Advancing Bladder Cancer Care by Imaging and Intravesical Immune Checkpoint Blockade

通过影像学和膀胱内免疫检查点阻断推进膀胱癌治疗

• 批准号: 10592433
• 负责人: Pradeep Tyagi
• 金额: $ 18.16万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10592433
• 关键词: Adverse effects; Anesthesia procedures; Antibodies; Antitumor Response; BCG Live; Bacillus Calmette-Guerin Therapy; Bladder; Bladder Neoplasm; Blood Substitutes; Cancer Patient; Carcinogens; Carcinoma in Situ; Catheters; Cells; Cessation of life; Common Neoplasm; Cystectomy; Cystoscopy; Diameter; Diarrhea; Diffusion; Dimethyl Sulfoxide; Drug Delivery Systems; Dyes; Early Diagnosis; Early identification; Emulsions; Epidermal Growth Factor Receptor; Exhibits; Experimental Designs; FGFR3 gene; Harvest; Healthcare Systems; Histopathology; Hyperplasia; Image; Image Enhancement; Imaging Techniques; Immune; Immune checkpoint inhibitor; Immunocompetent; Immunohistochemistry; Immunologic Surveillance; Immunotherapeutic agent; Immunotherapy; Infiltration; Injectable; Invaded; Isoflurane; Length of Stay; Ligands; Liposomes; Magnetic Resonance Imaging; Magnetism; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Maps; Measures; Mediating; Monitor; Mus; Muscle; Nitrosamines; Nivolumab; Operating Rooms; PD-1/PD-L1; PDL1 inhibitors; PTGS2 gene; Patients; Pattern; Permeability; Pharmaceutical Preparations; Probability; Proteins; Randomized; Recurrence; Relaxation; Resistance; Resolution; Route; Salvage Therapy; Secondary to; Self Tolerance; Spleen; Stains; Steroids; Survival Analysis; T cell infiltration; T-Lymphocyte; Testing; Thinness; Time; Toxic effect; Transitional Cell Carcinoma; Tumor Cell Invasion; Tumor Volume; Tumor-Associated Vasculature; Urethra; Urologic Neoplasms; Urothelium; Visualization; Water; Weight; angiogenesis; anti-PD-L1 antibodies; cancer care; cancer imaging; carcinogenesis; chemotherapy; contrast enhanced; contrast imaging; cost; dalton; feeding; gadobutrol; high risk; imaging approach; imaging modality; immune checkpoint blockade; improved; intravesical; minimally invasive; molecular size; novel; overexpression; programmed cell death ligand 1; programmed cell death protein 1; receptor; response; risk stratification; small molecule; soft tissue; treatment effect; tumor; tumor progression; uptake; virtual; virtual monitoring

This revised proposal leverages the preliminary findings of NCT04369560 to develop intravesical imaging and immunotherapy approach for bladder cancer (BCa). While cystoscopy can detect exophytic tumors (≥2mm in diameter), the poor soft tissue resolution of the available imaging modalities renders them inadequate to detect tumor invasion, carcinoma-in-situ (CIS) and the tumor vasculature associated with aggressive cancer. This critical gap in tumor visualization adversely impacts the early identification of high risk BCa patients and patients most likely to benefit from chemotherapy and/or immunotherapy. Although intravesical immunotherapy of Bacillus Calmette–Guérin (BCG) halts BCa progression and muscle invasion, still 40% of patients exhibit BCG-resistant tumor with the expression of: programmed death (PD)L1, PDL2 ligands for engaging with PD1 receptor on T cells to suppress the anti-tumor response. While the anti-tumor response is inhibited by injectable antibodies, adverse effects secondary to the breakdown of T-cell mediated immune surveillance creates a dire need for intravesical alternatives to injectable antibodies like Nivolumab. Hence, we will use the overexpression of PD-L1 by orthotropic tumor provoked by carcinogen, N-butyl-N-4-hydroxybutyl nitrosamine (BBN) to demonstrate that molecular size is the key determinant for the permeation of instilled drugs and dyes into cancer foci. Accordingly, we hypothesize that intravesical contrast enhanced magnetic resonance imaging (MRI) after the instillation of Gadobutrol (0.8nm) mixed with Perfluorodecalin emulsion (>150nm) leverages the tumoritropic infiltration of Gadobutrol and the size-restricted diffusion of magnetically inert, Perfluorodecalin to enhance the image contrast of cancer foci for accomplishing virtual monitoring of tumor progression and tumor regression following intravesical immunotherapy of BMS-1166, a small molecule (640 Daltons), PD-1/PD-L1 inhibitor (IC50 of 1.4 nM). Our hypotheses will be tested in these interlocking Specific Aims: 1) To assess the criterion validity of intravesical contrast-enhanced MRI for monitoring BBN induced tumor progression. 2) To assess the discriminant validity of intravesical contrast-enhanced MRI for monitoring immunotherapy mediated BBN tumor regression. By ad libitum feeding of 0.05% BBN in water for up to 12 weeks, we will provoke tumor in immunocompetent 18-24 weeks old B6D2F1 mice for quantitative T1 relaxometry of normal and cancer foci and tumor vasculature at different time points to monitor BBN tumor progression, later confirmed by whole mount bladder histopathology and the expression of angiogenesis markers (Aim 1). To monitor the treatment mediated tumor regression (Aim 2), mice fed BBN for 10 weeks will be randomized to receive either a single 0.1mL instillation at 3mg/mL of Nivolumab or BCG or water-insoluble BMS-1166 entrapped in Sphingosomes or 50% DMSO followed by MRI, 6 weeks later to assess the effect of treatment on tumor size and the associated vasculature. Thus, we will enable MRI for imaging CIS, muscle invasion and tumor vasculature as well as develop a novel intravesical immunotherapeutic option.

该修订的建议利用了NCT04369560的初步发现来开发内部成像和 膀胱癌（BCA）的免疫疗法方法。膀胱镜检查可以检测出外生肿瘤（≥2mm中 直径），可用成像方式的较差的软组织分辨率使它们不足检测 肿瘤侵袭，毒癌（CIS）和与侵袭性癌症相关的肿瘤脉管系统。这 肿瘤可视化中的关键差距会对高风险BCA患者的早期鉴定和 患者最有可能受益于化学疗法和/或免疫疗法。虽然静脉内免疫疗法 Calmette –Guérin（BCG）的杆菌停止BCA进展和肌肉入侵，仍有40％的患者表现出来 BCG耐药性肿瘤具有：编程死亡（PD）L1，PDL2配体用于与PD1互动的肿瘤 T细胞上的受体以抑制抗肿瘤反应。而抗肿瘤反应被抑制 可注射抗体，继发于T细胞介导的免疫监测的不良反应 对于尼沃鲁马布（Nivolumab）等可注射抗体的静脉内替代品创造了迫切的需求。因此，我们将使用 致癌物，N-丁基N-4-羟基丁基硝基胺引起的正交肿瘤对PD-L1的过表达 （BBN）证明分子大小是渗透药物和染料的关键决定剂 进入癌症焦点。彼此之间，我们假设静脉对比度增强了磁共振成像 （MRI）在将gadobutrol（0.8nm）与全氟二克林乳液（> 150nm）混合后滴注后 Gadobutrol的肿瘤浸润和磁性惰性，全氟甲林的尺寸限制扩散至 增强癌症焦点的图像对比度，以实现肿瘤进展和肿瘤的虚拟监测 BMS-1166，小分子（640 daltons），PD-1/PD-L1进行静脉内免疫疗法后的回归 抑制剂（IC50为1.4 nm）。我们的假设将在这些互锁的特定目的中进行检验：1）评估 静脉对比增强的MRI的标准有效性用于监测BBN诱导肿瘤进展。 2）到 评估静脉对比增强MRI的判别有效性，以监测免疫疗法介导 BBN肿瘤回归。通过在水中的0.05％BBN的自发进食长达12周，我们将引起肿瘤 在免疫能力18-24周大的B6D2F1小鼠中，用于定量T1正常和癌症灶 和不同时间点的肿瘤脉管系统以监测BBN肿瘤的进展，后来由整体证实 膀胱山组织病理学和血管生成标记的表达（AIM 1）。监测治疗 介导的肿瘤回归（AIM 2），喂养BBN的小鼠将被随机分配，以接收任何一个 0.1ml滴注nivolumab或bcg或水 - 不溶于水的BMS-1166，被输入鞘糖体的BMS-1166 或50％DMSO，然后是MRI，6周后，以评估治疗对肿瘤大小和 相关的脉管系统。这，我们将启用MRI，以成像顺式，肌肉侵袭和肿瘤脉管系统 以及开发一种新颖的静脉内免疫治疗选择。