Responses to human CD40 ligand/human interleukin-2 autologous cell vaccine in patients with B-cell chronic lymphocytic leukemia.
OBJECTIVE
Human CD40 ligand activates the malignant B-cell chronic lymphocytic leukemia cells and enhances their capacity to present tumor antigens. Human interleukin-2 further potentiates the immunogenicity of human CD40 ligand in preclinical murine models.


METHODS
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/10(6) 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-gamma, 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.
Biagi
Ettore
E
Center for Cell and Gene Therapy, Baylor College of Medicine, The Methodist Hospital, Houston, Texas 77030, USA. ettore.biagi@pediatriamonza.it
Rousseau
Raphael
R
Yvon
Eric
E
Schwartz
Mary
M
Dotti
Gianpietro
G
Foster
Aaron
A
Havlik-Cooper
Diana
D
Grilley
Bambi
B
Gee
Adrian
A
Baker
Kelty
K
Carrum
George
G
Rice
Lawrence
L
Andreeff
Michael
M
Popat
Uday
U
Brenner
Malcolm
M
D000368:Aged; D015703:Antigens, CD / Q000096:biosynthesis; D000970:Antineoplastic Agents / Q000378:metabolism; D019540:Area Under Curve; D051940:B7-2 Antigen / Q000096:biosynthesis; D017252:CD3 Complex / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D023201:CD40 Ligand / Q000378:metabolism*; D019496:Cancer Vaccines / Q000737:chemistry*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018920:Coculture Techniques; D005260:Female; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D006801:Humans; D007107:Immune System; D007376:Interleukin-2 / Q000378:metabolism*; D015448:Leukemia, B-Cell / Q000378:metabolism* / Q000628:therapy*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism* / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome; D000093322:Lymphocyte Activation Gene 3 Protein
D015703:Antigens, CD; D000970:Antineoplastic Agents; D051940:B7-2 Antigen; D017252:CD3 Complex; D019496:Cancer Vaccines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D023201:CD40 Ligand; D000093322:Lymphocyte Activation Gene 3 Protein; C000720326:Lag3 protein, human