Cancer Immunology, Immunotherapy

, Volume 60, Issue 8, pp 1137–1146

CTLA-4 blockade increases antigen-specific CD8+ T cells in prevaccinated patients with melanoma: three cases

  • Jianda Yuan
  • Brian Ginsberg
  • David Page
  • Yanyun Li
  • Teresa Rasalan
  • Humilidad F. Gallardo
  • Yinyan Xu
  • Sylvia Adams
  • Nina Bhardwaj
  • Klaus Busam
  • Lloyd J. Old
  • James P. Allison
  • Achim Jungbluth
  • Jedd D. Wolchok
Focussed Research Review

DOI: 10.1007/s00262-011-1011-9

Cite this article as:
Yuan, J., Ginsberg, B., Page, D. et al. Cancer Immunol Immunother (2011) 60: 1137. doi:10.1007/s00262-011-1011-9

Abstract

Background

Anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibodies, such as ipilimumab, have generated measurable immune responses to Melan-A, NY-ESO-1, and gp100 antigens in metastatic melanoma. Vaccination against such targets has potential for immunogenicity and may produce an effector-memory T-cell response.

Methods

To determine the effect of CTLA-4 blockade on antigen-specific responses following vaccination, in-depth immune monitoring was performed on three ipilimumab-treated patients prevaccinated with gp100 DNA (IMF-24), gp100209–217 and tyrosinase peptides plus GM-CSF DNA (IMF-32), or NY-ESO-1 protein plus imiquimod (IMF-11); peripheral blood mononuclear cells were analyzed by tetramer and/or intracellular cytokine staining following 10-day culture with HLA-A*0201-restricted gp100209–217 (ITDQVPFSV), tyrosinase369–377 (YMDGTMSQV), or 20-mer NY-ESO-1 overlapping peptides, respectively. Tumors from IMF-32 were analyzed by immunohistochemistry to help elucidate mechanism(s) underlying tumor escape.

Results

Following vaccination, patients generated weak to no CD4+ or CD8+ T-cell response specific to the vaccine antigen but demonstrated increases in effector-memory (CCR7loCD45RAlo) tetramer+CD8+ T cells. After ipilimumab induction, patients experienced a robust, although sometimes transient, antigen-specific response for gp100 (IMF-32 and IMF-24) or NY-ESO-1 (IMF-11) and produced polyfunctional intracellular cytokines. Primary and metastatic tumors expressed tyrosinase but not gp100 or class I/II MHC molecules.

Conclusion

Vaccination induced a measurable antigen-specific T-cell response that increased following CTLA-4 blockade, potentially “boosting” the vaccine-primed response. Tumor escape may be related to antigen loss or lack of MHC expression necessary for immune activity. These results in a limited number of patients support the need for further research into combining vaccination with ipilimumab and provide insight into mechanisms underlying tumor escape.

Keywords

MelanomaCytotoxic T-lymphocyte antigen-4IpilimumabT-cell responseVaccinesPIVAC 10

Abbreviations

ALC

Absolute lymphocyte count

CTLA-4

Cytotoxic T-lymphocyte antigen-4

GM-CSF

Granulocyte macrophage colony-stimulating factor

H&E

Hematoxylin and eosin

ICOS

Inducible co-stimulator

ICS

Intracellular cytokine staining

IHC

Immunohistochemistry

PBMC

Peripheral blood mononuclear cell

WBC

White blood cell

Supplementary material

262_2011_1011_MOESM1_ESM.pdf (663 kb)
Supplementary material 1 (PDF 662 kb)

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Jianda Yuan
    • 1
  • Brian Ginsberg
    • 1
  • David Page
    • 2
  • Yanyun Li
    • 2
  • Teresa Rasalan
    • 1
  • Humilidad F. Gallardo
    • 1
  • Yinyan Xu
    • 1
  • Sylvia Adams
    • 3
  • Nina Bhardwaj
    • 3
  • Klaus Busam
    • 4
  • Lloyd J. Old
    • 5
  • James P. Allison
    • 1
  • Achim Jungbluth
    • 5
  • Jedd D. Wolchok
    • 1
    • 2
  1. 1.Immunology ProgramLudwig Center for Cancer Immunotherapy, Sloan-Kettering InstituteNew YorkUSA
  2. 2.Department of MedicineMemorial Sloan-Kettering Cancer CenterNew YorkUSA
  3. 3.Department of MedicineNew York University Cancer Institute, NYU Langone Medical CenterNew YorkUSA
  4. 4.Department of PathologyMemorial Sloan-Kettering Cancer CenterNew YorkUSA
  5. 5.Ludwig Institute for Cancer Research, New York BranchMemorial Sloan-Kettering Cancer CenterNew YorkUSA