title: A phase I study of immune gene therapy for patients with CLL using a membrane-stable, humanized CD154.
abstract: Ligation of CD40 on chronic lymphocytic leukemia (CLL) cells induces phenotypic and biochemical changes that facilitate CLL cell-T cell interactions and enhances the sensitivity of CLL cells to clearance by adaptive and innate immune-effector mechanisms. CLL cells can be transduced to express CD40 ligand (CD154) using a replication-defective adenovirus vector, thereby cross-linking CD40 on transduced and non-transduced, bystander CLL cells. In a previous study, patients received infusions of autologous CLL cells, transduced to express murine CD154 (mCD154), which induced anti-leukemic immune responses, but also anti-mCD154 antibodies. In this study, we report a phase I study, in which patients were infused with 1 × 10(8), 3 × 10(8) or 1 × 10(9) autologous CLL cells transduced ex vivo to express ISF35, a humanized, membrane-stable CD154. Infusions were well tolerated and consistently followed by reductions in blood lymphocyte counts and lymphadenopathy. After infusion, circulating CLL cells had enhanced or de novo expression of CD95, DR5, p73 and Bid, which enhanced their susceptibility to death-receptor-mediated or drug-induced apoptosis, including CLL cells with deletions at 17p13.1 (del(17p)). Two patients who had CLL with del(17p) had subsequent chemoimmunotherapy and responded well to treatment. In summary, infusions of autologous, ISF35-transduced CLL cells were well tolerated, had biological and clinical activity, and might enhance the susceptibility of CLL cells with del(17p) to chemoimmunotherapy.
authors.affiliation: Department of Leukemia and CLL Research Consortium, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. wwierda@mdanderson.org
authors.forename: W G
authors.initials: WG
authors.lastname: Wierda
authors.forename: J E
authors.initials: JE
authors.lastname: Castro
authors.forename: R
authors.initials: R
authors.lastname: Aguillon
authors.forename: D
authors.initials: D
authors.lastname: Sampath
authors.forename: A
authors.initials: A
authors.lastname: Jalayer
authors.forename: J
authors.initials: J
authors.lastname: McMannis
authors.forename: C E
authors.initials: CE
authors.lastname: Prussak
authors.forename: M
authors.initials: M
authors.lastname: Keating
authors.forename: T J
authors.initials: TJ
authors.lastname: Kipps
mesh_terms: D000328:Adult; D000368:Aged; D019013:CD40 Antigens / Q000276:immunology; D023201:CD40 Ligand / Q000009:adverse effects / Q000627:therapeutic use*; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D005260:Female; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D008297:Male; D008856:Microscopy, Fluorescence / Q000379:methods; D008875:Middle Aged; D009367:Neoplasm Staging; D017384:Sequence Deletion; D019014:fas Receptor / Q000276:immunology
chemical_list: D019013:CD40 Antigens; D019014:fas Receptor; D023201:CD40 Ligand