Abstract EN:

Intravesical instillation of bacillus Calmette-Guérin (BCG) for bladder cancer is one of the few examples of successful immunotherapy in the clinic, though its precise mechanisms of action remain unclear. I established a mouse model to study the dynamics of the immune response following intravesical BCG. I demonstrated that BCG dissemination to bladder draining lymph nodes and T cell priming could occur following a single instillation; yet, repeated instillations with live BCG were necessary for a robust T cell infiltration in the bladder. Subcutaneous immunization with BCG prior to intravesical instillation overcame this requirement, triggering enhanced inflammation, suggestive of a delayed-type hypersensitivity reaction, and accelerating T cell entry into the bladder. Such findings translated into an improved anti-tumor response in mice that were subcutaneously immunized with BCG prior to intravesical treatment of an orthotopic tumor, while analysis of clinical data showed that patients with pre-existing immunity to BCG had significantly longer recurrence-free survival. I also contributed to construct and parameterize a mathematical model describing the interactions between BCG, the immune system, bladder mucosa and tumor cells. The model suggested a requirement for the adaptive immune response to achieve tumor extinction rates similar to the clinic, and helped predict optimal clinical parameters for BCG therapy. Together these data provide new insights into a long-standing clinically effective immunotherapy and predict strategies that may improve patient management, such as the parenteral exposure of patients without immune signature to BCG prior to intravesical therapy.