Inability of a fusion protein of IL-2 and diphtheria toxin (Denileukin Diftitox, DAB389IL-2, ONTAK) to eliminate regulatory T lymphocytes in patients with melanoma.
Elimination of regulatory T lymphocytes may provide a way to break self-tolerance and unleash the anti-tumor properties of circulating lymphocytes. The use of fusion proteins, which link cytotoxic molecules to receptor targets, provides one approach to this problem. This study examined the ability of a fusion protein of interleukin-2 (IL-2) and diphtheria toxin (Denileukin Diftitox, DAB389IL-2, ONTAK) to eliminate regulatory T lymphocytes based on their expression of high-affinity IL-2 receptors. Thirteen patients (12 with metastatic melanoma, 1 with metastatic renal cell carcinoma) were treated at one of the two Food and Drug Administration-approved doses of Denileukin Diftitox (seven patients at 9 microg/kg, six patients at 18 microg/kg). None of the patients experienced an objective clinical response. Foxp3 expression did not decrease significantly overall, although it did decrease minimally among patients receiving 18 microg/kg (-2.01+/-0.618 copies of Foxp3/10(3) copies of beta-actin; P=0.031). Denileukin Diftitox did not decrease the suppressive ability of CD4CD25 cells as quantified by an in vitro co-culture suppression assay. Furthermore, the increased numbers of lymphocytes in patients resulting from treatment with IL-2 were not susceptible to Denileukin Diftitox. Administration of Denileukin Diftitox does not appear to eliminate regulatory T lymphocytes or cause regression of metastatic melanoma.
Attia
Peter
P
Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-1201, USA.
Maker
Ajay V
AV
Haworth
Leah R
LR
Rogers-Freezer
Linda
L
Rosenberg
Steven A
SA
D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000276:immunology / Q000556:secondary; D045744:Cell Line, Tumor; D004167:Diphtheria Toxin / Q000627:therapeutic use*; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007376:Interleukin-2 / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology / Q000556:secondary; D008875:Middle Aged; D009362:Neoplasm Metastasis; D012333:RNA, Messenger / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000556:secondary; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology
D000970:Antineoplastic Agents; D004167:Diphtheria Toxin; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007376:Interleukin-2; D012333:RNA, Messenger; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins; C078456:denileukin diftitox