Mechanistic mathematical modeling of abscopal effect reveals mechanisms of off-target tumor response.

Introduction: Local radiotherapy rarely triggers regression of distant, non-irradiated tumors (the "abscopal" effect), but this outcome is unpredictable because it depends on interacting processes, such as antigen release, antigen presentation, T-cell priming and trafficking, and lymphoid health. To study these interactions quantitatively and identify dominant mechanisms that control off-target tumor responses, we built an integrated physiologically based pharmacokinetic - quantitative systems pharmacology (PBPK-QSP) model. Methods: The PBPK-QSP model tracks immune (dendritic cells, M1/M2 macrophages, Tregs, naïve and effector CD8 Results: Four mechanisms dominate outcome variability: antigen capture/processing by phagocytes (i.e., dendritic cells and macrophages), clearance of dead-cell debris and antigens, and naïve T-cell regenerative capacity in lymph nodes. Phagocytic and clearance rates have context-dependent effects, too fast shortens the antigen-priming window, and too slow results in less overall antigen-priming. Lymph-node irradiation shifts the dependence of immune response to T-cell recovery, which becomes the dominant mechanism. The model also highlights that impaired tumor vascular permeability can constrain effector infiltration and mute intratumoral CD8 Discussion: The PBPK-QSP model identifies specific, actionable mechanisms controlling abscopal responses and suggests three complementary strategies to increase the chance of abscopal responses: i) optimize radiotherapy dose/fractionation to maximize immunogenic antigen release while sparing lymphoid tissue when possible, ii) combine radiotherapy with interventions that prolong productive antigen presentation and modulate debris clearance, and iii) protect/restore lymphoid regenerative capacity.