Administration of a CD25-directed immunotoxin, LMB-2, to patients with metastatic melanoma induces a selective partial reduction in regulatory T cells in vivo.
CD25+ CD4+ T regulatory (Treg) cells regulate peripheral self tolerance and possess the ability to suppress antitumor responses, which may in part explain the poor clinical response of cancer patients undergoing active immunization protocols. We have previously shown that in vitro incubation of human PBMC with LMB-2, a CD25-directed immunotoxin, significantly reduced CD25+ FOXP3+ CD4+ Treg cells without impairing the function of the remaining lymphocytes. In the current study, eight patients with metastatic melanoma were treated with LMB-2 followed by MART-1 and gp100-specific peptide vaccination. LMB-2 administration resulted in a preferential, transient reduction in mean circulating CD25+ CD4+ T cell number, from 83 +/- 16 cells/microl to a nadir of 17 +/- 5 cells/microl, a 79.1% reduction. FOXP3 analysis revealed a less robust depletion with mean FOXP3+ CD4+ Treg cell number decreasing from 74 +/- 15 cells/microl to 36 +/- 8 cells/microl, a 51.4% reduction. FOXP3+ CD4+ Treg cells that survived LMB-2-mediated cytotoxicity expressed little or no CD25. Similar to the peripheral blood, immunohistochemical analysis showed a 68.9% mean reduction in FOXP3+ CD4+ Treg cell frequency in evaluable lesions. Despite inducing a reduction in Treg cell numbers in vivo, LMB-2 therapy did not augment the immune response to cancer vaccination and no patient experienced an objective response or autoimmunity. These data demonstrate the capacity of a CD25-directed immunotoxin to selectively mediate a transient partial reduction in circulating and tumor-infiltrating Treg cells in vivo, and suggest that more comprehensive Treg cell elimination may be required to bolster antitumor responses in patients with metastatic melanoma.
Powell
Daniel J
DJ
Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Daniel_Powell@nih.gov
Felipe-Silva
Aloisio
A
Merino
Maria J
MJ
Ahmadzadeh
Mojgan
M
Allen
Tamika
T
Levy
Catherine
C
White
Donald E
DE
Mavroukakis
Sharon
S
Kreitman
Robert J
RJ
Rosenberg
Steven A
SA
Pastan
Ira
I
D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005098:Exotoxins / Q000008:administration & dosage / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D000922:Immunotoxins / Q000008:administration & dosage / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use*; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology*; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D010455:Peptides / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D016896:Treatment Outcome; D014611:Vaccination
D000911:Antibodies, Monoclonal; C077707:B3(Fv)-PE38KDEL recombinant immunotoxin; D005098:Exotoxins; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D000922:Immunotoxins; D053645:Interleukin-2 Receptor alpha Subunit; D010455:Peptides