Research

Transient T cell depletion causes regression of melanoma metastases

Mary Ann Rasku¹ , Amy L Clem¹ , Sucheta Telang¹ , Beverly Taft¹ , Kelly Gettings¹ , Hana Gragg¹ , Daniel Cramer¹ , Sheron C Lear² , Kelly M McMasters³ , Donald M Miller¹ and Jason Chesney¹

¹Molecular Targets Program, James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA

²Department of Pathology, University of Louisville School of Medicine, Louisville, KY, USA

³Department of Surgery, University of Louisville School of Medicine, Louisville, KY, USA

author email corresponding author email

Journal of Translational Medicine 2008, 6:12doi:10.1186/1479-5876-6-12

Published:	11 March 2008

Abstract

Background

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.

Methods

We 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.

Results

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.

Conclusion

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.

Trial registration

NCT00299689 (ClinicalTrials.gov Identifier).