Preexisting BCG-Specific T Cells Improve Intravesical Immunotherapy for Bladder Cancer

Preexisting immunity to BCG improves treatment response to intravesical BCG therapy for bladder cancer in mouse models and humans. Bugs as Drugs Although still in its infancy for the treatment of many tumor types, immunotherapy has been and remains the standard of care for patients with bladder cancer. The concept behind this success is repeated instillations of bacillus Calmette-Guérin (BCG; the same bacteria used as a vaccine for Mycobacterium tuberculosis) in the bladder, inducing an immune response that fights the cancer. The clinical response rate in bladder cancer patients is 50 to 70%, higher than any other immunotherapy but still leaving room for improvement. Biot et al. provide new insight into the mechanisms behind BCG’s success in the bladder and suggest that parenteral BCG exposure may boost the success rate for bladder cancer treatment. Using a mouse model of bladder cancer, the authors show that a single instillation of BCG induced an immune response, but repetitive instillations were required for robust T cell trafficking to the bladder. Previous parenteral exposure to BCG overcame this requirement in the mice, inducing an enhanced innate immune response, accelerating T cell trafficking to the bladder, and improving the immune response to the tumor. Furthermore, bladder cancer patients who had preexisting immunity to BCG (secondary to their childhood M. tuberculosis vaccination) showed improved recurrence-free survival after standard BCG therapy relative to those patients without preexisting immunity. Thus, immunizing BCG-naïve cancer patients before therapy may provide a simple strategy that could improve therapeutic response. Therapeutic intravesical instillation of bacillus Calmette-Guérin (BCG) is effective at triggering inflammation and eliciting successful tumor immunity in patients with non–muscle invasive bladder cancer, with 50 to 70% clinical response. Therapeutic success relies on repeated instillations of live BCG administered as adjuvant therapy shortly after tumor resection; however, the precise mechanisms remain unclear. Using an experimental model, we demonstrate that after a single instillation, BCG could disseminate to bladder draining lymph nodes and prime interferon-γ–producing T cells. Nonetheless, repeated instillations with live BCG were necessary for a robust T cell infiltration into the bladder. Parenteral exposure to BCG before instillation overcame this requirement; after the first intravesical instillation, BCG triggered a more robust acute inflammatory process and accelerated T cell entry into the bladder, as compared to the standard protocol. Moreover, parenteral exposure to BCG before intravesical treatment of an orthotopic tumor markedly improved response to therapy. Indeed, patients with sustained preexisting immunity to BCG showed a significant improvement in recurrence-free survival. Together, these data suggest that monitoring patients’ response to purified protein derivative, and, in their absence, boosting BCG responses by parenteral exposure before intravesical treatment initiation, may be a safe and effective means of improving intravesical BCG-induced clinical responses.