Mechanisms of Synergy and Resistance: Modeling Dynamic PD-L1 Regulation in Combination Immunotherapy

Speaker: Bruce Pell

The efficacy of Immune Checkpoint Inhibitors (ICIs) is frequently limited by adaptive immune resistance via the PD-1/PD-L1 pathway. While pairing ICls with potent immunostimulants (such as NHS-mulL12) offers a strategy to overcome this, foundational mathematical models often struggle to capture complex preclinical behaviors, specifically non-monotonic tumor responses.

In this talk, we introduce a refined deterministic model that addresses this limitation by incorporating PD-L1 expression as a fully dynamic variable rather than a static parameter. We demonstrate that this model, using a single parameter set, successfully reproduces experimental data across six distinct treatment arms, including monotherapies and combinations. This framework provides a robust mechanistic explanation for dose-dependent treatment failure driven by adaptive PD-L1 upregulation, while also elucidating the drivers of therapeutic stability and dynamics.