Focussed Research Review

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 YuanAffiliated withImmunology Program, Ludwig Center for Cancer Immunotherapy, Sloan-Kettering Institute
  • , Brian GinsbergAffiliated withImmunology Program, Ludwig Center for Cancer Immunotherapy, Sloan-Kettering Institute
  • , David PageAffiliated withDepartment of Medicine, Memorial Sloan-Kettering Cancer Center
  • , Yanyun LiAffiliated withDepartment of Medicine, Memorial Sloan-Kettering Cancer Center
  • , Teresa RasalanAffiliated withImmunology Program, Ludwig Center for Cancer Immunotherapy, Sloan-Kettering Institute
  • , Humilidad F. GallardoAffiliated withImmunology Program, Ludwig Center for Cancer Immunotherapy, Sloan-Kettering Institute
  • , Yinyan XuAffiliated withImmunology Program, Ludwig Center for Cancer Immunotherapy, Sloan-Kettering Institute
  • , Sylvia AdamsAffiliated withDepartment of Medicine, New York University Cancer Institute, NYU Langone Medical Center
  • , Nina BhardwajAffiliated withDepartment of Medicine, New York University Cancer Institute, NYU Langone Medical Center
    • , Klaus BusamAffiliated withDepartment of Pathology, Memorial Sloan-Kettering Cancer Center
    • , Lloyd J. OldAffiliated withLudwig Institute for Cancer Research, New York Branch, Memorial Sloan-Kettering Cancer Center
    • , James P. AllisonAffiliated withImmunology Program, Ludwig Center for Cancer Immunotherapy, Sloan-Kettering Institute
    • , Achim JungbluthAffiliated withLudwig Institute for Cancer Research, New York Branch, Memorial Sloan-Kettering Cancer Center
    • , Jedd D. WolchokAffiliated withImmunology Program, Ludwig Center for Cancer Immunotherapy, Sloan-Kettering InstituteDepartment of Medicine, Memorial Sloan-Kettering Cancer Center Email author 

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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

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