Evaluation of innate immune memory in the antitumor efficacy of an immunotherapy based on recombinant BCG

• Grant number: 24/07426-8
• 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: Bruna Gennari Rosa
• 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

Trained immunity, an emerging concept in immunology, suggests that cells of the innate immune system can be "trained" after exposure to specific stimuli. This phenomenon strengthens and reprograms immune cells, resulting in a more effective and long-lasting response to different subsequent infectious diseases. Understanding trained immune response has significant implications for the development of new vaccine and immunotherapeutic strategies. Bacillus Calmette-Guérin (BCG) is known to induce innate immune memory, enhancing the immune system's ability to recognize heterologous antigens. BCG, known for its effectiveness in tuberculosis prevention, is also the gold standard in treating patients with non-muscle-invasive bladder cancer. However, about 30% of patients do not respond to BCG therapy. In this scenario, recombinant BCG (rBCG) vaccines are designed to express heterologous antigens capable of enhancing BCG's adjuvanticity. Our group has developed an rBCG expressing the A subunit of genetically detoxified Escherichia coli Heat-Labile Toxin, LTAK63, named rBCG-LTAK63. In a murine bladder cancer model, we demonstrated that rBCG-LTAK63 controls tumor growth both in vitro and in vivo. Since scientific literature indicate that trained immunity may play a crucial role in cancer response, in this project, we propose to evaluate the role of innate immune memory induced by BCG or rBCG-LTAK63 and its impact on enhancing the antitumor potential of intravesical immunotherapy in a murine orthotopic bladder cancer model. These studies aim to advance understanding of antitumor efficacy and mechanistic characterization of the proposed therapeutic approach, potentially yielding a novel immunobiological for bladder cancer treatment.