Translational Program

     Immune checkpoint inhibitors (ICI’s) are quickly becoming the standard of care for many cancers. As single agents, ICI’s show low response rates, but in combination with chemotherapies they benefit most patients (JAMA Netw Open., 2020, 3, e1920833). While exciting, these observations are largely empirical as we do not understand the mechanisms behind this “statistically synergy.” In addition, this result is counter-intuitive as high doses of chemotherapies are generally immunosuppressive.

Understanding the concentration and time-dependence of these immune-synergy effects is important to optimize the dose and time-interval, of clinical regimens. Clinically, drug-exposure is quantified by the product of the drug-concentration and exposure-time as the AUC (area under the cure of the blood-concentration time curve(Figure 2A)).

Different regimens result in different exposures due to the pharmacokinetic properties of different drugs. For example, for triple negative breast cancer Doxorubicin is infused over 3 hours and reaches a peak blood concentration (Cmax) of ~14 nM (Figure 2A). Once administered it’s half-life is approximately 17 hours in the body. Therefore, it is critical to evaluate Doxorubicin’s immuno-modulatory mechanisms under clinical relevant concentrations (< 14 nM) and time scales (~17 hrs).

Our working hypothesis is that both concentration and time influence the immuno-modulatory mechanisms of small molecule drugs. To better understand the time-dependence of cancer and immune-cell toxicity, we employ real-time cell-viability measurements to better understand small-molecule mechanisms under physiologically relevant concentrations and times (Figure 2B). These measurements are cross referenced with clinical regimens to clarify the temporal selectivity of clinical drugs.

Figure 2. Comparison of Clinical and Experimental Definitions of Drug-Exposure (A) Drug-concentration curves following intravenous administration of Doxorubicin (B) Dose-Response curves taken over several time points (1, 8, 10, 24, 36, 48 hours)