Quadrifunctional Cancer-Specific Microtheranostic Platform for the Management of Bladder Cancer
Abstract
Fiscal Year 2021 (FY21) Peer Reviewed Cancer Research Program (PRCRP) Military Health Focus Areas-Mission Readiness: Gaps in cancer diagnosis and treatment that may impact mission readiness and the health and well-being of military members, Veterans, their beneficiaries, and the general public. Bladder cancer is the 4th-6th most common cancer in Veterans and 12th in general population. At diagnosis, over 75% of bladder cancers do not invade the muscle layer of the bladder wall and are called non- muscle-invasive bladder cancer (NMIBC), which is the focus of this project. NMIBC is usually identified by a procedure named cystoscopy, in which an instrument is inserted into the bladder cavity to directly visualize the bladder. Once NMIBC is diagnosed, patients are taken to operating rooms and undergo resection using an instrument going through the urethra (called transurethral resection or TUR) followed by instillation of a therapeutic agent, usually live attenuated bacteria called Bacillus Calmette–Guérin (BCG) , into the bladder cavity. Sometimes, it is difficult to distinguish cancer versus non-cancer areas in the bladder. Hence, unfortunately over one-third of patients still have cancer left in the bladder after TUR; 75% of patients have cancer recurrence; and one-third of patients have cancer progression into advanced stages with poor prognosis. If patients fail the above treatment (TUR plus live bacteria), immunotherapy is sometimes used which boosts patient’s own immune system to kill bladder cancer cells. Although the risk of NMIBC to metastasize is low, immunotherapy is administered through intravenous infusion and less than 20% of patients achieve response for 1 year or longer, but causes severe to life-threatening toxicity in approximately 15% of patients. The FY21 PRCRP Overarching Challenge(s) to be studied: The goal of this project is to develop a multifunctional drug named SPRINT that can improve diagnosis, treatment, and outcomes for Veterans, military members, and general populations; improve immunotherapy and eliminate the toxicity associated with systemic intravenous immunotherapy. SPRINT is attenuated bacteria called Salmonella that we specially engineered in lab. Our Salmonella has four safety measures to ensure safe use in patients. In this project, Salmonella is armed with a molecule called PLZ4 that we invented. Salmonella-PLZ4 works like missiles with active guidance that can specifically seek, target, and then kill bladder cancer cells (a process called microbiotherapy) after instillation into the bladder cavity, as with BCG. Furthermore, we arm Salmonella-PLZ4 with two other proteins/weapons: KillerRed and immunotherapy protein (hence the name SPRINT for Salmonella-PLZ4 with KillerRed and Immunotherapy). KillerRed, when delivered to cancer cells by SPRINT, can emit red fluorescence to diagnose cancer and guide resection (called photodynamic diagnosis) and produce free radicals to kill cancer cells (called photodynamic therapy). Photodynamic diagnosis and therapy can be done in a single procedure instead of the current two separate diagnosis and therapy procedures. Photodynamic diagnosis can guide complete resection, reduce cancer recurrence, and prevent cancer progression. With decreased recurrence, patients may need less frequent cystoscopy examinations, which can reduce the cost. The immunotherapy protein delivered by SPRINT locally at the cancer site can boost patients’ own immune system to kill bladder cancer cells without systemic toxicity associated with intravenous immunotherapy currently approved by the Food and Drug Administration. Furthermore, microbiotherapy and photodynamic therapy can overcome multiple resistance mechanisms and boost immunotherapy. In this project, we will finish the efficacy and toxicity studies of quadrifunctional SPRINT for the diagnosis and treatment of NMIBC and determine its underlying mechanisms of action. The Salmonella used in this
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210568
Entities
People
- Chong-Xian Pan
Organizations
- Boston VA Research Institute
- United States Army