Abstract
BackgroundNumerous oncology combination therapies involving modulators of the cancer immune cycle are being developed, yet quantitative simulation models predictive of outcome are lacking. We here present a model-based analysis of tumor size dynamics and immune markers, which integrates experimental data from multiple studies and provides a validated simulation framework predictive of biomarkers and anti-tumor response rates, for untested dosing sequences and schedules of combined radiation (RT) and anti PD-(L)1 therapies.MethodsA quantitative systems pharmacology model, which includes key elements of the cancer immunity cycle and the tumor microenvironment, tumor growth, as well as dose-exposure-target modulation features, was developed to reproduce experimental data of CT26 tumor size dynamics upon administration of RT and/or a pharmacological IO treatment such as an anti-PD-L1 agent. Variability in individual tumor size dynamics was taken into account using a mixed-effects model at the level of tumor-infiltrating T cell influx.ResultsThe model allowed for a detailed quantitative understanding of the synergistic kinetic effects underlying immune cell interactions as linked to tumor size modulation, under these treatments. The model showed that the ability of T cells to infiltrate tumor tissue is a primary determinant of variability in individual tumor size dynamics and tumor response. The model was further used as an in silico evaluation tool to quantitatively predict, prospectively, untested treatment combination schedules and sequences. We demonstrate that anti-PD-L1 administration prior to, or concurrently with RT reveal further synergistic effects, which, according to the model, may materialize due to more favorable dynamics between RT-induced immuno-modulation and reduced immuno-suppression of T cells through anti-PD-L1.ConclusionsThis study provides quantitative mechanistic explanations of the links between RT and anti-tumor immune responses, and describes how optimized combinations and schedules of immunomodulation and radiation may tip the immune balance in favor of the host, sufficiently to lead to tumor shrinkage or rejection.
Highlights
Numerous oncology combination therapies involving modulators of the cancer immune cycle are being developed, yet quantitative simulation models predictive of outcome are lacking
RT may lead to immunogenic cell death (ICD), which is characterized by the release of damage-associated molecular patterns (DAMPs; e.g., ATP, HMGB-1) from cancer cells, translocation of calreticulin molecules to the plasma membrane, and activation of the cGAS-STING pathway [3]
Mathematical modeling of the cancer immunity cycle, with the incorporation of RT and anti-PD-L1 therapies We developed the mathematics of the quantitative systems pharmacology (QSP) model, which includes key elements of the cancer immunity cycle and the tumor microenvironment [16], tumor growth, as well as dose-exposure-target modulation features, to reproduce experimental data of CT26 tumor size dynamics upon administration of RT and/or a pharmacological IO treatment such as an anti-PD-L1 agent (Fig. 1a)
Summary
Numerous oncology combination therapies involving modulators of the cancer immune cycle are being developed, yet quantitative simulation models predictive of outcome are lacking. RT may lead to immunogenic cell death (ICD), which is characterized by the release of damage-associated molecular patterns (DAMPs; e.g., ATP, HMGB-1) from cancer cells, translocation of calreticulin molecules to the plasma membrane, and activation of the cGAS-STING pathway [3]. Together, these factors can facilitate the recruitment and activation of antigen presenting cells (APCs), such as dendritic cells (DCs), to prime tumor antigen specific T cells [4,5,6]. Therapeutic blockade of PD-1 or PD-L1 using monoclonal antibodies (mAbs) have demonstrated encouraging responses in patients with melanoma, nonsmall cell lung cancer (NSCLC), as well as renal cell and bladder cell carcinoma [10]
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