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

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.

How to build a tumor: An industry perspective

“…The advancement of microfluidic technologies led to the development of organ-on-a-chip systems that incorporate perfusion flow into cell culture systems, providing functions including oxygen and nutrient supply, fluid shear and gradient control that might be crucial to different aspects of cancer biology such as angiogenesis, metastasis and immune cell infiltration. 53 Applications range from toxicology to different disease models. [54] , [55] Regarding oncology, the fluidic connection of different cell compartments mirrors closely the metastasis cascade, making this technology predestined to studying this complex biological process.…”

Technological and computational advances driving high-throughput oncology

“…These tissue sections can be trapped on a multiwell microfluidic platform and tested for drug sensitivity (Figure 2B). In addition, these platforms permit the evaluation of responses to checkpoint inhibitors, as the microdissected tumor samples preserve and recapitulate the crucial cell-cell interactions between immune and cancer cells [81,82]. Although the complex setup currently keeps such methods at a low throughput for drug screening (less than 20 channels or chambers per device) [79,80], the approach tends to offer a more complete model of the tumor and its microenvironment in comparison to artificial organoids and spheroids.…”

Golden Syrian Hamster Models for Cancer Research

“…Notably, genetically engineered animal models have been extremely valuable in evaluating emerging precision cancer therapies. An example was the development of immune checkpoint inhibitors (ICIs) that were first tested in several types of mouse models (KO, immunodeficient, humanized, syngeneic) that recapitulate human immune responses to ICIs in vivo, including both efficacy [ 24 , 25 , 26 ] and the risk of adverse events [ 27 ]. At the cancer cell and molecular level, rodent models have been invaluable in understanding fundamental issues in cancer cell biology such as the role of environmental factors, both external factors such as UV exposure, air and water pollutants, viral infections, cigarette smoke, and internal factors such as how obesity and other metabolic disorders play a role in cancer development; how cancer cells grow; cancer gene–gene cooperation and cancer gene–environment interactions; factors that drive cancer progression from premalignant states through to metastasis; understanding mechanisms underlying cancer cell migration and invasion of neighboring normal tissues, in particular epithelial to mesenchymal transition (EMT); how cancers metastasize and target specific tissues; factors that determine how metastatic cancer cells can become dormant and resistant to chemotherapy and then awaken and cause cancer recurrence; the nature of cancer stem cell/progenitors in specific tissues; how cancer cells communicate with their neighboring stromal cells; how cancer cells develop chemoresistance; how cancer cells are influenced by and in turn influence local microbiomes; how the host immune system detects and responds to cancers, and how cancer cells adapt strategies to evade the host immune response, and how cancers can be detected at early stages that are more responsive to effective therapy.…”