3079 - Modeling RT-Induced Immune Priming to Optimize Immunotherapy Timing in Radiotherapy

05:00pm - 06:00pm PT

Hall F

Screen: 12

POSTER

Presenter(s)

Daisuke Kawahara, PhD - Hiroshima University, Hiroshima, Hiroshima

D. Kawahara¹, M. Kishi², Y. Murakami³, and Y. Watanabe⁴; ¹Department of Radiation Oncology, Hiroshima University Hospital, Hiroshima, Japan, ²Hiroshima University, Hiroshima, Japan, ³Department of Radiation Oncology, Graduate School of Biomedical Health Sciences, Hiroshima University, Hiroshima, Japan, ⁴University of Minnesota: Department of Radiation Oncology, Minneapolis, MN

Purpose/Objective(s):

Combination therapies with immunotherapy (IT) and radiotherapy (RT) are widely used, but the optimal IT timing is unclear. This study leverages a computational cellular automaton (CA) model, calibrated with clinical data, to investigate the timing of IT alongside fractionated RT, with the goal of maximizing Tumor Control Probability (TCP).

Materials/Methods:

A cellular automaton (CA) model was developed to simulate spatial and temporal tumor dynamics in head and neck cancer, calibrated to match clinical TCP data (~20-30%) by adjusting key parameters such as a, ß, repair rate, immune activation rate, and clearance rate. The CA model accounted for interactions between tumor proliferation, hypoxia-driven VEGF production, angiogenesis, and immune-mediated cell death. RT (35 fractions of 2 Gy) was simulated to induce RT-induced immune priming (RTIP), a process wherein RT-driven tumor cell death and antigen release enhance immune activation through APC stimulation, facilitated by reoxygenation and countered by immunosuppressive factors such as TGF-ß. IT effects were modeled as APC-mediated immune activation and effector recruitment, modulated by RTIP. The timing of IT initiation was adjusted between 0 and 35 days after RT start to investigate its relationship with TCP. Sensitivity analysis of oxygen consumption revealed that higher consumption levels tended to delay immune activation.

Results:

IT combined with RT significantly improved TCP compared to RT alone, achieving 80-86% when initiated within two weeks of RT start. TCP showed a transient drop when IT began within 6-8 days post-RT, improving between days 9 and 14 due to immune activation. The increase of immune cell activity corresponds to RTIP, in which antigen release from RT-induced tumor cell death and reoxygenation of the tumor microenvironment enhance APC activation, leading to T-cell recruitment and activation. Sensitivity analysis of oxygen consumption further indicated that greater oxygen consumption prolonged the time required for immune activation, likely due to delayed reoxygenation and subsequent RTIP.

Conclusion:

The highest TCP was achieved when IT was initiated within two weeks of RT start, underscoring the role of RT-induced immune priming (RTIP) in optimizing immune response timing. These findings highlight the potential of computational models to optimize combination cancer therapies and suggest that oxygen consumption dynamics play a critical role in RTIP and immune activation timing.