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 language | English (US) |
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Pages (from-to) | 1541-1552 |
Number of pages | 12 |
Journal | Cancer Immunology, Immunotherapy |
Volume | 64 |
Issue number | 12 |
DOIs | |
State | Published - Dec 1 2015 |
Keywords
- Anti-CTLA-4
- Bystander activation
- Checkpoint blockade
- Immunotherapy
- Toxicities
ASJC Scopus subject areas
- Immunology and Allergy
- Immunology
- Oncology
- Cancer Research