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.
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.
Rousseau
Raphaël F
RF
Center for Cell and Gene Therapy, 6621 Fannin St, MC3-3320, Houston, TX 77030, USA. rfrousse@texaschildrenshospital.org
Biagi
Ettore
E
Dutour
Aurélie
A
Yvon
Eric S
ES
Brown
Michael P
MP
Lin
Tiffany
T
Mei
Zhuyong
Z
Grilley
Bambi
B
Popek
Edwina
E
Heslop
Helen E
HE
Gee
Adrian P
AP
Krance
Robert A
RA
Popat
Uday
U
Carrum
George
G
Margolin
Judith F
JF
Brenner
Malcolm K
MK
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
D019496:Cancer Vaccines; D007376:Interleukin-2; D023201:CD40 Ligand