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

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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.

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Abbreviations

αCD40:

Anti-CD40

ALT:

Alanine aminotransferase

ANOVA:

Analysis of variance

CAR:

Chimeric antigen receptor

CTLA-4:

Cytotoxic T lymphocyte antigen 4

FDA:

Food and Drug Administration

IFN:

Interferon

IL:

Interleukin

IT:

Immunotherapy with anti-CD40/IL-2

MTD:

Maximum tolerated dose

NKG2D:

Natural killer group 2D

OVA:

Ovalbumin

PD-1:

Programmed death-1

PD-L1:

Programmed death ligand-1

TCR:

T cell receptor

TNF:

Tumor necrosis factor

TREG :

Regulatory T cell

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Acknowledgments

We would like to acknowledge both Monja Dawson-Metcalf and Weihong Ma for their excellent technical assistance. We would also like to acknowledge A. A. Hurwitz for helpful discussions and guidance with the preparation of this manuscript. This work was funded by a Grant from the NIH R01 CA095572.

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Authors and Affiliations

  1. Department of Dermatology, University of California, Davis, School of Medicine, IRC Building Rm 1630, 2921 Stockton Blvd., Sacramento, CA, 95817, USA

    Gail D. Sckisel, Annie Mirsoian, Myriam N. Bouchlaka, Julia K. Tietze & William J. Murphy

  2. Department of Pathology, University of California, School of Medicine, Sacramento, CA, USA

    Mingyi Chen

  3. Department of Pediatrics, Division of Bone Marrow Transplantation, University of Minnesota Cancer Center, Minneapolis, MN, USA

    Bruce R. Blazar

  4. Department of Internal Medicine, University of California, Davis, School of Medicine, Sacramento, CA, USA

    William J. Murphy

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  1. Gail D. Sckisel
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Correspondence to William J. Murphy.

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Sckisel, G.D., Mirsoian, A., Bouchlaka, M.N. et al. Late administration of murine CTLA-4 blockade prolongs CD8-mediated anti-tumor effects following stimulatory cancer immunotherapy. Cancer Immunol Immunother 64, 1541–1552 (2015). https://doi.org/10.1007/s00262-015-1759-4

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