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。非肌层浸润性膀胱癌 （NMIBC）占所有新诊断肿瘤的70-75%，只有一个FDA批准的一线治疗方案。 治疗选择，卡介苗（BCG）。BCG是唯一被批准的一线治疗药物， 40多年来一直是中等和高风险的NMIBC。虽然BCG可以诱导持久的反应，但约50%的 患者的疾病复发或进展。BCG抗结核的作用机制尚不明确 NMIBC中的肿瘤活性已经被描述。研究表明，PD-L1表现出显著的 BCG给药后增加，支持在BCG环境中使用PD-1或PD-L1阻断剂 阻力这些发现导致Pembrolizumab单药治疗，一种PD-1抑制剂，成为第一个FDA 20多年来，BCG难治性NMIBC的治疗获得批准。在KEYNOTE-057（n = 101）中，41%的BCG 耐药患者在3个月时有完全反应，但在12个月时只有19%的持久反应。正如我们 从KEYNOTE-057可以看出，PD-1的抑制对BCG抗性肿瘤具有适度的活性，即使 该肿瘤具有PD-1的上调。PD-1阻断未能在BCG中产生更完全的反应， 耐药患者表明我们对NMIBC中免疫耐药机制的理解是不完整的。 HLA-E/NKG 2A轴是一种新的免疫检查点，已显示出重要的临床前前景， 目标包括在PD-1抗性的设置中。该轴已在其他几种肿瘤类型中进行了研究。 也积累了大量的数据来鉴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，HLA-E BRIGHT肿瘤是高度 激活并产生趋化因子CXCL 9/10/11，导致NK和CD 8 T细胞（包括 调节性T细胞（TCLs））。这种招募导致免疫 失调允许肿瘤继续生长。这些数据共同描述了肿瘤的动态过程 细胞和免疫细胞的相互作用，这可以在一定的压力下改变。我们的核心假设是， BCG耐药发生在HLAE-EBRIGHT肿瘤细胞的背景下，导致细胞募集和细胞凋亡的失调。 免疫细胞允许HLA-EDIM细胞生长。我们寻求利用空间转录组测序 （STseq）和免疫质谱细胞术（IMC），具有革命性的潜力，我们的新技术， 在组织架构水平上理解NMIBC。

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.