Engineered VNP20009 expressing IL-15&15Rα augments anti-tumor immunity for bladder cancer treatment

Abstract

Surgical resection combined with intravesical instillation of chemotherapeutics or Bacillus Calmette-Guerin (BCG) to remove residual cancer cells is the gold standard for the clinical treatment of patients with bladder cancer. In a recent clinical trial, a new super-agonist complex of IL-15 - N803, has shown promising results when used in combination with BCG to treat patients with bladder cancer who do not respond to BCG. Herein, we used temperature-controlled pBV220 plasmid encoding Interleukin-15 and its receptor alpha subunit (IL-15&15Rα) to transform VNP20009, an attenuated salmonella typhimurium strain, obtaining engineered bacteria named 15&15Rα@VNP. After induction at 42 °C, 15&15Rα@VNP can secrete functional IL-15&15Rα stably. It was found that intravesical instillation of thermally activated 15&15Rα@VNP could inhibit the growth of bladder tumors if used alone. Moreover, the sequential intravesical instillation of epirubicin (EPI), a first-line bladder cancer drug, followed by thermally activated 15&15Rα@VNP, could achieve further improved therapeutic responses, without causing significant side effects. Therefore, this study shows that 15&15Rα@VNP can be effectively used in the treatment of bladder cancer and can be used as a complementary therapy to chemotherapy agents, promising for potential clinical translation in bladder cancer treatment.

Keywords: Bladder cancer; Engineered bacteria; IL-15&15Rα; VNP20009.