Evaluation of the antitumor effect of the therapeutic association between recombinant BCG and interleukin-15 super agonist in a murine model of orthotopic bladder cancer

• Grant number: 24/09989-0
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: February 01, 2025
• End date: December 31, 2025
• Field of knowledge: Biological Sciences - Microbiology - Applied Microbiology
• Principal Investigator: Ana Carolina Ramos Moreno
• Grantee: Isabelle Carolina Cotrim Gozzi
• Host Institution: Instituto Butantan. Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
• Associated research grant: 23/02577-5 - Study of the mechanisms responsible for trained immunity induced by Bacillus Calmette-Guérin (BCG) in infectious diseases and Cancer, AP.TEM

Abstract

Non-muscle invasive bladder cancer (NMIBC) represents approximately 70 to 80% of all bladder cancer cases. Standard treatment involves transurethral resection of the tumor followed by cycles of intravesical immunotherapy with Bacillus Calmette-Guérin (BCG). However, around 30% of patients either do not respond to treatment or experience recurrence, underscoring the urgent need for more effective therapies. In pursuit of enhancing NMIBC management, our laboratory developed a recombinant BCG strain (rBCG) expressing the detoxified pertussis toxin S1 subunit (rBCG-S1PT). In animal models of bladder cancer, this strain demonstrated superior antitumor effects compared to native BCG, promoting enhanced activation of natural killer (NK) cells and CD8 T cells. Recently, an emerging immunotherapy utilizing the interleukin-15 (IL-15) complex and IL-15 receptor alpha chain (IL-15 superagonist - SA-IL-15) has shown promising therapeutic efficacy in clinical trials focused on in situ bladder carcinoma. SA-IL-15 is recognized for its ability to stimulate the proliferation and activation of CD8 T cells, memory T cells, and NK cells, critical components of the antitumor immune response. We hypothesize that the therapeutic combination of rBCG-S1PT and SA-IL-15 represents a more effective and promising strategy for treating NMIBC. Accordingly, we propose investigating the antitumor effects of combining BCG or rBCG-S1PT with SA-IL-15, aiming to determine whether the rBCG-S1PT combination offers the most favorable outcomes. Our objective is to generate proof-of-concept data in animal models to promote the transition to future clinical trials.