Cancer treatment by radioimmunotherapy: insights from a dynamical model of cancer stem cells and hypoxia effects

Abstract Cancer remains a major challenge for conventional treatments. This is due to the resistance mechanisms driven by cancer stem cells (CSCs) which sustain tumor growth. In this work, we investigate both analytically and computationally the effects of radioimmunotherapy (RIT), a cutting-edge technique that uses radiolabeled antibodies to precisely target and irradiate cancer cells. The work considers time delay modeling and the interactions between microRNAs and differentiated cancer cells (DCs). We evaluate the effects of extrapolated dose rates from four important radionuclides including yttrium-90 (^90Y), lutetium-177 (^177Lu), iodine-131 (^131I) and actinium-225 (^225Ac) in the preventive treatment of cancer before recurrence. A sensitivity analysis of model parameters is also performed to assess the robustness of the predictions and to identify the most influential biological and physical variables. Using the linear-quadratic formalism, we compare their biological effective dose, surviving fraction, and tumor control probability. The results demonstrate that an extrapolated initial dose of 165 Gy. year^{-1} leads to an eradication of CSCs using ^225Ac and ^177Lu within 1. 4636 year and 1. 5736 year, respectively. Similarly, DCs are eliminated with ^225Ac and ^177Lu over treatment durations of 0. 9396 year and 1. 0496 year, respectively. These results highlight the potent effects of ^225Ac and ^177Lu in targeting CSCs and DCs at this dose rate. Under these conditions, microRNAs act as tumor suppressors, thus preventing pro-tumorigenic effects. Exceeding the dose threshold (beyond 165 Gy. year^{-1}) disrupts the therapeutic balance with an efficacy which decreases progressively. For the doses above 326 Gy. year^{-1}, the overproliferation of CSCs and DCs is observed with an oncogenic behavior of microRNAs. We further examine the role of tumor oxygenation in modulating RIT efficacy. The results reveal that enhancing oxygen availability significantly increases CSC radiosensitivity, which is otherwise reduced under hypoxic conditions. The results of this work provide insight in optimizing RIT protocols using radiolabeled agents with improved pharmacokinetics and biological half-lives.