title: Immunotherapy of high-risk acute leukemia with a recipient (autologous) vaccine expressing transgenic human CD40L and IL-2 after chemotherapy and allogeneic stem cell transplantation.
abstract: CD40L generates immune responses in leukemia-bearing mice, an effect that is potentiated by IL-2. We studied the feasibility, safety, and immunologic efficacy of an IL-2- and CD40L-expressing recipient-derived tumor vaccine consisting of leukemic blasts admixed with skin fibroblasts transduced with adenoviral vectors encoding human IL-2 (hIL-2) and hCD40L. Ten patients (including 7 children) with high-risk acute myeloid (n = 4) or lymphoblastic (n = 6) leukemia in cytologic remission (after allogeneic stem cell transplantation [n = 9] or chemotherapy alone [n = 1]) received up to 6 subcutaneous injections of the IL-2/CD40L vaccine. None of the patients were receiving immunosuppressive drugs. No severe adverse reactions were noted. Immunization produced a 10- to 890-fold increase in the frequencies of major histocompatibility complex (MHC)-restricted T cells reactive against recipient-derived blasts. These leukemia-reactive T cells included both T-cytotoxic/T-helper 1 (Th1) and Th2 subclasses, as determined from their production of granzyme B, interferon-gamma, and interleukin-5. Two patients produced systemic IgG antibodies that bound to their blasts. Eight patients remained disease free for 27 to 62 months after treatment (5-year overall survival, 90%). Thus, even in heavily treated patients, including recipients of allogeneic stem cell transplants, recipient-derived antileukemia vaccines can induce immune responses reactive against leukemic blasts. This approach may be worthy of further study, particularly in patients with a high risk of relapse.
authors.affiliation: Center for Cell and Gene Therapy, 6621 Fannin St, MC3-3320, Houston, TX 77030, USA. rfrousse@texaschildrenshospital.org
authors.forename: Raphaël F
authors.initials: RF
authors.lastname: Rousseau
authors.forename: Ettore
authors.initials: E
authors.lastname: Biagi
authors.forename: Aurélie
authors.initials: A
authors.lastname: Dutour
authors.forename: Eric S
authors.initials: ES
authors.lastname: Yvon
authors.forename: Michael P
authors.initials: MP
authors.lastname: Brown
authors.forename: Tiffany
authors.initials: T
authors.lastname: Lin
authors.forename: Zhuyong
authors.initials: Z
authors.lastname: Mei
authors.forename: Bambi
authors.initials: B
authors.lastname: Grilley
authors.forename: Edwina
authors.initials: E
authors.lastname: Popek
authors.forename: Helen E
authors.initials: HE
authors.lastname: Heslop
authors.forename: Adrian P
authors.initials: AP
authors.lastname: Gee
authors.forename: Robert A
authors.initials: RA
authors.lastname: Krance
authors.forename: Uday
authors.initials: U
authors.lastname: Popat
authors.forename: George
authors.initials: G
authors.lastname: Carrum
authors.forename: Judith F
authors.initials: JF
authors.lastname: Margolin
authors.forename: Malcolm K
authors.initials: MK
authors.lastname: Brenner
mesh_terms: D023201:CD40 Ligand / Q000276:immunology*; D019496:Cancer Vaccines; D006801:Humans; D007376:Interleukin-2 / Q000276:immunology*; D007938:Leukemia / Q000276:immunology* / Q000628:therapy*; D033581:Stem Cell Transplantation; D013601:T-Lymphocytes / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D014182:Transplantation, Autologous / Q000276:immunology; D014184:Transplantation, Homologous
chemical_list: D019496:Cancer Vaccines; D007376:Interleukin-2; D023201:CD40 Ligand