Background: Blue light cystoscopy (BLC)with hexaminolevulinate (HAL) is routinely used as an adjunct to white light cystoscopy to allow improved detection of malignant tumors, leading to more complete tumor resection and improved short and long-term recurrence rates. Rate of progression has been found to be significantly lower in patients treated with HAL- vs WL guided TURBT. Studies have also demonstrated improved outcomes after cystectomy in patients who had undergone prior BLC-TURB, indicating an additional effect beyond pure detection of PDD. The principle of photodynamic therapy (PDT) is well-established in the treatment of other cancer types and has been demonstrated to destroy tumor via direct cell destruction, vascular shutdown, induction of local inflammatory response and activation of the immune system.
Method: The aim of this study was to assess the antitumor effect and induced systemic immune effects of HAL used in PDD doses in an orthotopic model of rat bladder cancer. We conducted the treatment at different irradiation regimens – within the diagnostic range of light doses – and histologically evaluated the treatment efficacy, induction of apoptosis, expression of immune cells and expression of PD-L1 on tumor cells at different time points after exposure.
Rat bladders were pretreated with HCl followed by neutralization with NaOH and a PBS rinse. Then, a suspension of the rat bladder cancer cell line AY-27 was instilled. After 5 days, Hexvix (hexamino-levulinate (HAL)), was instilled into bladder, followed by whole bladder irradiation with blue light (BL) (401nm) in PDD relevant doses and intensities. Bladders were assessed at 4 h, 48 h, 7 and 30 days after illumination to study both immediate and long-term effects of the treatment.
Results/Conclusion: Immediately after treatment, a statistically significant increase of apoptotic tumor cells was seen in the Hexvix groups, albeit the level of apoptosis was weak. A delayed anti-tumor effect was demonstrated after 7 and 30 days, possibly indicating a systemic immunotherapeutic effect. After 30 days, immune cells CD3+ and CD8+, were mostly localized around tumor cells in HAL-PDT groups compared to control groups. A transient increase of PD-L1 expression was also observed after 7 days in irradiated groups of the animals. Further studies to assess the effects of combining PDD and PD-L1 inhibition are warranted to clarify the role of combination treatment for improved patient outcomes.
Disclosures: Kari Myren and Gry Stensrud are employees of Photocure ASA, Aslak Godal is consulting for Photocure ASA.
