SUMMARY
Better methods are needed to identify effective combinations of immunotherapies with chemotherapies and targeted anti-cancer agents. Here we present a Multiplex Implantable Microdevice Assay (MIMA) system for rapid in vivo assessment of the effects of multiple, spatially separate anticancer drugs directly in the complex tumor microenvironment. In prototypic experiments, olaparib, lenvatinib, palbociclib, venetoclax, panobinostat, doxorubicin, and paclitaxel and combinations thereof were administered simultaneously to murine mammary tumor models. Quantitative multiplex immunohistochemistry and spatial systems analyses of each local drug response defined cellular relations of fibroblasts, endothelial cells, immune lineages, immunogenic cell death, tumor proliferation and/or cancer stem cells that were used to predict effective drug combinations. A predicted combination of panobinostat, venetoclax and anti-CD40 showed long-term anti-tumor efficacy in multiple mouse models with no observable toxicity when administered systemically. Future MIMA use promises to design effective drug combinations for tumor cell control and immune activation on a personalized basis.
Competing Interest Statement
J.E.K. is a cofounder and stock holder of Convergent Genomics. GBM has licensed technologies to Myriad Genetics and Nanostring; is on the SAB or is a consultant to Amphista, AstraZeneca, Chrysallis Biotechnology, GSK, ImmunoMET, Ionis, Lilly, PDX Pharmaceuticals, Signalchem Lifesciences, Symphogen, Tarveda, Turbine, and Zentalis Pharmaceuticals; and has stock/options/financial interests in Catena Pharmaceuticals, ImmunoMet, SignalChem, and Tarveda. LMC is a paid consultant for Cell Signaling Technologies, Shasqi Inc., and AbbVie Inc.; received reagent and/or research support from Janssen Research & Development, LLC, Abbott Labs, Eisai, Inc., ImClone, Aduro Biotech, Inc., Becton Dickinson, Plexxikon Inc., Pharmacyclics, Inc., Acerta Pharma, LLC, Deciphera Pharmaceuticals, LLC, Genentech, Inc., Roche Glycart AG, Syndax Pharmaceuticals Inc., Innate Pharma, and NanoString Technologies, and Cell Signaling Technologies; and is a member of the Scientific Advisory Boards of Syndax Pharmaceuticals, Carisma Therapeutics, Zymeworks, Inc, Verseau Therapeutics, Cytomix Therapeutics, Inc., and Kineta Inc., Hibercell, Inc., Cell Signaling Technologies, Alkermes, Inc. O.J. is a consultant to Kibur Medical. Interests or Dr. Jonas were reviewed and are managed by BWH and Mass General Brigham in accordance with their conflict of interest policies. JWG has licensed technologies to Abbott Diagnostics, PDX Pharmaceuticals and Zorro Bio; has ownership positions in Convergent Genomics, Health Technology Innovations, Zorro Bio and PDX Pharmaceuticals; serves as a paid consultant to New Leaf Ventures; has received research support from Thermo Fisher Scientific (formerly FEI), Zeiss, Miltenyi Biotech, Quantitative Imaging, Health Technology Innovations and Micron Technologies; and owns stock in Abbott Diagnostics, AbbVie, Alphabet, Amazon, AMD, Amgen, Apple, Berkshire, Cisco systems, Clorox, Colgate Palmolive, Crown Castle Int., Humana, Keysight, Linde, Proctor and Gamble, Qualcomm, Unilever, Gilead, Intel, Johnson & Johnson, Microsoft, Nvidia, Taiwan Semiconductor, and Zimmer Biomet. The other authors declare no competing interests.