Abstract
Tumour hypoxia has long presented a challenge for cancer therapy: Poor vascularisation in hypoxic regions hinders both the delivery of chemotherapeutic agents and the response to radiotherapy, and hypoxic cancer cells that survive treatment can trigger tumour regrowth after treatment has ended. Tumour-associated macrophages are attractive vehicles for drug delivery because they localise in hypoxic areas of the tumour. In this paper, we derive a mathematical model for the infiltration of an in vitro tumour spheroid by macrophages that have been engineered to release an oncolytic adenovirus under hypoxic conditions. We use this model to predict the efficacy of treatment schedules in which radiotherapy and the engineered macrophages are given in combination. Our work suggests that engineered macrophages should be introduced immediately after radiotherapy for maximum treatment efficacy. Our model provides a framework that may guide future experiments to determine how multiple rounds of radiotherapy and macrophage virotherapy should be coordinated to maximise therapeutic responses.
Highlights
Surgical removal of a tumour accompanied by adjuvant radiotherapy is a mainstay of cancer treatment, but tumour hypoxia Höckel and Vaupel (2001) limits the efficacy of radiotherapy in a number of ways
Having established that our mathematical model produces results which are qualitatively similar to experimental data for macrophage infiltration into an avascular tumour spheroid, we extend it to account for treatment with radiotherapy and macrophage-delivered oncolytic virotherapy
These results suggest that treatment where radiotherapy and macrophage-delivered virotherapy are given together is more successful at reducing tumour size than treatment with only radiotherapy or treatment with only macrophage-delivered virotherapy
Summary
Surgical removal of a tumour accompanied by adjuvant radiotherapy is a mainstay of cancer treatment, but tumour hypoxia Höckel and Vaupel (2001) limits the efficacy of radiotherapy in a number of ways. Hypoxia modifies the hypoxia-inducible factor 1 (HIF1) pathway to make the tumour microenvironment antioxidantrich Sattler and Mueller-Klieser (2009). This helps to negate the DNA damaging effects of the reactive oxygen radicals created by the radiotherapy, leading to radioresistance of the tumour. In addition to limiting the efficacy of radiotherapy, hypoxia poses a number of other challenges for conventional treatment: poor vascularisation in hypoxic areas inhibits the delivery of chemotherapeutic agents Carmeliet et al (1998); Minchinton and Tannock (2006), antitumour immune responses are often disrupted Noman et al (2015),
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