BCG therapy of bladder cancer induces a T-cell mediated, tumor-specific response
Gil Redelman-Sidi1*, Anna Binyamin1, Michael S. Glickman1
1Memorial Sloan Kettering Cancer Center, NY
* Corresponding author
Bladder cancer remains a major cause of morbidity and mortality. At initial diagnosis, 70% of patients have non–muscle-invasive bladder cancer (NMIBC). The treatment of choice for most patients with NMIBC is cystoscopic resection followed by intravesical BCG therapy. BCG therapy improves outcomes compared to cystoscopic resection alone, but patients treated with BCG still have a substantial risk of recurrence or progression and no reliable methods exist to predict an individual’s outcome.
The mechanism of action of BCG therapy of bladder cancer remains an area of active investigation. Data suggest that both CD4+ and CD8+ T-cells are required for the efficacy of BCG. However, the antigenic targets of the T-cell response that ultimately eliminates the tumor are unknown. One model posits that cancer cells are non-specifically destroyed as part of an inflammatory response targeting mycobacterial antigens. A second model is that BCG elicits an immune response to the tumor cell, possibly directed at neoantigens derived from tumor-specific mutations.
Recently, using the MB49 orthotopic bladder cancer mouse model of BCG therapy, we have gathered data supporting the second model. We have found that mice cured of MB49 bladder cancer by BCG therapy, but not mice that received intravesical BCG therapy without tumor cells, were resistant to a subsequent challenge with subcutaneous MB49 tumors but not with a different cell line. Moreover, adoptive transfer of T-cells from mice surviving MB49 bladder cancer after BCG therapy, but not from mice who received intravesical BCG therapy alone, conferred a survival advantage to naïve mice instilled with intravesical MB49. These results strongly suggest that BCG therapy induces a T-cell-dependent tumor immunity.
Our current efforts are focused on identifying the neoantigens that determine the efficacy of BCG in the MB49 model and testing methods to improve the efficacy of BCG by augmenting tumor-specific immunity.