title: Combining a CD20 chimeric antigen receptor and an inducible caspase 9 suicide switch to improve the efficacy and safety of T cell adoptive immunotherapy for lymphoma.
abstract: Modification of T cells with chimeric antigen receptors (CAR) has emerged as a promising treatment modality for human malignancies. Integration of co-stimulatory domains into CARs can augment the activation and function of genetically targeted T cells against tumors. However, the potential for insertional mutagenesis and toxicities due to the infused cells have made development of safe methods for removing transferred cells an important consideration. We have genetically modified human T cells with a lentiviral vector to express a CD20-CAR containing both CD28 and CD137 co-stimulatory domains, a "suicide gene" relying on inducible activation of caspase 9 (iC9), and a truncated CD19 selectable marker. Rapid expansion (2000 fold) of the transduced T cells was achieved in 28 days after stimulation with artificial antigen presenting cells. Transduced T cells exhibited effective CD20-specific cytotoxic activity in vitro and in a mouse xenograft tumor model. Activation of the iC9 suicide switch resulted in efficient removal of transduced T cells both in vitro and in vivo. Our work demonstrates the feasibility and promise of this approach for treating CD20(+) malignancies in a safe and more efficient manner. A phase I clinical trial using this approach in patients with relapsed indolent B-NHL is planned.
authors.affiliation: Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California, United States of America ; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America ; Departments of Medicine and Bioengineering, University of Washington, Seattle, Washington, United States of America.
authors.forename: Lihua E
authors.initials: LE
authors.lastname: Budde
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Carolina
authors.initials: C
authors.lastname: Berger
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Yukang
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Jinjuan
authors.initials: J
authors.lastname: Wang
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Xubin
authors.initials: X
authors.lastname: Lin
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Shani E
authors.initials: SE
authors.lastname: Frayo
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Shaunda A
authors.initials: SA
authors.lastname: Brouns
authors.affiliation: Pathology and Immunology, Baylor College of Medicine, Houston, Texas, United States of America ; Bellicum Pharmaceuticals, Inc., Houston, Texas, United States of America.
authors.forename: David M
authors.initials: DM
authors.lastname: Spencer
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America ; Departments of Medicine and Bioengineering, University of Washington, Seattle, Washington, United States of America.
authors.forename: Brian G
authors.initials: BG
authors.lastname: Till
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America ; Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, Washington, United States of America.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Jensen
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America ; Departments of Medicine and Bioengineering, University of Washington, Seattle, Washington, United States of America ; Institute for Advanced Study, Technical University of Munich, Munich, Germany.
authors.forename: Stanley R
authors.initials: SR
authors.lastname: Riddell
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America ; Departments of Medicine and Bioengineering, University of Washington, Seattle, Washington, United States of America.
authors.forename: Oliver W
authors.initials: OW
authors.lastname: Press
mesh_terms: D000818:Animals; D018951:Antigens, CD20 / Q000235:genetics*; D053453:Caspase 9 / Q000235:genetics*; D002478:Cells, Cultured; D041722:Genes, Transgenic, Suicide; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D019169:Jurkat Cells; D008223:Lymphoma / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D041681:NIH 3T3 Cells; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000235:genetics; D013601:T-Lymphocytes / Q000378:metabolism / Q000637:transplantation*; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D018951:Antigens, CD20; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D053453:Caspase 9