Immune checkpoint inhibition combined with targeted therapy using a novel virus-like drug conjugate induces complete responses in a murine model of local and distant tumors

Abstract

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.

Tumor Pigmentation Does Not Affect Light-Activated Belzupacap Sarotalocan Treatment but Influences Macrophage Polarization in a Murine Melanoma Model

“…The International Classification of Diseases (ICD) and favorable microenvironment triggered by Bel-sar treatment are indicators for combination with immune check point inhibitors to induce the local and distant tumor cure. 16 , 17 , 63 Further preclinical and clinical studies to investigate the combination Bel-sar treatment and immune checkpoint inhibitors should be conducted. Our results indicate that despite the light-absorbing function of pigments, which was proposed to be detrimental for laser therapy, we could show that Bel-sar treatment can enhance antitumor immune effects even in pigmented malignancies.…”

“…We recently published a paper stating that combining either PDT or light-activated Belzupacap sarotalocan (Bel-sar) with an immune checkpoint inhibitor induces a better antitumor response in mice than either treatment alone. 16 , 17 …”

The Future of Checkpoint Inhibitors in Uveal Melanoma: A Narrative Review

“…Kim et al suggested that the combination of the rho-kinase (ROCK) inhibitor ripasudil, PD0L1 inhibitor, and local photodynamic therapy (PDT) could reduce the primary tumor burden and prevent metastasis in an orthotopic intraocular melanoma model [ 56 ]. A new virus-like drug conjugate (AU-011) and the inhibitor of the receptor for the hepatocyte growth factor (HGF) are also worth studying in systemic treatment combined with ICIs [ 57 , 58 ].…”

“…With a similar conclusion, Kashyap et al also found a potential association between higher LAG3 expression and shorter metastasis-free survival [ 74 ]. An in vivo experiment by Huis In 't Veld et al showed a CR rate of 75% in a murine model with distant MC38 tumors after treatment with AU-011 and a LAG3 inhibitor [ 57 ]. Thus, by observing valuable results from in vitro and in vivo experiments, the clinical effect of antibodies against LAG3 in UM, especially in the process of tumor metastasis, deserves to be investigated and validated.…”

In Vitro Testing of the Virus-Like Drug Conjugate Belzupacap Sarotalocan (AU-011) on Uveal Melanoma Suggests BAP1-Related Immunostimulatory Capacity

“… 9 , 30 We recently showed that treatment with AU-011 and ICIs induced an abscopal effect in a murine model using MC38 cells. 28 Prior in vitro tests showed that AU-011 worked well on UM cell lines.…”