"Designer Nanoparticles" for Immunotherapeutic Treatment of Bladder Cancer
Abstract
Objective and Rationale: Bladder cancer is a common cancer, with more than 70,000 new cases and 15,000 deaths each year in the United States. It is common in both in active and retired military personnel, estimated to be the fourth most common cancer in the US Department of Veterans Affairs (VA) medical system. Despite the common nature of this disease, the treatment approach for bladder cancer has changed very little in the last several decades until recently. Since 2016, five new immunotherapy agents have been approved for metastatic bladder cancer. With all the interest in immunotherapy across many types of cancer, it’s important to note that in bladder cancer these agents are only approved for late stage, metastatic disease, typically after failure of standard chemotherapy. It’s also notable that only a minority of bladder cancer patients, generally around 20%, respond to this approach. Therefore, there is a significant clinical gap in moving these immunotherapies to early-stage bladder cancer to prevent progression and increasing the response rate in bladder cancer. In this idea project we will develop a novel immunotherapeutic approach using a “designer nanoparticle” platform that is based upon bacteriophage lambda, a virus that infects bacteria but that is non-infectious in humans. We have coopted the lambda capsid which is an icosahedral-shaped particle in the nanometer size range that we can then decorate with targeting antibodies, small molecules (e.g., drugs), DNA, bioactive proteins, etc., in a user-defined manner. We propose to develop this designer nanoparticle, aka “phage-like particle” (PLP), for targeting bladder cancer and activating an anti-tumor immune pathway for treatment of this disease. We are specifically targeting a pathway which was recently recognized to contribute to immune responses against cancer cells. This pathway, the stimulator of interferon genes (STING), when activated, produces anti-tumor proteins termed Type I interferons that promote a robust and durable anti-tumor response by recruitment of other immune cells to attack the tumor. We have performed preliminary experiments that show our capability to make the PLPs and demonstrate that they are taken up into bladder cancer cells. We would like to expand upon these preliminary findings to optimize the PLPs for uptake into bladder cancer cells and activation of the STING pathway. While the primary goal of our proposal is to provide strong proof of concept for development of PLPs, the future clinical application would be targeted toward patients with unresponsive high-risk non-muscle invasive bladder cancer. The PLP treatment could be given directly into the bladder (with no systemic toxicity) over a set period of time and possibly in conjunction with current therapies such as systemic checkpoint inhibitor treatment. Impact: Currently the treatment for localized bladder cancer includes a surgical “scraping” of the tumors via a scope inserted into the bladder, followed by the administration of a tuberculosis vaccine (i.e., BCG) into the bladder via a catheter. Remarkably, this approach to early stage bladder cancer has changed very little in the past three decades, and recurrence after this treatment remains common. For early-stage bladder cancer patients with recurrence, the treatment options currently include: Repeated therapy with the ineffective BCG, administration of toxic chemotherapy into the bladder, or even the substantial step of removing the bladder surgically. In contrast to the current approach for early stage bladder cancer, we propose to develop PLPs that can be delivered directly to the bladder, target cancer cells and have the ability to produce a robust and durable immune response against the tumor. In this proposal we will use a combination of bladder cancer cell models and a mouse model of bladder cancer to test our hypothesis that PLPs can be engineered to specifically target bladder cancer cells and trigger th
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010544
Entities
People
- Jared Brown
Organizations
- United States Army
- University of Colorado Denver