Photofrin dark effects and heme oxygenase inducers as therapeutic in mesothelioma

University Of Pennsylvania, Philadelphia PA

Investigators

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive malignant neoplasm with a devastating prognosis. Median survival from the time of diagnosis is approximately 18 months and limited improvement has been gained in this expectation over the past 25 years. Disease progression is driven through a local inflammatory response, thus there is therapeutic potential in methods that combat this inflammation or its related effects on innate immunity. We have revealed a strong, immune-mediated response of murine mesothelioma tumors to the FDA- approved drug Photofrin. Generally employed as a photosensitizer for photodynamic therapy (PDT), we noted the antitumor activity of Photofrin to mesothelioma tumor was independent of its light activation for photodynamic therapy (i.e., “dark effects”). Other of our preliminary data show that Photofrin, again independent of activation by light, is associated with increased expression of the antioxidant enzyme, heme oxygenase (HO) -1 in both murine and human mesothelioma. Moreover, another drug used in PDT, the photosensitizing pro-drug 5- aminolevulinic acid (ALA), is clinically employed as a HO-1 inducer and found in our data to increase the survival of mice with orthotopic mesothelioma tumors (again, independent of light activation). Due to their antioxidant properties, HO-1 inducers are applied in inflammatory disease. Although not traditionally employed in cancer because they could impede oxidative-dependent therapeutics, it is noted that HO-1 expression correlates with better prognosis in some malignancies. This may be related to the prevalence of inflammation in a particular histology. Overall, HO-1 inducers may stimulate antitumor immunity via effects on immune cell populations. Photofrin data show it to establish CD8+ T cell dependent immunity, which could be transferred to new hosts. Accompanying actions could include anti-inflammatory activity that combats mesothelioma tumor growth, and antioxidative action in T cells, potentially re-invigorating these cells and associated antitumor immunity. Moreover, these effects could cooperate with immune checkpoint blockade. Based on the above described preliminary and published data, studies of this proposal are directed toward the hypothesis that FDA approved porphyrin derivative, Photofrin, is immunomodulatory in mesothelioma and can augment immune checkpoint blockade. Research will be conducted with HO-1 inducers, Photofrin, ALA, hemin and docosahexaenoic acid (DHA) in primarily orthotopic models of murine mesothelioma. The research aims to: 1) characterize the tumor control and antitumor immunity generated by Photofrin and other HO-1 inducing drugs and 2) utilize transcriptomics to inform mechanisms of therapeutic effect by HO-1 inducers and guide their combination with immune checkpoint blockade. Data produced by this proposal will provide insight on application of Photofrin, ALA and/or other HO-1 inducers for treatment of MPM; fill knowledge gaps in antitumor activity by HO-1 inducers; and provide the mechanistic foundation for clinical translation of Photofrin, ALA and/or other HO- 1 inducers in combination with immune checkpoint blockade for the treatment of MPM.