Radiation and anti-PD-L1 treatment combinations: Immune cell responses and dose scheduling optimization using a joint experimental and systems modeling approach
Yuri Kosinsky (1), Simon Dovedi (2), Kirill Peskov (1), Veronika Voronova (1), Lulu Chu (3a), Eric Masson (3a), Helen Tomkinson (3b), Nidal Al-Huniti (3a), Don Stanski (3c), Gabriel Helmlinger (3a)
1 M&S Decisions, Moscow, Russia; 2 MedImmune, Cambridge, UK; 3 Early Clinical Development, IMED Biotech Unit, AstraZeneca; 3a Waltham, MA, USA; 3b Cambridge, UK;3c Gaithersburg, MD, USA
Objectives: Investigations into the interactions between radiotherapy(RT) and the host immune system have uncovered new mechanisms that can potentially be exploited to improve the efficacy of RT . RT not only exerts direct cytotoxic effects on tumor cells, but may also modulate the tumor microenvironment to facilitate a significant anti-tumor immune response. Combination therapies of radiation and mAb blockade of the immuno-suppressive programmed death-ligand 1 (PD-L1) have indeed shown synergy in a number of preclinical studies [2, 3].
Methods: Based on data from , we developed and independently validated a semi-mechanistic population model of anti-tumor T cell immune response development linked to CT26 tumor size dynamics in mice, under control, mono- and combination settings of RT and anti-PD-L1 treatments. Variability in individual tumor size dynamics was taken into account using a mixed effects model at the level of tumor infiltrating T effector cell influx.
Results: Upon validation, the proposed model was used successfully to reproduce anti-tumor efficacy in a broad range of therapeutically-realistic RT and anti-PD-L1 mono- and combination dosing schedules. Also the model is able to reproduce the tumor size dynamics under CD8+ cell depletion conditions, highlighting a pivotal role of T effector cells in RT-induced tumor growth inhibition.
Using such a validated QSP model, we gained a detailed quantitative understanding of the synergistic effects underlying immune cell interactions as linked to tumor size modulation, under RT and anti-PD-L1 treatments. We further show the potential in using this model as an in-silico evaluation tool to explore, prospectively, different combination dosing regimens and sequencing, in order to achieve optimal anti-tumor responses. Particularly, a single-dose RT 10 Gy scenario with concurrent anti-PD-L1 (0.2 mg 3qw) was found to be optimal for CT26 tumor bearing mice.
Conclusions: This modeling study provided quantitative mechanistic explanations of the links between RT and anti-tumor immune responses, and described how appropriate combinations and schedules of immuno-modulation and radiation may tip the immune balance in favor of host, robustly enough to lead to tumor shrinkage or rejection.
 R. R.Weichselbaum et al. “Radiotherapy and immunotherapy: a beneficial liaison?” (2017) Nature Rev Clin Oncol. doi:10.1038/nrclinonc.2016.211
 S. J. Dovedi et al. “Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade”. (2014) Cancer Res 74: 5458-5468.
 L. Deng et al. “Irradiation and anti–PD-L1 treatment synergistically promote antitumor immunity in mice”. (2014) J Clin Invest. 124:687–695.