title: Decade-long safety and function of retroviral-modified chimeric antigen receptor T cells.
abstract: The success of adoptive T cell gene transfer for treatment of cancer and HIV is predicated on generating a response that is both durable and safe. We report long-term results from three clinical trials to evaluate gammaretroviral vector-engineered T cells for HIV. The vector encoded a chimeric antigen receptor (CAR) composed of CD4 linked to the CD3ζ signaling chain (CD4ζ). CAR T cells were detected in 98% of samples tested for at least 11 years after infusion at frequencies that exceeded average T cell levels after most vaccine approaches. The CD4ζ transgene retained expression and function. There was no evidence of vector-induced immortalization of cells; integration site distributions showed no evidence of persistent clonal expansion or enrichment for integration sites near genes implicated in growth control or transformation. The CD4ζ T cells had stable levels of engraftment, with decay half-lives that exceeded 16 years, in marked contrast to previous trials testing engineered T cells. These findings indicate that host immunosuppression before T cell transfer is not required to achieve long-term persistence of gene-modified T cells. Further, our results emphasize the safety of T cells modified by retroviral gene transfer in clinical application, as measured in >500 patient-years of follow-up. Thus, previous safety issues with integrating viral vectors are hematopoietic stem cell or transgene intrinsic, and not a general feature of retroviral vectors. Engineered T cells are a promising form of synthetic biology for long-term delivery of protein-based therapeutics. These results provide a framework to guide the therapy of a wide spectrum of human diseases.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104-6076, USA.
authors.forename: John
authors.initials: J
authors.lastname: Scholler
authors.forename: Troy L
authors.initials: TL
authors.lastname: Brady
authors.forename: Gwendolyn
authors.initials: G
authors.lastname: Binder-Scholl
authors.forename: Wei-Ting
authors.initials: WT
authors.lastname: Hwang
authors.forename: Gabriela
authors.initials: G
authors.lastname: Plesa
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Hege
authors.forename: Ashley N
authors.initials: AN
authors.lastname: Vogel
authors.forename: Michael
authors.initials: M
authors.lastname: Kalos
authors.forename: James L
authors.initials: JL
authors.lastname: Riley
authors.forename: Steven G
authors.initials: SG
authors.lastname: Deeks
authors.forename: Ronald T
authors.initials: RT
authors.lastname: Mitsuyasu
authors.forename: Wendy B
authors.initials: WB
authors.lastname: Bernstein
authors.forename: Naomi E
authors.initials: NE
authors.lastname: Aronson
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Levine
authors.forename: Frederic D
authors.initials: FD
authors.lastname: Bushman
authors.forename: Carl H
authors.initials: CH
authors.lastname: June
mesh_terms: D019264:Adoptive Transfer / Q000009:adverse effects*; D017252:CD3 Complex / Q000378:metabolism; D015704:CD4 Antigens / Q000378:metabolism; D015331:Cohort Studies; D044127:Epigenesis, Genetic; D005500:Follow-Up Studies; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics; D023281:Genomics; D006207:Half-Life; D006801:Humans; D007376:Interleukin-2 / Q000008:administration & dosage / Q000276:immunology; D016254:Mutagenesis, Insertional / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology*; D012190:Retroviridae / Q000235:genetics*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation*; D013997:Time Factors; D014158:Transcription, Genetic; D019076:Transgenes / Q000235:genetics
chemical_list: D017252:CD3 Complex; D015704:CD4 Antigens; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D011994:Recombinant Proteins