Transient T cell depletion causes regression of melanoma metastases

• Published in: Journal of translational medicine Vol. 6; no. 1; p. 12
• Main Authors: Rasku, Mary Ann, Clem, Amy L, Telang, Sucheta, Taft, Beverly, Gettings, Kelly, Gragg, Hana, Cramer, Daniel, Lear, Sheron C, McMasters, Kelly M, Miller, Donald M, Chesney, Jason
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 11.03.2008; BioMed Central; BMC
• Subjects: Adult; Aged; Antigens, Neoplasm - metabolism; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Causes of; Cell Line, Tumor; Development and progression; Diphtheria Toxin - pharmacology; Diphtheria Toxin - therapeutic use; Female; Health aspects; Humans; Immunoglobulin G - metabolism; Interleukin-2 - pharmacology; Interleukin-2 - therapeutic use; Leukocyte Count; Male; Melanoma - drug therapy; Melanoma - immunology; Melanoma - pathology; Metastasis; Middle Aged; Neoplasm Metastasis - drug therapy; Neoplasm Metastasis - immunology; Neoplasm Metastasis - pathology; Physiological aspects; Recombinant Fusion Proteins - pharmacology; Recombinant Fusion Proteins - therapeutic use; Remission Induction; Skin Neoplasms - drug therapy; Skin Neoplasms - immunology; Skin Neoplasms - pathology; T cells; T-Lymphocyte Subsets - drug effects; T-Lymphocyte Subsets - immunology; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology; Time Factors; Treatment Outcome; Tumor Burden; United States
• DOI: 10.1186/1479-5876-6-12
• ISSN: 1479-5876

Cognate immunity against neoplastic cells depends on a balance between effector T cells and regulatory T (Treg) cells. Treg cells prevent immune attack against normal and neoplastic cells by directly suppressing the activation of effector CD4+ and CD8+ T cells. We postulated that a recombinant interleukin 2/diphtheria toxin conjugate (DAB/IL2; Denileukin Diftitox; Ontak) may serve as a useful strategy to deplete Treg cells and break tolerance against neoplastic tumors in humans. We administered DAB/IL2 (12 microg/kg; four daily doses; 21 day cycles) to 16 patients with metastatic melanoma and measured the effects on the peripheral blood concentration of several T cell subsets and on tumor burden. We found that DAB/IL2 caused a transient depletion of Treg cells as well as total CD4+ and CD8+ T cells (< 21 days). T cell repopulation coincided with the de novo appearance of melanoma antigen-specific CD8+ T cells in several patients as determined by flow cytometry using tetrameric MART-1, tyrosinase and gp100 peptide/MHC conjugates. Sixteen patients received at least one cycle of DAB/IL2 and five of these patients experienced regressions of melanoma metastases as measured by CT and/or PET imaging. One patient experienced a near complete response with the regression of several hepatic and pulmonary metastases coupled to the de novo appearance of MART-1-specific CD8+ T cells. A single metastatic tumor remained in this patient and, after surgical resection, immunohistochemical analysis revealed MART1+ melanoma cells surrounded by CD8+ T cells. Taken together, these data indicate that transient depletion of T cells in cancer patients may disrupt the homeostatic control of cognate immunity and allow for the expansion of effector T cells with specificity against neoplastic cells. Several T cell depleting agents are clinically available and this study provides strong rationale for an examination of their efficacy in cancer patients. NCT00299689 (ClinicalTrials.gov Identifier).