Recently, single-agent immunotherapies have been shown to cure previously untreatable cancers. Unfortunately, these cures are only realized in small percentages of patients and most immunotherapy indications are combinations with conventional chemotherapies (chemo-IO) (Figure 1).Strikingly, some cytotoxic chemotherapies have shown evidence of statistical synergy with checkpoint inhibitors which partially explains their improved response rates.(JAMA Netw Open., 2020, 3, e1920833). While exciting, this synergy is difficult to define mechanistically which is necessary to:
- Optimize current combinations: identify ideal dosing regimen
- Build Clinical Diagnostics: distinguish responders from non-responders
- Scientific Mechanisms: to design new combinations for non-responders
The Douglass Lab’s long term goal is to define how oncology drugs affect immune cells to improve design and application of combination regimens. We hope to address these challenges with three complementary and independent approaches:
- Our Experimental Program focuses on identification (and modification) of FDA-approved drugs that that (1) selectively kill cancer cells and (2) augment a type-1 anti-cancer immune response. This work focuses on drug-transporter and metabolism enzymes that act like “armor” for different cell types by reducing the intracellular concentrations of drugs (#3 challenge above).
- Our Translational Program focuses on understanding the time-dependence of drug-efficacy and immune-adjuvant effects by measuring the viability of cancer and primary immune cells over time. This work will aid the design of optimal chemotherapy-regimens (dose, interval) to maximize chemo-IO synergy (#1 challenge above).
- Our Clinical Program focuses on developing algorithms to take a “census” of the cancer-immune “battlefield” in primary tumors. This work will aid the development of diagnostics to match chemo-IO regimens to individual patients (#2 challenge above)