakka
authors.forename: Egbert
authors.initials: E
authors.lastname: Oosterwijk
authors.forename: Stefan
authors.initials: S
authors.lastname: Sleijfer
authors.forename: Reno
authors.initials: R
authors.lastname: Debets
authors.forename: Jan W
authors.initials: JW
authors.lastname: Gratama
mesh_terms: D019264:Adoptive Transfer; D000595:Amino Acid Sequence; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology*; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000235:genetics / Q000276:immunology*; D002292:Carcinoma, Renal Cell / Q000276:immunology / Q000628:therapy*; D015331:Cohort Studies; D005818:Genetic Engineering; D005822:Genetic Vectors / Q000276:immunology*; D006801:Humans; D007680:Kidney Neoplasms / Q000276:immunology / Q000628:therapy*; D008213:Lymphocyte Activation; D008969:Molecular Sequence Data; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology*; D019076:Transgenes / Q000276:immunology* / Q000502:physiology
chemical_list: D000951:Antigens, Neoplasm; D011948:Receptors, Antigen, T-Cell; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases