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

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 b...

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Published in:Cancer Immunology, Immunotherapy Immunotherapy, 2015-12, Vol.64 (12), p.1541-1552
Main Authors: Sckisel, Gail D., Mirsoian, Annie, Bouchlaka, Myriam N., Tietze, Julia K., Chen, Mingyi, Blazar, Bruce R., Murphy, William J.
Format: Article
Language:English
Subjects:
Animals
Antigens
Cancer Research
Cancer therapies
CD8 Antigens - metabolism
CD8-Positive T-Lymphocytes - cytology
CD8-Positive T-Lymphocytes - immunology
Cell Line, Tumor
Cell Proliferation - drug effects
CTLA-4 Antigen - antagonists & inhibitors
Cytokines
Cytotoxicity
Drug dosages
FDA approval
Flow Cytometry
Humans
Immunology
Immunotherapy
Interleukin-2 - pharmacology
Ligands
Lymphocytes
Medicine
Medicine & Public Health
Metastasis
Mice
Mice, Inbred C57BL
Neoplasms - immunology
Neoplasms - mortality
Neoplasms - therapy
Oncology
Original Article
Recombinant Fusion Proteins - administration & dosage
Recombinant Fusion Proteins - pharmacology
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Summary: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.
ISSN:0340-7004
1432-0851
DOI:10.1007/s00262-015-1759-4