Multicenter phase 1-2 trial of LOAd703-induced tumor microenvironment gene engineering plus atezolizumab for metastatic malignant melanoma

A multicenter phase 1-2 trial evaluated tumor microenvironment (TME) gene engineering by intratumoral injection of a viral vector with transgenes encoding CD40L and 4-1BBL (LOAd703) combined with intravenous atezolizumab to induce immune activation in 24 patients with stage IV malignant melanoma refractory to PD-1 inhibition. Treatment was well-tolerated (primary objective) in both dose cohort (1 x 10¹¹ and 5 x 10¹¹ viral particles). Th1 immune biomarkers were increased in TME as well in blood. In long-term survivors, increased markers for T cell fitness and for immunoproteasome were observed. The overall response rate was 17% and and disease control was observed in 54%. Forty-six percent of patients were still alive two years after enrollment. In post-hoc analysis, the lower dose showed a median progression-free survival of 9.7 months and a median overall survival of 26.3 months. The authors conclude that TME gene engineering may have re-sensitized refractory patients to checkpoint inhibition or acted alone to control tumor growth.