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


Authors: Yuan, J.; Ginsberg, B.; Page, D.; Li, Y.; Rasalan, T.; Gallardo, H. F.; Xu, Y.; Adams, S.; Bhardwaj, N.; Busam, K.; Old, L. J.; Allison, J. P.; Jungbluth, A.; Wolchok, J. D.
Article Title: CTLA-4 blockade increases antigen-specific CD8+ T cells in prevaccinated patients with melanoma: Three cases
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. © 2011 Springer-Verlag.
Keywords: adult; human tissue; protein expression; aged; unclassified drug; human cell; review; case report; sorafenib; cisplatin; temozolomide; drug megadose; lymph node dissection; sentinel lymph node biopsy; cd8+ t lymphocyte; glycoprotein gp 100; interleukin 2; ipilimumab; low drug dose; melanoma; multiple cycle treatment; imiquimod; granulocyte macrophage colony stimulating factor; vinblastine; immune response; antigen specificity; ny eso 1 antigen; major histocompatibility antigen class 2; antibody response; cancer immunization; cd4+ t lymphocyte; cytokine production; dna vaccine; monophenol monooxygenase; peptide vaccine; cytotoxic t lymphocyte antigen 4; vaccines; skin surgery; protein antibody; major histocompatibility antigen class 1; t-cell response; cytotoxic t-lymphocyte antigen-4; pivac 10; integrin antibody; isoleucylthreonylaspartylglutaminylvalylpropylphenylalanylserylvaline; tyrosylmethionylaspartylglycylthreonylmethionylserylglutaminylvaline
Journal Title: Cancer Immunology, Immunotherapy
Volume: 60
Issue: 8
ISSN: 0340-7004
Publisher: Springer  
Date Published: 2011-08-01
Start Page: 1137
End Page: 1146
Language: English
DOI: 10.1007/s00262-011-1011-9
PROVIDER: scopus
PUBMED: 21465316
PMCID: PMC3654853
DOI/URL:
Notes: --- - "Export Date: 3 October 2011" - "CODEN: CIIMD" - "Source: Scopus"
Altmetric
Citation Impact
MSK Authors
  1. Jedd D Wolchok
    822 Wolchok
  2. James P Allison
    129 Allison
  3. Achim Jungbluth
    413 Jungbluth
  4. Jianda Yuan
    105 Yuan
  5. Klaus J Busam
    601 Busam
  6. Lloyd J Old
    549 Old
  7. Yanyun Li
    29 Li
  8. Teresa Rasalan
    28 Rasalan
  9. David B Page
    29 Page
  10. Yinyan Xu
    11 Xu