Oncolytic adenovirus ORCA-010 a valuable immunotherapeutic agent for melanoma
April 23, 2020
Abstract
Immune checkpoint blockade has resulted in durable responses in patients with metastatic melanoma, but only in a fraction of treated patients. For immune checkpoint inhibitors (ICI) to be effective, sufficient infiltration with tumor-reactive T cells is essential. Oncolytic viruses (OV) selectively replicate in and lyse tumor cells and so induce an immunogenic form of cell death, providing at once a source of tumor-associated (neo)antigens and of danger signals that together induce effective T cell immunity and tumor infiltration. Melanoma-associated suppression of dendritic cell (DC) differentiation effectively hampers OV- or immune checkpoint inhibitor (ICI)-induced antitumor immunity, due to a consequent inability to prime and attract antitumor effector T cells. Here, we set out to study the effect of ORCA-010, a clinical stage oncolytic adenovirus, on DC differentiation and functionality in the context of human melanoma. In melanoma and monocyte co-cultures, employing a panel of five melanoma cell lines with varying origins and oncogenic mutation status, we observed clear suppression of DC development with apparent skewing of monocyte differentiation to a more M2-macrophage-like state. We established the ability of ORCA-010 to productively infect and lyse the melanoma cells. Moreover, although ORCA-010 was unable to restore DC differentiation, it did induce activation and an increased co-stimulatory capacity of monocyte-derived antigen-presenting cells. Their subsequent ability to prime effector T cells with a type-I cytokine profile was significantly increased in a subsequent allogeneic mixed leukocyte reaction. Our findings suggest that ORCA-010 is a valuable immunotherapeutic agent for melanoma.
Source:
López González M, van de Ven R, de Haan H, et al. Oncolytic adenovirus ORCA-010 increases the type-1 T cell stimulatory capacity of melanoma-conditioned dendritic cells. Clinical and Experimental Immunology. 2020 Apr DOI: 10.1111/cei.13442.