Development of a Photothermal Treatment Planning Workflow for use in Synergistic Immuno-Photothermal-Nanotherapy (SYMPHONY)

Approximately half of bladder cancer diagnoses are late stage/show metastatic spread. The current standard treatment option for these diagnoses is cisplatin chemotherapy, however 40% of patients are ineligible to receive this treatment, leaving few alternatives. The most common alternative to chemotherapy that is currently used is immune checkpoint blockade or immunotherapy. However, immunotherapy alone has proven largely ineffective as a curative treatment option for the metastatic disease, indicating a critical need for new systemic treatment options. Our group has previously demonstrated in a pilot study the efficacy of a novel combination therapy incorporating two treatment arms: clinically available immunotherapy and gold nanostar mediated photothermal therapy (abbreviated as PTT). This treatment is called Synergistic Immuno Photothermal Nanotherapy (abbreviated as SYMPHONY). In this study, C57BL/6 mice were implanted with MB49 bladder cancer cells at two locations. One of the two subsequent tumors was treated with one of five total treatment arms. After treatment, one of the mice treated with SYMPHONY showed total tumor local control and no tumor regrowth upon MB49 cell rechallenge, suggesting long term cancer immunity induced by SYMPHONY treatment. Currently, the treatment paradigm for SYMPHONY follows as: 1) Gold nanostar (abbreviated as GNS) injection followed by a 24-hour waiting period 2) Mice are put under anesthesia and laser irradiation of the tumor is performed at a constant power density for 10 minutes 3) Anti-PD-L1 immunotherapy injections are given following irradiation. For SYMPHONY’s photothermal therapy treatment arm, quantitative characterization of the GNS photothermal effect and a photothermal treatment planning process are crucial aspects of SYMPHONY that remain undeveloped. The overall goal of SYMPHONY is to provide a systemic, curative treatment option for patients diagnosed with late-stage bladder cancer. The objective of this work is to characterize the photothermal effect as well as develop and validate a photothermal treatment planning workflow to be used in SYMPHONY treatment that accurately predicts thermal dose delivery. The goals of this work were completed using a variety of materials and methods, including: In vitro agarose-GNS gel phantoms along with thermocouples for thermal dosimetry, radiative transport and heat transfer software used to create photothermal simulations, a multitude of characterization methods to extract key GNS physical properties, as well as image segmentation and model generation techniques to analyze animal images and create simulation models. Results from in vitro phantom heating studies and their accompanying photothermal simulations are presented. Additionally, optical absorption characterization data is presented to serve as the basis for selected optical modeling parameters. Trends in GNS-mediated photothermal effect and the dependence on concentration are discussed, as well as their implications for future SYMPHONY studies.