Late administration of murine CTLA-4 blockade prolongs CD8-mediated anti-tumor effects following stimulatory cancer immunotherapy

Gail D. Sckisel, Annie Mirsoian, Myriam N. Bouchlaka, Julia K. Tietze, Mingyi Chen, Bruce R. Blazar, William J. Murphy

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

We have demonstrated that immunostimulatory therapies such as interleukin-2 (IL-2) and anti-CD40 (αCD40) can be combined to deliver synergistic anti-tumor effects. While this strategy has shown success, efficacy varies depending on a number of factors including tumor type and severe toxicities can be seen. We sought to determine whether blockade of negative regulators such as cytotoxic T lymphocyte antigen-4 (CTLA-4) could simultaneously prolong CD8+ T cell responses and augment T cell anti-tumor effects. We devised a regimen in which anti-CTLA-4 was administered late so as to delay contraction and minimize toxicities. This late administration both enhanced and prolonged CD8 T cell activation without the need for additional IL-2. The quality of the T cell response was improved with increased frequency of effector/effector memory phenotype cells along with improved lytic ability and bystander expansion. This enhanced CD8 response translated to improved anti-tumor responses both at the primary and metastatic sites. Importantly, toxicities were not exacerbated with combination. This study provides a platform for rational design of immunotherapy combinations to maximize anti-tumor immunity while minimizing toxicities.

Original languageEnglish (US)
Pages (from-to)1541-1552
Number of pages12
JournalCancer Immunology, Immunotherapy
Volume64
Issue number12
DOIs
StatePublished - Dec 1 2015

Keywords

  • Anti-CTLA-4
  • Bystander activation
  • Checkpoint blockade
  • Immunotherapy
  • Toxicities

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