Transient T cell depletion causes regression of melanoma metastases

J Transl Med. 2008 Mar 11;6:12. doi: 10.1186/1479-5876-6-12.

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 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).

Publication types

  • Clinical Trial, Phase II
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antigens, Neoplasm / metabolism
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Cell Line, Tumor
  • Diphtheria Toxin / pharmacology*
  • Diphtheria Toxin / therapeutic use
  • Female
  • Humans
  • Immunoglobulin G / metabolism
  • Interleukin-2 / pharmacology*
  • Interleukin-2 / therapeutic use
  • Leukocyte Count
  • Male
  • Melanoma / drug therapy*
  • Melanoma / immunology*
  • Melanoma / pathology
  • Middle Aged
  • Neoplasm Metastasis / drug therapy
  • Neoplasm Metastasis / immunology
  • Neoplasm Metastasis / pathology
  • Recombinant Fusion Proteins / pharmacology
  • Recombinant Fusion Proteins / therapeutic use
  • Remission Induction
  • Skin Neoplasms / drug therapy
  • Skin Neoplasms / immunology
  • Skin Neoplasms / pathology
  • T-Lymphocyte Subsets / drug effects*
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocytes, Regulatory / drug effects*
  • T-Lymphocytes, Regulatory / immunology
  • Time Factors
  • Treatment Outcome
  • Tumor Burden

Substances

  • Antigens, Neoplasm
  • Antineoplastic Agents
  • Diphtheria Toxin
  • Immunoglobulin G
  • Interleukin-2
  • Recombinant Fusion Proteins
  • denileukin diftitox

Associated data

  • ClinicalTrials.gov/NCT00299689