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01-08-2011 | Focussed Research Review

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

Authors: 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

Published in: Cancer Immunology, Immunotherapy | Issue 8/2011

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), gp100^209–217 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), tyrosinase^369–377 (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 (CCR7^loCD45RA^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.

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Title: CTLA-4 blockade increases antigen-specific CD8+ T cells in prevaccinated patients with melanoma: three cases
Authors: 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
Publication date: 01-08-2011
Publisher: Springer-Verlag
Published in: Cancer Immunology, Immunotherapy / Issue 8/2011
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-011-1011-9

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