Identifying novel resistance mechanisms in non-muscle invasive bladder cancer treated with Bacillus Calmette-Guerin (BCG)

项目总结

Project Summary Bladder cancer is the most expensive cancer per capita to treat in the US. Non-muscle invasive bladder cancer (NMIBC) which accounts for 70-75% of all newly diagnosed tumors only has a single FDA approved first-line treatment option, Bacillus Calmette-Guérin (BCG). BCG has been the only approved first-line therapy for intermediate and high-risk NMIBC for more than 40 years. While BCG can induce durable responses, ~50% of patients have recurrence or progression of their disease. No clear mechanism of action behind BCG’s anti- neoplastic activity in NMIBC has been delineated. Studies have demonstrated that PD-L1 showed significant increases following BCG administration, supporting the use of PD-1 or PD-L1 blockade in settings of BCG resistance. These finding have led to Pembrolizumab monotherapy, a PD-1 inhibitor, becoming the first FDA approved treatment for BCG refractory NMIBC in over 20 years. In KEYNOTE-057 (n = 101), 41% of BCG resistant patients had complete response at 3 months, but only a 19% durable response at 12 months. As we can see from KEYNOTE-057 inhibition of PD-1 has modest activity against BCG resistant tumors even though the tumor has upregulation of PD-1. The failure of PD-1 blockade to yield a more complete response in BCG- resistant patients suggests that our understanding of immune resistance mechanisms in NMIBC is incomplete. The HLA-E/NKG2A axis is a novel immune checkpoint that has shown significant preclinical promise as a target including in the setting of PD-1 resistance. This axis has been studied in several other tumor types. Significant data has also accumulated identifying the ability of tumor cells to modulate the tumor microenvironment leading to anti-tumor immunity. We have demonstrated that HLA-E BRIGHT tumors are highly activated and produce chemokines, CXCL9/10/11, leading to recruitment of NK and CD8 T cells (including regulatory T cells (Tregs)) within proximity of HLA-EBRIGHT tumor nests. This recruitment leads to immune dysregulation allowing for continued tumor growth. Together this data describes a dynamic process of tumor cell and immune cell interactions, which can be altered under certain pressures. Our central hypothesis is that BCG resistance occurs in the setting of HLAE-EBRIGHT tumor cell causing recruitment and dysregulation of immune cells allowing for HLA-EDIM cells to grow. We seek to capitalize on spatial transcriptomic sequencing (STseq) and immue mass cytometry (IMC), novel technologies with the potential to revolutionize our understanding of NMIBC at the tissue-architecture level.