title: Engineering CD19-specific T lymphocytes with interleukin-15 and a suicide gene to enhance their anti-lymphoma/leukemia effects and safety.
abstract: T lymphocytes expressing a chimeric antigen receptor (CAR) targeting the CD19 antigen (CAR.19) may be of value for the therapy of B-cell malignancies. Because the in vivo survival, expansion and anti-lymphoma activity of CAR.19(+) T cells remain suboptimal even when the CAR contains a CD28 costimulatory endodomain, we generated a novel construct that also incorporates the interleukin-15 (IL-15) gene and an inducible caspase-9-based suicide gene (iC9/CAR.19/IL-15). We found that compared with CAR.19(+) T cells, iC9/CAR.19/IL-15(+) T cells had: (1) greater numeric expansion upon antigen stimulation (10-fold greater expansion in vitro, and 3- to 15-fold greater expansion in vivo) and reduced cell death rate (Annexin-V(+)/7-AAD(+) cells 10+/-6% for iC9/CAR.19/IL-15(+) T cells and 32+/-19% for CAR.19(+) T cells); (2) reduced expression of the programmed death 1 (PD-1) receptor upon antigen stimulation (PD-1(+) cells <15% for iC9/CAR.19/IL-15(+) T cells versus >40% for CAR.19(+) T cells); and (3) improved antitumor effects in vivo (from 4.7- to 5.4-fold reduced tumor growth). In addition, iC9/CAR.19/IL-15(+) T cells were efficiently eliminated upon pharmacologic activation of the suicide gene. In summary, this strategy safely increases the anti-lymphoma/leukemia effects of CAR.19-redirected T lymphocytes and may be a useful approach for treatment of patients with B-cell malignancies.
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, The Methodist Hospital and Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: V
authors.initials: V
authors.lastname: Hoyos
authors.forename: B
authors.initials: B
authors.lastname: Savoldo
authors.forename: C
authors.initials: C
authors.lastname: Quintarelli
authors.forename: A
authors.initials: A
authors.lastname: Mahendravada
authors.forename: M
authors.initials: M
authors.lastname: Zhang
authors.forename: J
authors.initials: J
authors.lastname: Vera
authors.forename: H E
authors.initials: HE
authors.lastname: Heslop
authors.forename: C M
authors.initials: CM
authors.lastname: Rooney
authors.forename: M K
authors.initials: MK
authors.lastname: Brenner
authors.forename: G
authors.initials: G
authors.lastname: Dotti
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D018941:Antigens, CD19 / Q000235:genetics / Q000276:immunology*; D018106:CD28 Antigens / Q000235:genetics / Q000276:immunology; D053453:Caspase 9 / Q000235:genetics / Q000276:immunology*; D005822:Genetic Vectors; D006801:Humans; D016130:Immunophenotyping; D019409:Interleukin-15 / Q000235:genetics / Q000276:immunology*; D007938:Leukemia / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D008213:Lymphocyte Activation; D008223:Lymphoma / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D051379:Mice; D016513:Mice, SCID; D013601:T-Lymphocytes / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D018941:Antigens, CD19; D018106:CD28 Antigens; D019409:Interleukin-15; D053453:Caspase 9