Acquired drug resistance in cancer encompasses a range of cellular processes that, in aggregate, reduce the efficacy of all chemotherapeutic drugs. In contrast, modern cancer immunotherapies have mechanisms of action that are fundamentally orthogonal to drug resistance. Our research program combines these paradigms by targeting the action of immunotherapeutics to two common mechanisms of acquired drug resistance: irregular metabolism and drug efflux. To do this, we have developed a process termed Bystander-Assisted ImmunoTherapy (BAIT) that <i>exploits</i> both of these mechanisms of drug resistance in tandem to elicit therapeutic immunogenicity. In BAIT, an enzyme-directed prodrug is first taken up and metabolized to active immunotherapeutic through enzymes upregulated in drug-resistant cancers. The immunostimulant metabolite then undergoes drug efflux to the extracellular space. This results in immunogenicity, as measured by transcription of NF-κB (measured in RAW-Blue macrophages) and production of T<sub>H</sub>1 polarizing cytokines (measured in JAWSII monocytes). Importantly, healthy cells do not cause immunogenicity. To-date, we have established β-galactosidase, α-mannosidase, and nitroreductase-directed BAIT prodrugs. In a murine model system, we demonstrate that BAIT prodrugs result in lower systemic inflammatory toxicity, relative to parent immunostimulant (as measured by inflammatory cytokines), with retention of anti-cancer immunogenicity. Based upon these results, we anticipate that BAIT will find use as a new mechanism of action that exploits drug resistance to generate an anti-cancer immune response.

Bystander-assisted immunotherapy: A molecular approach to drugging drug resistance

256th National Meeting (2018)

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