Transient T cell depletion causes regression of melanoma metastases.
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.


CONCLUSIONS
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.


BACKGROUND
NCT00299689 (ClinicalTrials.gov Identifier).
Rasku
Mary Ann
MA
Molecular Targets Program, James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA. m0rask01@gwise.louisville.edu
Clem
Amy L
AL
Telang
Sucheta
S
Taft
Beverly
B
Gettings
Kelly
K
Gragg
Hana
H
Cramer
Daniel
D
Lear
Sheron C
SC
McMasters
Kelly M
KM
Miller
Donald M
DM
Chesney
Jason
J
D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004167:Diphtheria Toxin / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D007376:Interleukin-2 / Q000494:pharmacology* / Q000627:therapeutic use; D007958:Leukocyte Count; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D011993:Recombinant Fusion Proteins / Q000494:pharmacology / Q000627:therapeutic use; D012074:Remission Induction; D012878:Skin Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology; D013997:Time Factors; D016896:Treatment Outcome; D047368:Tumor Burden
D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004167:Diphtheria Toxin; D007074:Immunoglobulin G; D007376:Interleukin-2; D011993:Recombinant Fusion Proteins; C078456:denileukin diftitox