Partial reduction of human FOXP3+ CD4 T cells in vivo after CD25-directed recombinant immunotoxin administration.
The regulation of tolerance to self-proteins and the suppression of T-cell responses have in part been attributed to the activity of CD25+CD4+ T regulatory (Treg) cells. Further, Treg cells can inhibit the antitumor effectiveness of adoptive immunotherapy and active immunization approaches in preclinical models. In an effort to selectively eliminate Treg cells from human peripheral blood mononuclear cell to potentially bolster antitumor responses, we have evaluated the Treg-cell depleting capacity of the CD25-directed immunotoxin, RFT5-SMPT-dgA. In preclinical studies, incubation of human peripheral blood mononuclear cell with RFT5-SMPT-dgA mediated a partial reduction in the levels of CD25+, Foxp3-expressing CD4+ T cells in vitro. Administration of RFT5-SMPT-dgA to 6 patients with metastatic melanoma induced a transient but robust reduction in the number of CD25high CD4 T cells in vivo (a 97.5% mean reduction at nadir; from 69.4 +/- 12.4 cells/miroL to 1.7 +/- 0.3 cells/microL). The reduction in FOXP3+ CD4 T-cell number was less comprehensive (a 71.3% mean reduction at nadir; from 66.6 +/- 16.5 cells/microL to 14.2 +/- 3.9 cells/tL). This resulted in the selective persistence of a stable number of CD25(low/neg) FOXP3+ CD4+ T cells in vivo. No objective antitumor responses were seen in any patient. Our results indicate that the CD25-directed, RFT5-SMPT-dgA immunotoxin can mediate a transient, partial reduction in Treg-cell frequency and number in vitro and in vivo and suggest that comprehensive eradication of human Treg cells in vivo may require the ability to target and eliminate FOXP3+ CD4+ T cells expressing both high and low levels of CD25.
Powell
Daniel J
DJ
Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. poda@mail.med.upenn.edu
Attia
Peter
P
Ghetie
Victor
V
Schindler
John
J
Vitetta
Ellen S
ES
Rosenberg
Steven A
SA
D000328:Adult; D000906:Antibodies / Q000097:blood / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D018414:CD8-Positive T-Lymphocytes / Q000737:chemistry / Q000166:cytology / Q000187:drug effects; D002452:Cell Count; D005260:Female; D051858:Forkhead Transcription Factors / Q000032:analysis*; D006801:Humans; D018796:Immunoconjugates; D007167:Immunotherapy / Q000009:adverse effects / Q000379:methods; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects; D018655:Lymphocyte Count; D008212:Lymphocyte Depletion / Q000379:methods; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000473:pathology / Q000628:therapy; D008875:Middle Aged; D009362:Neoplasm Metastasis; D012276:Ricin / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D016176:T-Lymphocyte Subsets / Q000737:chemistry / Q000166:cytology / Q000187:drug effects; D050378:T-Lymphocytes, Regulatory / Q000737:chemistry / Q000166:cytology / Q000187:drug effects*; D016896:Treatment Outcome
D000906:Antibodies; D000911:Antibodies, Monoclonal; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D018796:Immunoconjugates; D053645:Interleukin-2 Receptor alpha Subunit; C114847:RFT5-SMPT-dgA immunotoxin; D012276:Ricin