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

• Published in: Cancer Immunology, Immunotherapy Immunotherapy, 2011-08, Vol.60 (8), p.1137-1146
• Main Authors: Yuan, Jianda, Ginsberg, Brian, Page, David, Li, Yanyun, Rasalan, Teresa, Gallardo, Humilidad F, Xu, Yinyan, Adams, Sylvia, Bhardwaj, Nina, Busam, Klaus, Old, Lloyd J, Allison, James P, Jungbluth, Achim, Wolchok, Jedd D
• Format: Article
• Language: English
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-011-1011-9

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 super(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 super(209-217) (ITDQVPFSV), tyrosinase super(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 super(+) or CD8 super(+) T-cell response specific to the vaccine antigen but demonstrated increases in effector-memory (CCR7 super(lo)CD45RA super(lo)) tetramer super(+)CD8 super(+) 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.