This phase I/II study evaluated the capacity of tumor microenvironment (TME) gene engineering by intratumoral injection of a viral vector encoding a designed CD40L and 4-1BBL combined with intravenous atezolizumab (anti-PD-L1 antibody) to induce immune activation in 24 patients with stage IV malignant melanoma refractory to PD-1 inhibition. The gene discussed is CD40LG; the disease is melanoma.