A multiplex implantable microdevice assay identifies synergistic combinations of cancer immunotherapies and conventional drugs

Zuzana Tatarova, Dylan C. Blumberg, James E. Korkola, Laura M. Heiser, John L. Muschler, Pepper J. Schedin, Sebastian W. Ahn, Gordon B. Mills, Lisa M. Coussens, Oliver Jonas, Joe W. Gray

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Systematically identifying synergistic combinations of targeted agents and immunotherapies for cancer treatments remains difficult. In this study, we integrated high-throughput and high-content techniques—an implantable microdevice to administer multiple drugs into different sites in tumors at nanodoses and multiplexed imaging of tumor microenvironmental states—to investigate the tumor cell and immunological response signatures to different treatment regimens. Using a mouse model of breast cancer, we identified effective combinations from among numerous agents within days. In vivo studies in three immunocompetent mammary carcinoma models demonstrated that the predicted combinations synergistically increased therapeutic efficacy. We identified at least five promising treatment strategies, of which the panobinostat, venetoclax and anti-CD40 triple therapy was the most effective in inducing complete tumor remission across models. Successful drug combinations increased spatial association of cancer stem cells with dendritic cells during immunogenic cell death, suggesting this as an important mechanism of action in long-term breast cancer control.

Original languageEnglish (US)
Pages (from-to)1823-1833
Number of pages11
JournalNature biotechnology
Volume40
Issue number12
DOIs
StatePublished - Dec 2022

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Biomedical Engineering
  • Applied Microbiology and Biotechnology
  • Molecular Medicine

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