Transient T cell depletion causes regression of melanoma metastases.

J Transl Med 2008 Mar 11;6:12. Epub 2008 Mar 11.

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

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 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.

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).

Download full-text PDF

Source
http://dx.doi.org/10.1186/1479-5876-6-12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2330026PMC
March 2008
4 Reads

Publication Analysis

Top Keywords

treg cells
16
cd8+ cells
16
cells
15
neoplastic cells
12
melanoma metastases
8
cognate immunity
8
effector cells
8
transient depletion
8
novo appearance
8
cd4+ cd8+
8
melanoma
5
cd8+
5
patients
5
cell subsets
4
metastatic tumor
4
subsets tumor
4
tumor remained
4
concentration cell
4
appearance mart-1-specific
4
single metastatic
4

Similar Publications