Advancing Bladder Cancer Care by Imaging and Intravesical Immune Checkpoint Blockade

点击翻译按钮获取中文摘要

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.