Fractionated photoimmunotherapy stimulates an anti-tumour immune response: an integrated mathematical and in vitro study

BACKGROUND: Advanced epithelial ovarian cancer (EOC) has high recurrence rates due to disseminated initial disease presentation. Cytotoxic phototherapies, such as photodynamic therapy (PDT) and photoimmunotherapy (PIT, cell-targeted PDT), have the potential to treat disseminated malignancies due to safe intraperitoneal delivery. METHODS: We use in vitro measurements of EOC tumour cell and T cell responses to chemotherapy, PDT, and epidermal growth factor receptor targeted PIT as inputs to a mathematical model of non-linear tumour and immune effector cell interaction. The model outputs were used to calculate how photoimmunotherapy could be utilised for tumour control. RESULTS: In vitro measurements of PIT dose responses revealed that although low light doses (<10 J/cm²) lead to limited tumour cell killing they also increased proliferation of anti-tumour immune effector cells. Model simulations demonstrated that breaking up a larger light dose into multiple lower dose fractions (vis-à-vis fractionated radiotherapy) could be utilised to effect tumour control via stimulation of an anti-tumour immune response. CONCLUSIONS: There is promise for applying fractionated PIT in the setting of EOC. However, recommending specific fractionated PIT dosimetry and timing will require appropriate model calibration on tumour-immune interaction data in human patients and subsequent validation of model predictions in prospective clinical trials.

Mohammad U. Zahid, Matthew Waguespack, Rebecca C. Harman, Eric M. Kercher, Shubhankar Nath, Tayyaba Hasan, Imran Rizvi, Bryan Q. Spring, Heiko Enderling