TY - JOUR
T1 - Responses to human CD40 ligand/human interleukin-2 autologous cell vaccine in patients with B-cell chronic lymphocytic leukemia
AU - Biagi, Ettore
AU - Rousseau, Raphael
AU - Yvon, Eric
AU - Schwartz, Mary
AU - Dotti, Gianpietro
AU - Foster, Aaron
AU - Havlik-Cooper, Diana
AU - Grilley, Bambi
AU - Gee, Adrian
AU - Baker, Kelty
AU - Carrum, George
AU - Rice, Lawrence
AU - Andreeff, Michael
AU - Popat, Uday
AU - Brenner, Malcolm
PY - 2005/10/1
Y1 - 2005/10/1
N2 - Purpose: Human CD40 ligand activates the malignant B-cell chronic lymphocytic leukemia cells and enhances their capacity to present tumor antigens. Human interteukin-2 further potentiates the immunogenicity of human CD40 ligand in preclinical marine models. Experimental Design: We prepared autologous B-cell chronic lymphocytic leukemia cells that expressed both human CD40 ligand (>90% positive) and human interleukin-2 (median secretion, 1,822 pg/mL/106 cells; range, 174-3,604 pg). Nine patients were enrolled in a phase I trial, receiving three to eight s.c. vaccinations. Results: Vaccinations were administered without evidence of significant local or systemic toxicity. A B-cell chronic lymphocytic leukemia-specific T-cell response was detected in seven patients. The mean frequencies of IFN-γ, granzyme-B, and IL-5 spot-forming cells were 1/1,230, 1/1,450, and 1/4,500, respectively, representing a 43- to 164-fold increase over the frequency before vaccine administration. Three patients produced leukemia-specific immunoglobulins. Three patients had >50% reduction in the size of affected lymph nodes. Nonetheless, the antitumor immune responses were observed only transiently once immunization ceased. High levels of circulating CD4+/CD25 +/LAG-3+/FoxP-3+ immunoregulatory T cells were present before, during and after treatment and in vitro removal of these cells increased the antileukemic T-cell reactivity. Conclusions: These results suggest that immune responses to B-cell chronic lymphocytic leukemia can be obtained with human CD40 ligand/human interleukin-2- expressing s.c. vaccines but that these responses are transient. High levels of circulating regulatory T cells are present, and it will be of interest to see if their removal in vivo augments and prolongs the antitumor immune response.
AB - Purpose: Human CD40 ligand activates the malignant B-cell chronic lymphocytic leukemia cells and enhances their capacity to present tumor antigens. Human interteukin-2 further potentiates the immunogenicity of human CD40 ligand in preclinical marine models. Experimental Design: We prepared autologous B-cell chronic lymphocytic leukemia cells that expressed both human CD40 ligand (>90% positive) and human interleukin-2 (median secretion, 1,822 pg/mL/106 cells; range, 174-3,604 pg). Nine patients were enrolled in a phase I trial, receiving three to eight s.c. vaccinations. Results: Vaccinations were administered without evidence of significant local or systemic toxicity. A B-cell chronic lymphocytic leukemia-specific T-cell response was detected in seven patients. The mean frequencies of IFN-γ, granzyme-B, and IL-5 spot-forming cells were 1/1,230, 1/1,450, and 1/4,500, respectively, representing a 43- to 164-fold increase over the frequency before vaccine administration. Three patients produced leukemia-specific immunoglobulins. Three patients had >50% reduction in the size of affected lymph nodes. Nonetheless, the antitumor immune responses were observed only transiently once immunization ceased. High levels of circulating CD4+/CD25 +/LAG-3+/FoxP-3+ immunoregulatory T cells were present before, during and after treatment and in vitro removal of these cells increased the antileukemic T-cell reactivity. Conclusions: These results suggest that immune responses to B-cell chronic lymphocytic leukemia can be obtained with human CD40 ligand/human interleukin-2- expressing s.c. vaccines but that these responses are transient. High levels of circulating regulatory T cells are present, and it will be of interest to see if their removal in vivo augments and prolongs the antitumor immune response.
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U2 - 10.1158/1078-0432.CCR-05-0484
DO - 10.1158/1078-0432.CCR-05-0484
M3 - Article
C2 - 16203783
AN - SCOPUS:26444566785
SN - 1078-0432
VL - 11
SP - 6916
EP - 6923
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 19 I
ER -