# Advancing Bladder Cancer Care by Imaging and Intravesical Immune Checkpoint Blockade

> **NIH NIH R21** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $209,468

## Abstract

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 s...

## Key facts

- **NIH application ID:** 10435605
- **Project number:** 1R21CA263243-01A1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Pradeep Tyagi
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $209,468
- **Award type:** 1
- **Project period:** 2022-03-15 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10435605

## Citation

> US National Institutes of Health, RePORTER application 10435605, Advancing Bladder Cancer Care by Imaging and Intravesical Immune Checkpoint Blockade (1R21CA263243-01A1). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10435605. Licensed CC0.

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