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Open AccessArticle

Modeling Immune Checkpoint Inhibitor Efficacy in Syngeneic Mouse Tumors in an Ex Vivo Immuno-Oncology Dynamic Environment

1
Draper, Bioengineering Division, Cambridge, MA 02139, USA
2
Charles River Research Services Germany GmbH, 79108 Freiburg, Germany
3
Charles River Laboratories, Wilmington, MA 01887, USA
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2020, 21(18), 6478; https://doi.org/10.3390/ijms21186478
Received: 13 July 2020 / Revised: 20 August 2020 / Accepted: 26 August 2020 / Published: 4 September 2020
(This article belongs to the Special Issue Therapeutic Molecular Targets in Tumor Microenvironment)
The immune checkpoint blockade represents a revolution in cancer therapy, with the potential to increase survival for many patients for whom current treatments are not effective. However, response rates to current immune checkpoint inhibitors vary widely between patients and different types of cancer, and the mechanisms underlying these varied responses are poorly understood. Insights into the antitumor activities of checkpoint inhibitors are often obtained using syngeneic mouse models, which provide an in vivo preclinical basis for predicting efficacy in human clinical trials. Efforts to establish in vitro syngeneic mouse equivalents, which could increase throughput and permit real-time evaluation of lymphocyte infiltration and tumor killing, have been hampered by difficulties in recapitulating the tumor microenvironment in laboratory systems. Here, we describe a multiplex in vitro system that overcomes many of the deficiencies seen in current static histocultures, which we applied to the evaluation of checkpoint blockade in tumors derived from syngeneic mouse models. Our system enables both precision-controlled perfusion across biopsied tumor fragments and the introduction of checkpoint-inhibited tumor-infiltrating lymphocytes in a single experiment. Through real-time high-resolution confocal imaging and analytics, we demonstrated excellent correlations between in vivo syngeneic mouse and in vitro tumor biopsy responses to checkpoint inhibitors, suggesting the use of this platform for higher throughput evaluation of checkpoint efficacy as a tool for drug development. View Full-Text
Keywords: immune checkpoint blockade; cancer; tumor microenvironment; lymphocytes; syngeneic models; microfluidics immune checkpoint blockade; cancer; tumor microenvironment; lymphocytes; syngeneic models; microfluidics
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Doty, D.T.; Schueler, J.; Mott, V.L.; Bryan, C.M.; Moore, N.F.; Ho, J.C.; Borenstein, J.T. Modeling Immune Checkpoint Inhibitor Efficacy in Syngeneic Mouse Tumors in an Ex Vivo Immuno-Oncology Dynamic Environment. Int. J. Mol. Sci. 2020, 21, 6478.

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