Abstract 6178: Photochemical immune stimulation eradicates primary tumor and induces long-lasting anti-tumor immunity in a murine cutaneous melanoma model

Abstract Background: Photodynamic therapy with light-activation of photosensitizers to induce cell death has been used in the treatment of various tumor types but has been ineffective to date in melanoma due to tumor pigmentation that limits the depth of light penetration. In previous studies in immunodeficient mice using a combination of tumor-cell and vascular targeting we demonstrated eradication of thin primary tumors. Here, we extend this to immunocompetent mice bearing full-thickness primary tumor, investigating both the primary and metastatic responses. Initial evidence of strong immune stimulation was also seen in multifunctional porphyrin-lipid nanoparticles (Porphysomes) as the photosensitizer. Methods: S91 tumors were induced in the flank of DBA mice by intradermal injection of 106 cells in 40µL PBS. Tumor growth was monitored by ultrasound imaging. The main treatment protocol comprised a combination of the clinical photosensitizers: chlorin e6 (1 mg/kg) plus Visudyne (0.8 mg/kg) at 1 h and 15 min drug-light intervals using light fluences of 50 J/cm2 at 670 and 690 nm, respectively. Immune biomarkers were measured in spleen, blood, tumor-draining lymph nodes and tumors at 3, 6, 12, 24, 72 h and 5 and 10 d post-treatment. The mice were monitored for 90 d to determine disease-free and overall survival. The functionality of the immune stimulation was demonstrated by tumor re-challenge, abscopal and adoptive immune transfer experiments. Initial studies were also performed using multifunctional porphyrin-lipid nanoparticles (Porphysomes, PS). Results: The dual-agent protocol resulted in disease-free and overall survival rates >95% at 90 d post-treatment. A robust immune response was triggered, with recruitment and activation of both innate and adaptive immune systems. Upon re-challenge with 106 tumor cells at 45d post primary tumor treatment, mice previously treated with PCIS showed no systemic tumor development at 30 d, confirming induction of long-lasting anti-tumor immunity. Adoptive immune transfer was demonstrated by delayed growth of primary intradermal tumor in naïve mice co-injected with splenocytes from previously-treated mice. Abscopal response was seen in mice bearing bilateral tumors when only one tumor was treated. Survival was reduced (20% at 90 d) in CD8+ T cell-depleted mice. PS-mediated treatment exhibited strong immune stimulation even at a fraction of the light dose (25 J/cm2), as measured by adoptive immune transfer and immune biomarkers. Conclusions: This study provides the first evidence that, using non-conventional treatment protocols, photodynamic tumor cell kill can eradicate primary pigmented melanoma far beyond the depth of light penetration and markedly impact systemic metastatic disease. PCIS could be used either stand-alone or an adjunctive treatment with surgery, chemotherapy and/or immunotherapy. Citation Format: Layla Pires, Carla Calcada, Tracy McGaha, Gang Zheng, Brian Wilson. Photochemical immune stimulation eradicates primary tumor and induces long-lasting anti-tumor immunity in a murine cutaneous melanoma model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6178.