Split-dose photodynamic therapy: Optimizing cures while preventing disseminated tumors
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Photodynamic therapy (PDT) is an FDA approved treatment for a number of malignant and non-malignant conditions in humans. Previous pre-clinical work in murine tumor models has shown that low-inflammation ( high-fluence ) PDT regimens are more effective in obtaining cure of the primary tumor but induce minimal memory anti-tumor immune response. On the contrary, high-inflammation ( low-fluence ) PDT regimens confer durable anti-tumor immunity but generate significantly lower cures. We proposed that an optimum split-dose PDT regimen could be designed that would enable cure of primary tumor while preventing disseminated disease via induction of anti-tumor immunity. Four experimental groups were defined using a murine tumor model Colon 26 transfected with hemagglutinin cDNA (CT 26-HA). Controls received only the photosensitizer, a second group was given high-inflammation PDT and a third group received low-inflammation PDT. The fourth group was retreated with low-inflammation PDT seven days after initial treatment with high-inflammation PDT. Analysis of tumor responses showed only slightly higher cure rates (∼40%) with split-dose PDT compared to mice receiving only high-inflammation PDT (∼20%). However, it was noticed that there was a delay in progression of tumor growth with split-dose PDT. The experimental parameters were then modified and the split-dose gap was increased to ten days . This resulted in significantly higher cure rates (∼60%). All cured mice were re-challenged with tumor cells intra-dermally, sixty days after cure. The results exhibit a trend similar to that seen in tumor response experiments—ten day split-dose PDT regimen confers a degree of anti-tumor protection comparable to high-inflammation PDT alone, whereas seven day split dose PDT regimen does not. Enhancement of anti-tumor immunity by high-inflammation PDT regimen is accompanied by increased cellularity of tumor draining lymph nodes and activation of tumor specific T cells. Split-dose PDT regimens also lead to enhanced T cell activation as measured by increased expression of the early T-cell activation marker CD25; interestingly CD69 expression, a second activation marker for T cells, was not increased. We have concluded from the results that ten-day split-dose PDT regimen enables significantly higher cure rates compared to high-inflammation PDT while maintaining the anti-tumor efficacy, as evidenced by resistance to subsequent tumor re-challenges. The results of our experiments indicate that the split-dose PDT regimen has the potential of being introduced as a useful therapeutic option in the clinical practice of PDT as it has exhibited the ability to target distant disease via activation of host immune defenses while successfully ablating the primary tumor.