BACKGROUND: Photodynamic therapy (PDT) is an established, minimally invasive treatment for specific types of cancer. During PDT, reactive oxygen species (ROS) are generated that ultimately induce cell death and disruption of the tumor area. Moreover, PDT can result in damage to the tumor vasculature and induce the release and/or exposure of damage-associated molecular patterns (DAMPs) that may initiate an antitumor immune response. However, there are currently several challenges of PDT that limit its widespread application for certain indications in the clinic. METHODS: A literature study was conducted to comprehensively discuss these challenges and to identify opportunities for improvement. RESULTS: The most notable challenges of PDT and opportunities to improve them have been identified and discussed. CONCLUSIONS: The recent efforts to improve the current challenges of PDT are promising, most notably those that focus on enhancing immune responses initiated by the treatment. The application of these improvements has the potential to enhance the antitumor efficacy of PDT, thereby broadening its potential application in the clinic.

Metastases remain the leading cause of cancer-related death worldwide. Therefore, improving the treatment efficacy against such tumors is essential to enhance patient survival. AU-011 (belzupacap sarotalocan) is a new virus-like drug conjugate which is currently in clinical development for the treatment of small choroidal melanoma and high-risk indeterminate lesions in the eye. Upon light activation, AU-011 induces rapid necrotic cell death which is pro-inflammatory and pro-immunogenic, resulting in an anti-tumor immune response. As AU-011 is known to induce systemic anti-tumor immune responses, we investigated whether this combination therapy would also be effective against distant, untreated tumors, as a model for treating local and distant tumors by abscopal immune effects. We compared the efficacy of combining AU-011 with several different checkpoint blockade antibodies to identify optimal treatment regimens in an in vivo tumor model. We show that AU-011 induces immunogenic cell death through the release and exposure of damage-associated molecular patterns (DAMPs), resulting in the maturation of dendritic cells in vitro. Furthermore, we show that AU-011 accumulates in MC38 tumors over time and that ICI enhances the efficacy of AU-011 against established tumors in mice, resulting in complete responses for specific combinations in all treated animals bearing a single MC38 tumor. Finally, we show that AU-011 and anti-PD-L1/anti-LAG-3 antibody treatment was an optimal combination in an abscopal model, inducing complete responses in approximately 75% of animals. Our data show the feasibility of combining AU-011 with PD-L1 and LAG-3 antibodies for the treatment of primary and distant tumors.

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e14544 Background: Although there has been great progress in the early diagnosis of choroidal melanoma, metastases remain the leading cause of cancer-related death. Therefore, improving the treatment efficacy against metastases is essential to enhance patient survival. A new targeted therapy, the virus-like drug conjugate (VDC) AU-011 (belzupacap sarotalocan), is currently in clinical development to treat early-stage choroidal melanoma with an intra-ocular administration followed by near-infrared (NIR) light activation using a photodynamic therapy (PDT) laser. Murine experiments have shown that AU-011 enhances immune checkpoint inhibition (ICI) and protects against tumor rechallenge. Methods: We investigated whether this combination therapy had an effect not only on primary tumors but also on distant, untreated tumors, as a model for treating metastatic cancer by abscopal immune effects and compared the efficacy of combining AU-011 with several ICI antibodies. Results: In vitro, AU-011 treatment induced a preferential cytotoxicity in cancer over antigen presenting cells, confirming the tumor-targeting of AU-011. AU-011 treatment induced immunogenic cell death in several murine cancer cell lines through the release and exposure of damage-associated molecular patterns (DAMPs), resulting in the maturation of dendritic cells. Furthermore, AU-011 in combination with ICI antibodies demonstrated greater efficacy than AU-011 alone, or ICI antibodies alone against established MC38 tumors in mice, resulting in complete tumor response in all treated animals for specific combinations. Finally, AU-011 and anti-PD-L1/ anti-LAG-3 antibody treatment was an optimal combination in an abscopal model of metastatic disease, inducing complete cures in approximately 75 % of animals. Conclusions: Based on our observations, we conclude that AU-011 treatment combined with immune checkpoint inhibition is effective against both primary tumors and distant metastases, and identify anti-PD-L1/ anti-LAG-3 as the most potent combination with AU-011. These data may support an investigation of AU-011 in this combination in future clinical trials.[Table: see text]