(331g) Combined Radiation-Induced Photodynamic Therapy and Immunotherapy Using Calcium Tungstate Nanoparticles, 5-Aminolevulinic Acid, and Epacadostat

Head and neck squamous cell carcinoma (HNSCC) is the 7^th most common cancer worldwide with a 5-year survival rate of around 50%. It is predominantly diagnosed at the locally advanced stage, for which the chemotherapy-radiotherapy combination (“chemoradiation”, CT-RT) is the primary form of treatment. However, development of resistance to these treatments results in high rates of cancer recurrence and unfavorable prognosis. Therefore, there is need for alternative treatment modalities that use different mechanisms of action.

Photodynamic therapy (PDT) is one such option that has shown promise in achieving complete responses in patients with residual or recurrent HNSCC following conventional RT. The combination of RT and PDT (RT-PDT) has demonstrated improved outcomes for a multitude of cancers, with their synergism further bolstered when the two therapies are applied concurrently rather than sequentially. However, conventional concurrent RT-PDT is limited in three important ways; (1) an optical device is required to deliver light to the site of PDT; (2) conventional PDT is limited to surface tumors due to the small penetration depth of visible light in human tissue; (3) it is highly localized and cannot treat metastasis.

This talk will discuss our recent work on a new concurrent RT-PDT method that addresses the limitations of current RT(-PDT) approaches for treatment of HNSCC. This method uses a new RT-to-PDT transducer, namely, radio-luminescent CaWO₄ (CWO) nanoparticles (NPs) encapsulated within micellar self-assemblies formed by poly(ethylene glycol)-poly(lactic acid) (PEG-PLA) block copolymers (“PEG-PLA/CWO NPs”). These NPs are used in combination with 5-aminolevulinic acid (ALA), an FDA-approved endogenous water-soluble prodrug that causes preferential accumulation of an endogenous photosensitizer, protoporphyrin IX (PPIX), in cancer cells. Under ionizing radiation, CWO NPs emit UV-A/blue light, which activates PPIX. A confocal microscopy imaging study suggests that the radio-luminescence energy transfer process potentiates a type-II photodynamic reaction which converts molecular oxygen into cytotoxic reactive oxygen species (ROS), particularly, singlet oxygen (¹O₂) which oxidizes organelle and cytoplasmic membranes. In vitro clonogenic cell survival assays (performed using multiple cell lines having varying radiation sensitivity characteristics) confirmed that concurrent CWO NPs indeed significantly enhance the cell kill effects of X-rays. MTT assay results show that PEG-PLA/CWO NPs do not produce any dark toxicity in cells.

Furthermore, we are exploring the possibility of combining RT-PDT with immune inhibition blockade immunotherapy (IT) using Epacadostat (IDOi). IDOi is an inhibitor for indoleamine 2,3-dioxygenase (IDO), an enzyme that promotes T cell anergy in the tumor microenvironment and is frequently overexpressed in HNSCC. The hypothesis is that IDO inhibition coupled with localized cell death due to RT-PDT promotes T cell growth and maturation within the tumor microenvironment, resulting in systemic anti-tumor immune responses. A study is ongoing to validate the efficacy of the RT-PDT-IT combination therapy in vivo.