Abstract
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.
Highlights
The emergence of monoclonal antibodies that target immune checkpoint pathways is one of the most promising developments in the recent history of cancer treatment, with extraordinary clinical responses observed for particular groups of patients and specific types of cancers
This study showed for the first time that a dynamic in vitro tumor microenvironment can be utilized to distinguish differences in response between two different immune checkpoint inhibitors (ICIs) therapies, anti-CTLA4 and anti-PD-1, against three different syngeneic mouse lines, MC38, CT26 and B16F10, all well-established models for cancer research [40,41]
The EVIDENT results obtained on the three different syngeneic mouse tumor lines for each of two checkpoint inhibitors and a control compound were contextualized by comparison with in vivo studies using the same tumor models and same treatment compounds
Summary
The emergence of monoclonal antibodies that target immune checkpoint pathways is one of the most promising developments in the recent history of cancer treatment, with extraordinary clinical responses observed for particular groups of patients and specific types of cancers. Immune checkpoint inhibitors target specific pathways such as CTLA4 and PD-1, and have shown remarkable success against melanoma [4], non-small-cell lung cancer [5], and Hodgkin’s lymphoma [6], with mixed results in several other cancers Since their approval in 2014, two immune checkpoint inhibitors have vaulted into the ten top-selling prescription drugs in the world, and approvals for new drugs and applications to additional types of cancer continue to mount. In spite of these dramatic successes, further progress is limited by additional resistance pathways and the potential need for involvement of multiple checkpoint inhibitors Exploration of these pathways and mechanisms would benefit from preclinical models with higher throughput; systems that can shed light on underlying mechanisms of resistance, response, and off-target effects; and technologies capable of directly evaluating human tumor tissue. These requirements have spurred efforts toward the development of model systems that recapitulate key aspects of the tumor microenvironment and that can be used to screen responses to emerging ICIs and combination therapies, which will be critical to future advances in immunotherapy [7]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
