Modeling Radioimmune Response-Current Status and Perspectives

Abstract

The combination of immune therapy with radiation offers an exciting and promising treatment modality in cancer therapy. It has been hypothesized that radiation induces damage signals within the tumor, making it more detectable for the immune system. In combination with inhibiting immune checkpoints an effective anti-tumor immune response may be established. This inversion from tumor immune evasion raises numerous questions to be solved to support an effective clinical implementation: These include the optimum immune drug and radiation dose time courses, the amount of damage and associated doses required to stimulate an immune response, and the impact of lymphocyte status and dynamics. Biophysical modeling can offer unique insights, providing quantitative information addressing these factors and highlighting mechanisms of action. In this work we review the existing modeling approaches of combined 'radioimmune' response, as well as associated fields of study. We propose modeling attempts that appear relevant for an effective and predictive model. We emphasize the importance of the time course of drug and dose delivery in view to the time course of the triggered biological processes. Special attention is also paid to the dose distribution to circulating blood lymphocytes and the effect this has on immune competence.

Keywords: immunotherapy; modeling; radiation effect; radiation immunity; radiation therapy.

Figure 1

General paradigm underlying RIT using immune checkpoint blockers from a modeler’s perspective: The abundance of tumor cells, lymphocyte attracting signals and activated lymphocytes are three quantities that depend on each other, but are also impacted by external agents such as radiation and immune checkpoint blockers. The synergy of coupling radiation and immune therapy emerges, as radiation amplifies signals that are exploited for tumor cell recognition, which in combination with aCTLA-4 lead to an effective lymphocyte activation, resulting in a tumor cell predation driven by cytotoxic lymphocytes.

Figure 2

Logic underlying the simulation of combined radiation and immunotherapy effects: In a first step, initial conditions are defined which characterize tumor growth and the immune system’s capability (e.g., represented by the number of lymphocytes effectively taking part in tumor cell eradication) without therapy. In a second step the targeted radiation effects as well as checkpoint blocking is simulated, leading to a synergistic immune response. Finally, this results in an enhancement of cytotoxic T lymphocytes (CTL) in the tumor microenvironment (TME) of the irradiated and—if applicable—of an abscopal site. The T cells may eradicate tumor cells, which eventually leads to tumor control. If the therapy design is successful, typically within the therapy block or shortly after the tumor growth will turn into shrinkage as indicated by the color scale in the time arrow (green, no tumor; red, large tumor mass).