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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要膀胱癌是美国人均治疗费用最高的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 批准的一线药物卡介苗 (BCG) 是唯一被批准的一线治疗方法。中度和高风险 NMIBC 超过 40 年，而 BCG 可以诱导持久反应，约 50%。患者的疾病复发或进展，卡介苗的抗作用尚无明确的作用机制。研究表明，PD-L1 在 NMIBC 中具有显着的肿瘤活性。 BCG 给药后增加，支持在 BCG 治疗中使用 PD-1 或 PD-L1 阻断剂这些发现导致 Pembrolizumab（一种 PD-1 抑制剂）单一疗法成为第一个 FDA 批准的药物。在 KEYNOTE-057 (n = 101) 中，41% 的 BCG 已被批准用于治疗难治性 NMIBC。耐药患者在 3 个月时获得完全缓解，但在 12 个月时只有 19% 的持久缓解。从 KEYNOTE-057 可以看出，PD-1 的抑制对 BCG 耐药肿瘤具有适度的活性，尽管肿瘤的 PD-1 上调，PD-1 阻断未能在 BCG 中产生更完整的反应。耐药患者表明我们对 NMIBC 免疫耐药机制的理解并不完整。 HLA-E/NKG2A 轴是一种新型免疫检查点，已显示出作为免疫检查点的重要临床前前景。该轴已在其他几种肿瘤类型中进行了研究。还积累了重要的数据来确定肿瘤细胞调节肿瘤的能力我们已经证明 HLA-E BRIGHT 肿瘤具有高度的抗肿瘤免疫力。激活并产生趋化因子 CXCL9/10/11，导致 NK 和 CD8 T 细胞（包括 HLA-EBRIGHT 肿瘤巢附近的调节性 T 细胞 (Treg) 募集会导致免疫。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，可能会在一定的压力下发生。 BCG 耐药性发生在 HLAE-EBRIGHT 肿瘤细胞的环境中，导致细胞募集和失调我们寻求利用空间转录组测序来促进 HLA-EDIM 细胞生长。（STseq）和免疫质谱流式细胞仪（IMC），新技术有可能彻底改变我们的在组织结构层面上理解 NMIBC。