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

识别卡介苗 (BCG) 治疗的非肌层浸润性膀胱癌的新耐药机制

• 批准号: 10742368
• 负责人: Amir Horowitz
• 金额: $ 23.7万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-04 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10742368
• 关键词: Aftercare; Antineoplastic Agents; Architecture; Autologous; Autologous Tumor Cell; Automobile Driving; BCG Live; Bacillus Calmette-Guerin Therapy; Bacteria; Binding; Biological Assay; Bladder Neoplasm; CD8-Positive T-Lymphocytes; CD8B1 gene; CXCL9 gene; CXCR3 gene; Cell Communication; Cell Separation; Cell physiology; Cells; Complex; Cultured Tumor Cells; Cytometry; Data; Disease; Environment; FDA approved; Failure; Future; Genes; Grant; HLA Antigens; Hematopoietic; Image; Immune; Immunotherapeutic agent; In Vitro; In complete remission; Incubated; Infiltration; Inflammatory; Interferon Type II; KLRD1 gene; Link; Major Histocompatibility Complex; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Measures; Mediating; Natural Killer Cells; Newly Diagnosed; PD-1 blockade; PD-1 inhibitors; PD-L1 blockade; Pathway interactions; Patients; Phenotype; Production; Proteins; Proteomics; Recurrence; Recurrent tumor; Refractory; Regulatory T-Lymphocyte; Resistance; Resolution; Sampling; Signal Transduction; Sorting; System; T cell response; T-Lymphocyte; Testing; Therapeutic; Tissues; Tuberculosis; Tumor Immunity; Tumor Subtype; Tumor Tissue; Tumor-Associated Process; Tumor-infiltrating immune cells; Up-Regulation; cell killing; cell motility; chemokine; cytokine; functional status; high risk; immune activation; immune checkpoint; immune resistance; improved; innovation; insight; intravesical; neoplastic cell; new technology; non-muscle invasive bladder cancer; novel; paracrine; pembrolizumab; pre-clinical; pressure; programmed cell death ligand 1; programmed cell death protein 1; recruit; resistance mechanism; response; single-cell RNA sequencing; spatial relationship; success; therapy resistant; transcriptome sequencing; transcriptomics; tumor; tumor diagnosis; tumor growth; tumor microenvironment

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.

项目摘要 膀胱癌是美国治疗的人均癌症。非肌肉侵入性膀胱癌 （NMIBC）占所有新诊断肿瘤的70-75％的70-75％ 治疗方案，芽孢杆菌Calmette-guérin（BCG）。 BCG是唯一获得批准的一线疗法 中级和高风险NMIBC超过40年。虽然BCG可以诱导持久的响应，但约有50％ 患者患有疾病的复发或进展。 BCG的反 - 背后没有明确的行动机制 NMIBC中的肿瘤活性已被描述。研究表明，PD-L1显示出明显的 BCG给药后增加，支持在BCG设置中使用PD-1或PD-L1封锁 反抗。这些发现导致Pembrolizumab单一疗法，PD-1抑制剂，成为第一个FDA 在20多年的时间内，批准了BCG难治性NMIBC的治疗方法。在Keynote-057（n = 101）中，占BCG的41％ 耐药患者在3个月时具有完全反应，但在12个月时只有19％的耐用响应。像我们 从Keynote-057抑制PD-1可以看出，尽管 肿瘤的上调PD-1。 PD-1封锁失败在BCG-中产生更完整的响应 耐药患者表明，我们对NMIBC中免疫抗性机制的理解是不完整的。 HLA-E/NKG2A轴是一种新型的免疫光切点，已显示出明显的临床前希望作为一个 目标包括在PD-1电阻的情况下。该轴已在其他几种肿瘤类型中进行了研究。 重要的数据还积累了鉴定肿瘤细胞调节肿瘤的能力 微环境导致抗肿瘤免疫。我们已经证明了HLA-E明亮的肿瘤很高 激活和产生的趋化因子CXCL9/10/11，导致NK和CD8 T细胞的募集（包括 在HLA-ebright肿瘤巢的接近内，调节性T细胞（Tregs））。这次招聘导致免疫 失调允许继续肿瘤生长。这些数据一起描述了肿瘤的动态过程 细胞和免疫细胞相互作用，可以在某些压力下改变。我们的中心假设是 BCG耐药性发生在HLAE-ebright肿瘤细胞的环境中，导致募集和失调 免疫细胞允许HLA-EDIM细胞生长。我们试图利用空间转录组测序 （STSEQ）和免疫质量细胞仪（IMC），具有革新我们的新技术 了解NMIBC在组织结构水平上。