Malignant melanoma is an aggressive type of skin cancer whose incidence is increasing globally. Although surgery is effective in early stage melanoma, patients with advanced melanoma only have a 20% 5-year survival rate. Hence, combinations of existing and new immunotherapy technologies and immunotherapeutic agents are being evaluated. ONCOS-102 is an oncolytic adenovirus armed with human GM-CSF and an Ad5/3 chimeric capsid. It has shown to be well tolerated in phase I study (NCT01598129) wherein it induced antitumor immunity, infiltration of CD8 + T cells to tumors, and up-regulation of PD-L1. We propose that ONCOS-102 could serve as an immunosensitizer in combination therapies with checkpoint inhibitors. In this preclinical study, we investigated the cytotoxicity of ONCOS-102 and pembrolizumab, an anti-PD-1 antibody, in four human melanoma cell lines, A375, A2058, SK-Mel-2 and SK-Mel-28. Humanized mice engrafted with A2058 melanoma cells showed significant tumor volume reduction after ONCOS-102 treatment. Combination of pembrolizumab with ONCOS-102 reduced tumor volume to an even greater extent, while pembrolizumab (200 µg, or 400 µg) did not show any therapeutic benefit by itself. Body weight loss, and metastasis were not significantly affected by any treatment. These data support the scientific rationale for the ongoing clinical study of combination therapy of ONCOS-102 and pembrolizumab for the treatment of melanoma (NCT03003676).

Chemokines are important in regulating leukocyte traffic during infection. We analyzed plasma chemokine levels of monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1 alpha , interleukin (IL)-8, and RANTES in patients with meningococcal infection and correlated these to plasma lipopolysaccharide (LPS) levels, which are closely associated with clinical presentation. In patients with fulminant meningococcal septicemia, versus distinct meningitis or mild systemic meningococcal disease, MCP-1 (both P<.0001), MIP-1 alpha (both P<.0001), and IL-8 (P<.0001 and P=.011) were significantly higher and RANTES significantly lower (P=.007 and P=.021). MCP-1 (r=.88), MIP-1 alpha (r=.82), and IL-8 (r=.89) were positively correlated to plasma LPS levels, whereas RANTES was negatively correlated (r=-.49). In an ex vivo whole-blood model, heat-inactivated wild-type Neisseria meningitidis, purified meningococcal LPS, and (to a negligible extent) heat-inactivated LPS-deficient mutant N. meningitidis induced these chemokines. N. meningitidis LPS is the major cause of chemokine release in meningococcal disease.

Melanoma, an immunogenic tumor, is the first indication where oncolytic viruses are now becoming part of clinical practice. ONCOS‐102, a transgened adenovirus, has shown to act as a primer of relevant tumor targeting immune cells both in preclinical and clinical melanoma studies. Strategies to augment its effectiveness warrant investigation. Combination therapy of ONCOS‐102 with the checkpoint inhibitor (CPI) pembrolizumab was evaluated in a quasi‐human animal model, the humanized NOG mouse model. A dosing schedule of the combination, beginning the CPI concurrently with the oncolytic viral therapy and continuing the CPI treatment, appeared to induce an abscopal effect in untreated tumor lesions. Concurrent combination therapy with checkpoint inhibitors may improve the induction of antitumor immune responses of ONCOS‐102.

Fulminant meningococcal sepsis has been termed the prototypical lipopolysaccharide (LPS)-mediated gramnegative septic shock. Systemic inflammation by activated complement and cytokines is important in the pathogenesis of this disease. We investigated the involvement of meningococcal LPS in complement activation, complement-dependent inflammatory effects, and cytokine or chemokine production. Whole blood anticoagulated with lepirudin was stimulated with wild-type Neisseria meningitidis H44/76 (LPS ؉ ), LPS-deficient N. meningitidis H44/76lpxA (LPS ؊ ), or purified meningococcal LPS (NmLPS) at concentrations that were relevant to meningococcal sepsis. Complement activation products, chemokines, and cytokines were measured by enzyme-linked immunosorbent assays, and granulocyte CR3 (CD11b/CD18) upregulation and oxidative burst were measured by flow cytometry. The LPS ؉ and LPS ؊ N. meningitidis strains both activated complement effectively and to comparable extents. Purified NmLPS, used at a concentration matched to the amount present in whole bacteria, did not induce any complement activation. Both CR3 upregulation and oxidative burst were also induced, independent of LPS. Interleukin-1␤ (IL-1␤), tumor necrosis factor alpha, and macrophage inflammatory protein 1␣ production was predominantly dependent on LPS, in contrast to IL-8 production, which was also markedly induced by the LPS ؊ meningococci. In this whole blood model of meningococcal sepsis, complement activation and the immediate complement-dependent inflammatory effects of CR3 upregulation and oxidative burst occurred independent of LPS.

Despite new therapies, the estimated 229 875 women living with ovarian cancer have a 5‐year survival rate of 47.6%. This cavity‐localized cancer lends itself to local administration of modalities, such as the oncolytic adenovirus (Ad) Ad5/3‐D24‐granulocyte‐macrophage colony‐stimulating factor virus (ONCOS‐102). Its repeated administration to a patient with chemotherapy‐refractory ovarian cancer induced CD8+ antitumor immune responses with the overall survival reaching 40 months. Here we probe the dominant receptor used by ONCOS‐102 in four established epithelial ovarian cancer cell lines. Ad3 can use the desmoglein‐2 (DSG2) and CD46 receptors on susceptible cells. DSG2 was nearly absent in A2780 cells but was expressed in more than 90% of OAW42, OVCAR3, and OV‐90 cells. After 96 hours, ONCOS‐102 treatment showed significant oncolytic activity (≧50%) in OAW42, OVCAR3, and OV‐90 cells, but minimal activity in A2780 cells, suggesting DSG2 as the dominant receptor for ONCOS‐102. Furthermore, retrospective analyses of phase I clinical trial of ONCOS‐102 treatment of 12 patients with varied tumors indicated a correlation between viral genomes in blood and DSG2 RNA expression. These data support the role of DSG2 expression on cancer cells in virus infectivity and the continued development of ONCOS‐102 for ovarian cancer treatment.