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

项目摘要 膀胱癌是美国人均治疗费用最高的癌症。非肌肉浸润性膀胱癌 (NMIBC)，占所有新诊断肿瘤的70%-75%，只有一个FDA批准的一线 治疗选择卡介苗(BCG)。卡介苗是唯一被批准的一线治疗方法 中高风险NMIBC已有40多年。虽然卡介苗可以诱导持久的反应，但~50%的 患者的疾病会复发或恶化。卡介苗抗肺炎的作用机制尚不明确 NMIBC的肿瘤活动已被勾画出来。研究表明，PD-L1表现出显著的 卡介苗给药后增加，支持在卡介苗设置中使用PD-1或PD-L1阻滞剂 抵抗。这些发现导致pembrolizumab单一疗法，PD-1抑制剂，成为第一个FDA 20多年来批准治疗卡介苗难治性NMIBC。在基调-057(n=101)中，41%的卡介苗 耐药患者在3个月后完全缓解，但在12个月时仅有19%的持久有效。因为我们 从Keynote-057可以看出，PD-1的抑制对卡介苗耐药肿瘤具有适度的活性 肿瘤组织中PD-1表达上调。PD-1阻断未能在卡介苗中产生更完全的反应- 耐药患者提示，我们对NMIBC免疫耐药机制的了解是不完整的。 人类白细胞抗原-E/NKG2A轴是一种新的免疫检查点，已显示出显著的临床前前景 包括在PD-1电阻设置中的目标。这个轴已经在其他几种肿瘤类型中进行了研究。 还积累了大量数据，以确定肿瘤细胞调节肿瘤的能力 导致抗肿瘤免疫的微环境。我们已经证明，人类白细胞抗原-E高亮度肿瘤是高度 激活并产生趋化因子，CXCL9/10/11，导致NK和CD8 T细胞的招募(包括 肿瘤巢附近的调节性T细胞(Tregs)。这种招募导致了免疫 允许肿瘤继续生长的调节失调。这些数据一起描述了肿瘤的动态过程 细胞和免疫细胞的相互作用，在一定的压力下可以改变。我们的中心假设是 卡介苗耐药发生在HLAE-Ebright肿瘤细胞的环境中，导致募集和 允许人类白细胞抗原-EDIM细胞生长的免疫细胞。我们寻求利用空间转录测序 (STseq)和免疫质量细胞术(IMC)，这些新技术有可能彻底改变我们的 在组织结构水平上对NMIBC的理解。

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.