The combined use of anti-PD1 antibodies and intravesical immunotherapy with rBCG-LTAK63 to enhance bladder cancer treatment in a murine orthotopic model.

• Grant number: 25/03267-5
• Support Opportunities: Scholarships in Brazil - Master
• Start date: August 01, 2025
• End date: February 28, 2026
• Field of knowledge: Biological Sciences - Microbiology - Applied Microbiology
• Principal Investigator: Ana Carolina Ramos Moreno
• Grantee: Johanna Christine Van Vliet
• 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) accounts for approximately 70% of diagnosed bladder cancer cases and is treated by transurethral resection of the lesion, followed by intravesical therapy with Bacillus Calmette-Guérin (BCG). However, around 30% of patients do not respond to treatment, highlighting the need for novel therapeutic approaches. In 2020, the U.S. regulatory agency approved the use of the anti-PD-1 monoclonal antibody for NMIBC patients refractory to BCG, reinforcing the potential of this immunotherapy as an alternative treatment. Our laboratory has developed a recombinant BCG, rBCG-LTAK63, which expresses the nontoxic A subunit of Escherichia coli heat-labile toxin. In a murine model, we demonstrated that rBCG-LTAK63 exhibits superior antitumor effects compared to parental BCG, promoting increased infiltration of CD4¿ and CD8¿ T lymphocytes into the tumor microenvironment. However, we observed an upregulation of PD-1 expression in these cells, suggesting a potential tumor escape mechanism. Thus, we hypothesize that the combination of rBCG-LTAK63 with PD-1 inhibitors will enhance the antitumor immune response, leading to improved tumor control and increased survival. This project aims to evaluate the efficacy and safety of combining rBCG-LTAK63 with anti-PD-1 immunotherapy, assessing its impact on immune system activation and tumor progression inhibition in an orthotopic murine model of NMIBC. Additionally, we aim to optimize the anti-PD-1 dosage, reducing treatment-associated toxicity and improving cost-effectiveness. If successful, this strategy could represent a new therapeutic paradigm for bladder cancer, reducing the need for radical cystectomy and improving patients' quality of life. (AU)