The Immune Checkpoint Kick Start: Optimization of Neoadjuvant Combination Therapy Using Game Theory

Abstract

Purpose In an upcoming clinical trial at the Moffitt Cancer Center for women with stage 2/3 estrogen receptor–positive breast cancer, treatment with an aromatase inhibitor and a PD-L1 checkpoint inhibitor combination will be investigated to lower a preoperative endocrine prognostic index (PEPI) that correlates with relapse-free survival. PEPI is fundamentally a static index, measured at the end of neoadjuvant therapy before surgery. We have developed a mathematical model of the essential components of the PEPI score to identify successful combination therapy regimens that minimize tumor burden and metastatic potential, on the basis of time-dependent trade-offs in the system. Methods We considered two molecular traits, CCR7 and PD-L1, which correlate with treatment response and increased metastatic risk. We used a matrix game model with the four phenotypic strategies to examine the frequency-dependent interactions of cancer cells. This game was embedded in an ecological model of tumor population-growth dynamics. The resulting model predicts evolutionary and ecological dynamics that track with changes in the PEPI score. Results We considered various treatment regimens on the basis of combinations of the two therapies with drug holidays. By considering the trade off between tumor burden and metastatic potential, the optimal therapy plan was a 1-month kick start of the immune checkpoint inhibitor followed by 5 months of continuous combination therapy. Relative to a protocol giving both therapeutics together from the start, this delayed regimen resulted in transient suboptimal tumor regression while maintaining a phenotypic constitution that is more amenable to fast tumor regression for the final 5 months of therapy. Conclusion The mathematical model provides a useful abstraction of clinical intuition, enabling hypothesis generation and testing of clinical assumptions.

Disease Classification in Health Care Systems With Game Theory Approach

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Introduction to Mathematical Oncology

“…Using a mathematical modeling approach known as game theory, West et al 13 investigate potential strategies to optimize neoadjuvant combination therapies that include checkpoint inhibitors. They examined a clinical trial design that combines an aromatase inhibitor and a checkpoint inhibitor to treat women with stage 2 or 3 estrogen receptor–positive breast cancer.…”

Macrophage-mediated immunoediting drives ductal carcinoma evolution: Space is the game changer

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