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Journal of Translational Medicine

, 6:12

First Online: 11 March 2008Received: 07 January 2008Accepted: 11 March 2008DOI: 10.1186-1479-5876-6-12

Cite this article as: Rasku, M.A., Clem, A.L., Telang, S. et al. J Transl Med 2008 6: 12. doi:10.1186-1479-5876-6-12

Abstract

BackgroundCognate 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.

MethodsWe administered DAB-IL2 12 μg-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.

ResultsWe 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.

ConclusionTaken 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.

Trial registrationNCT00299689 ClinicalTrials.gov Identifier.

AbbreviationsThe abbreviations used in this manuscript incudedTreg, T regulatory cells

MHCMajor histocompatibility complex

DAB-IL2Denileukin diftitox or Ontak

CTLA-4Cytotoxic T lymphocyte antigen-4

CTCLCutaneous T cell lymphoma

IL-2Interleukin 2

MART-1Melanoma-associated antigen recognized by T cells

PET-CTPositron emission tomography and computed tomography

CRComplete response

PRPartial response

PDProgressive disease.

Electronic supplementary materialThe online version of this article doi:10.1186-1479-5876-6-12 contains supplementary material, which is available to authorized users.

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Autor: Mary Ann Rasku - Amy L Clem - Sucheta Telang - Beverly Taft - Kelly Gettings - Hana Gragg - Daniel Cramer - Sheron C Le

Fuente: https://link.springer.com/







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