CTLA-4 blockade plus adoptive T-cell transfer promotes optimal melanoma immunity in mice

David A. Mahvi, Justin V. Meyers, Andrew J. Tatar, Amanda Contreras, Marulasiddappa Suresh, Glen E. Leverson, Siddhartha Sen, Clifford S. Cho*

*Corresponding author for this work

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

Immunotherapeutic approaches to the treatment of advanced melanoma have relied on strategies that augment the responsiveness of endogenous tumor-specific T-cell populations [eg, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade-mediated checkpoint inhibition] or introduce exogenously prepared tumor-specific T-cell populations [eg, adoptive cell transfer (ACT)]. Although both approaches have shown considerable promise, response rates to these therapies remain suboptimal. We hypothesized that a combinatorial approach to immunotherapy using both CTLA-4 blockade and nonlymphodepletional ACT could offer additive therapeutic benefit. C57BL/6 mice were inoculated with syngeneic B16F10 melanoma tumors transfected to express low levels of the lymphocytic choriomeningitis virus peptide GP33 (B16GP33), and treated with no immunotherapy, CTLA-4 blockade, ACT, or combination immunotherapy of CTLA-4 blockade with ACT. Combination immunotherapy resulted in optimal control of B16GP33 melanoma tumors. Combination immunotherapy promoted a stronger local immune response reflected by enhanced tumor-infiltrating lymphocyte populations, and a stronger systemic immune responses reflected by more potent tumor antigen-specific T-cell activity in splenocytes. In addition, whereas both CTLA-4 blockade and combination immunotherapy were able to promote long-term immunity against B16GP33 tumors, only combination immunotherapy was capable of promoting immunity against parental B16F10 tumors as well. Our findings suggest that a combinatorial approach using CTLA-4 blockade with nonlymphodepletional ACT may promote additive endogenous and exogenous T-cell activities that enable greater therapeutic efficacy in the treatment of melanoma.

Original languageEnglish (US)
Pages (from-to)54-61
Number of pages8
JournalJournal of Immunotherapy
Volume38
Issue number2
DOIs
StatePublished - Feb 14 2015

Keywords

  • CTLA-4
  • T cell
  • adoptive cell transfer
  • cancer
  • immunotherapy
  • melanoma

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Pharmacology
  • Cancer Research

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  • Cite this

    Mahvi, D. A., Meyers, J. V., Tatar, A. J., Contreras, A., Suresh, M., Leverson, G. E., Sen, S., & Cho, C. S. (2015). CTLA-4 blockade plus adoptive T-cell transfer promotes optimal melanoma immunity in mice. Journal of Immunotherapy, 38(2), 54-61. https://doi.org/10.1097/CJI.0000000000000064