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Development of a precision immunovirotherapy expressing a folate receptor α bispecific immune cell engager for treatment of ovarian cancer

A Naskretski(1,2) R J Bayliss(1) S Jones(2) T Phesse(1) A L Parker(1)

1:Cardiff University; 2:University Hospital Wales

The biology and silent spread of ovarian cancer make systemic therapy fail rapidly while complete surgical resection is often not possible. Immunotherapies provide a much-needed alternative to standard treatment options. We developed a precision virotherapy utilising an αvβ6 integrin selective adenovirus type 5 virus, Ad5NULL-A20 expressing a bispecific T-cell engager binding Folate receptor alpha (FLOR1), both overexpressed on ovarian cancer, to activate T-cells leading to enhanced immune mediated cancer cell regression.

The efficacy of the newly developed immunovirotherapy was tested in vitro in ovarian cancer lines and ex vivo ascites co-cultured with healthy donor peripheral blood mononuclear cells (PMBCs). T-cell activation was assessed in conjunction with IFN-gamma and TNF-alpha secretion by ELISA and cell viability assays determine cancer cell killing.

Ad5NULL-A20.αFLOR1XCD3 was successfully developed and validated. Co-culture assays with PBMCs show an increase in T-cell activation of up to 80% following transduction with the engineered virotherapy. Increased levels of IFN-gamma and TNF-alpha was evident in cells expressing the bispecific compared to untreated cells. Cell viability assays indicate around 50% decrease in cancer cell viability following virus transduction. In addition, FOLR1 positive ascites-derived ovarian cancer models were established from patients and used for testing the efficacy of the viral vectors ex vivo confirming T-cell activation and cancer cell regression when treated with Ad5NULL-A20.αFLOR1XCD3.

Results indicate Ad5NULL-A20.αFLOR1XCD3 leads to T-cell activation and immune mediated tumour killing in vitro and ex vivo. This novel approach has the potential to become a much-needed alternative treatment option for patients with advanced ovarian cancer.

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