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

Research output: Contribution to journalReview articlepeer-review

77 Scopus citations

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 gp100 209-217 (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 (CCR7loCD45RA lo) 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.

Original languageEnglish
Pages (from-to)1137-1146
Number of pages10
JournalCancer Immunology, Immunotherapy
Volume60
Issue number8
DOIs
StatePublished - Aug 2011
Externally publishedYes

Keywords

  • Cytotoxic T-lymphocyte antigen-4
  • Ipilimumab
  • Melanoma
  • PIVAC 10
  • T-cell response
  • Vaccines

Fingerprint

Dive into the research topics of 'CTLA-4 blockade increases antigen-specific CD8+ T cells in prevaccinated patients with melanoma: Three cases'. Together they form a unique fingerprint.

Cite this