Dendritic cell vaccination in combination with anti-CD25 monoclonal antibody treatment: a phase I/II study in metastatic melanoma patients.
OBJECTIVE
The success of cancer immunotherapy depends on the balance between effector T cells and suppressive immune regulatory mechanisms within the tumor microenvironment. In this study we investigated whether transient monoclonal antibody-mediated depletion of CD25(high) regulatory T cells (Treg) is capable of enhancing the immunostimulatory efficacy of dendritic cell vaccines.


METHODS
Thirty HLA-A2.1(+) metastatic melanoma patients were vaccinated with mature dendritic cells pulsed with tumor peptide and keyhole limpet hemocyanin (KLH). Half of the patients were pretreated with daclizumab, a humanized antibody against the interleukin-2 (IL-2) receptor α-chain (CD25), either four or eight days before dendritic cell vaccinations. Clinical and immunologic parameters were determined.


RESULTS
Daclizumab efficiently depleted all CD25(high) immune cells, including CD4(+)FoxP3(+)CD25(high) cells, from the peripheral blood within four days of administration. Thirty days after administration, daclizumab was cleared from the circulation and all CD25(+) cells reappeared. The presence of daclizumab during dendritic cell vaccinations prevented the induction of specific antibodies in vivo but not the presence of antigen-specific T cells. Daclizumab, however, did prevent these CD25(+) T cells from acquiring effector functions. Consequently, significantly less patients pretreated with daclizumab developed functional, vaccine-specific effector T cells and antibodies compared with controls. Daclizumab pretreatment had no significant effect on progression-free survival compared with the control group.


CONCLUSIONS
Although daclizumab depleted the CD4(+)FoxP3(+)CD25(high) Tregs from the peripheral circulation, it did not enhance the efficacy of the dendritic cell vaccine. Residual daclizumab functionally suppressed de novo induced CD25(+) effector cells during dendritic cell vaccinations. Our results indicate that for immunotherapeutic benefit of transient Treg depletion, timing and dosing as well as Treg specificity are extremely important.
Jacobs
Joannes F M
JF
Department of Medical Oncology, Laboratory of Medical Immunology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
Punt
Cornelis J A
CJ
Lesterhuis
W Joost
WJ
Sutmuller
Roger P M
RP
Brouwer
H Mary-Lène H
HM
Scharenborg
Nicole M
NM
Klasen
Ina S
IS
Hilbrands
Luuk B
LB
Figdor
Carl G
CG
de Vries
I Jolanda M
IJ
Adema
Gosse J
GJ
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000077561:Daclizumab; D003713:Dendritic Cells / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D015789:HLA-A2 Antigen / Q000276:immunology; D006433:Hemocyanins / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D016219:Immunotherapy, Adoptive; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000378:metabolism / Q000556:secondary / Q000628:therapy*; D008875:Middle Aged; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D016896:Treatment Outcome; D055815:Young Adult
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; C508017:IL2RA protein, human; D007074:Immunoglobulin G; D053645:Interleukin-2 Receptor alpha Subunit; D006433:Hemocyanins; D000077561:Daclizumab; C032808:keyhole-limpet hemocyanin