Belzupacap Sarotalocan Therapy Causes Uveal Melanoma Cell Death

Belzupacap sarotalocan (AU-011) induces immunogenic cell death in uveal melanoma (UM) cell lines and may be a suitable candidate for in vivo treatment in combination with immunotherapy, suggest findings from an in vitro study published in Investigative Ophthalmology & Vision Science.

UM is a common and often fatal ocular malignancy with limited treatment options. The study investigated the potential of belzupacap sarotalocan as a combination treatment option for UM by evaluating its tumor cell killing and immunostimulatory capacity. The researchers evaluated 10 cell lines of primary or metastatic UM for binding and uptake of belzupacap sarotalocan, cytotoxicity, and exposure to damage-associated molecular patterns (DAMPs).

After incubation at 37˚ C, most of the agent was taken up by the cell and localized to the cytoplasm. Cell lines that were deficient in BRCA1-associated protein-1 (BAP1) had substantially reduced uptake compared with BAP1-positive UM cell lines. BAP1 inactivation affects half of primary UM tumors and increases risk of metastasis. 

In line with their lower uptake, BAP1-negative cell lines also had a higher half maximal effective concentration (EC₅₀) compared with BAP1-positive cells lines (P <.01). However, all UM cell lines had EC₅₀ values in the picomolar range (15-40 pmol/L), indicating that these cells are sensitive to treatment with belzupacap sarotalocan.

Treatment with light-activated belzupacap sarotalocan also induces markers of immunogenic death, including DAMPs such as calreticulin (CRT) and heat shock protein-90 (HSP90). These markers highlight the immunostimulatory capacity of belzupacap sarotalocan and its potential capacity to induce immunogenic death. Although CRT exposure was lower in BAP1-negative cell lines compared with BAP1-positive lines, HSP90 exposure was similar. Thus, the treatment may induce high immunogenicity through other DAMPs.

Taken together, these data indicate that belzupacap sarotalocan has cytotoxic and immunostimulatory properties in vitro that make it a candidate for in vivo investigation as an adjuvant treatment for immunotherapy. 

“In the context of the eye, light-activated AU-011 may locally overcome the immune privilege which tends to suppress local immune responses,” the study authors explain.