Enhancing Radiation Therapy Through Cherenkov Light-Activated Phototherapy from Clinical Megavoltage Treatment Beams

Abstract

This work investigates a new approach to improving the efficacy of megavoltage radiation therapy through addition of a photo-therapeutic agent activated at the time of radiation treatment by Cherenkov light produced directly from the therapeutic photon beam. The approach is termed Cherenkov Light Activated Phototherapy (CLAP). While CLAP is compatible with a range of photo-therapeutics, we focus here on psoralen, a well-known ultra-violet (UV) light activated anti-cancer therapeutic, which has extensive application in superficial and extracorporeal settings. CLAP has potential to extend the scope of psoralen application beyond these settings. In vitro studies in B16 melanoma and 4T1 murine breast cancer cells were performed to investigate the potential of CLAP for increasing cytotoxicity and Major Histocompatibility Complex (MHC1) expression when compared to controls (both radiation alone, and CLAP treatment but without the presence of Cherenkov light). Cells were cultured in transparent well-plate dishes. Plates were then irradiated from below while resting on a 3 cm solid water slab such that during irradiation, Cherenkov light generated in the solid water penetrated the transparent plates to illuminate the cells. All wells received the same radiation dose, but only half the wells received Cherenkov light by virtue of a thin light block placed under half the plate. Luminescence and cell cytometry assays were performed 48-72 hours after irradiation to assess cell viability and MHCI over expression related to CLAP. Clonogenic assays were also performed. Increased cytotoxicity would suggest potential for increased local control, and increased MHCI would support increased potential of stimulation of a systemic immune response, similar to that reported in other psoralen treatments. In addition to in-vitro work, Monte Carlo GEANT4/GAMOS simulations were performed to evaluate the potential for optimizing the clinical spectrum to maximize psoralen activation. Our results demonstrate a statistically significant increase in cytotoxicity in cells treated with CLAP compared to control cells receiving the same dose of radiation and psoralen but where the Cherenkov light was blocked (20% and 9.5% for 4T1 and B16 cells respectively, P < 0.01). In addition, median MHC I expression was observed to increase by factors of ∼4.2 and 2.1 at radiation doses of 3 Gy and 6 Gy respectively (P < 0.01). Our results indicate CLAP has potential to enhance radiation therapy treatment through increased local cytotoxicity (local control). Furthermore CLAP increased MHCI expression which is consistent with increased potential for systemic immunogenic response similar to that reported in other psoralen treatments. This work represents a first step in developing a novel approach to enhance radiation therapy through addition of a photo-therapeutic component activated in-situ, by the treatment beam, concurrently with radiation treatment.