Peer Reviewed Cancer
Posted June 12, 2019
Brant Inman, MD, MS Duke University
Dr. Brant Inman
Bladder cancer (BlCa) is a devastating disease, with an estimated 80,470 new cases expected to be diagnosed in 2019. It is a particular health concern to the military and Veteran health systems as BlCa is approximately three times more common in men than women (the majority of the military and Veteran populations are men), and tobacco smoking is the primary exposure linked to causing BlCa (68% of military personnel are active or past smokers). These factors contribute to BlCa being the fourth most diagnosed cancer in the VA health system. Furthermore, because BlCa has a high recurrence rate requiring patients to undergo regular cystoscopies and urine tests for surveillance purposes, BlCa is one of the most expensive cancers to treat. There is an urgent need for improved therapies that reduce BlCa recurrence, improve patient quality of life, and reduce the cost of treatment.
Dr. Inman, a urologic oncologist with extensive experience in translational research and conducting clinical trials, received a fiscal year 2016 Idea Award with Special Focus to optimize a novel gold nanoparticle-based hyperthermia therapy (i.e., using heat to treat cancer) and demonstrate the proof-of principle that it can be developed into a highly effective treatment for BlCa.
Hyperthermia is known to improve chemotherapy by increasing the size of blood vessels, in turn increasing the blood flow through a tumor, and by making cellular membranes more permeable. The combination of these two events increases drug delivery to a tumor. However, the high cost of some pieces of equipment, the need for a specially shielded therapy room, the need for a uniquely skilled team to provide the treatment, and the uneven application of heat to tumors currently prevent the broad application of hyperthermia to cancer patients. To overcome these challenges, Dr. Inman and his team have developed star-shaped gold nanoparticles termed gold nanostars (GNS). The GNS offer several advantages to previous hyperthermia treatments. GNS size and shape properties can be controlled so that they selectively accumulate in tumors. Once localized to the tumors, focused light may be applied to the tumor in a way that only the tumor is heated and that the surrounding, healthy tissue is minimally affected.
The optimization of the GNS is only part of the novelty of Dr. Inman’s current project. To greatly increase the impact of the project, he will be combining the GNS with immunotherapy in a treatment called SIMPHONY (Synergistic IMmuno PHOtothermal NanotherapY). Preliminary studies demonstrated that GNS-mediated hyperthermia treatment resulted in tumor cell death in a way that resulted in a strong immune response. SIMPHONY was designed to take advantage of this immune response as much as possible. Additional data support the observation that the antitumor immune response generated by GNS-mediated tumor cell death can be amplified by simultaneous treatment with a PD-L1 immune checkpoint inhibitor that prevents suppression of the immune response.
During the first year of this award, Dr. Inman and his team successfully optimized the size and shape properties of GNS. Validation studies demonstrated that GNS were heated by the prescribed wavelength of light expected to yield the best tissue penetration, and GNS imbedded in gel, a surrogate for tissue, were significantly and selectively heated relative to the surrounding gel.
Also during the first year, Dr. Inman started testing SIMPHONY in mouse models of BlCa. Preliminary toxicity studies in mice indicate that the GNS are well-tolerated and are not detrimental to non-target tissues (e.g., brain or heart). Applying SIMPHONY to a mouse model of BlCa resulted in the majority of the mice being “cured” as compared to lower response rates to treatment with either GNS or a PD-L1 inhibitor alone. Even more promising, when the mice that had received SIMPHONY were re-exposed to BlCa, no tumor growth was observed. This means that SIMPHONY appears to not only kill BlCa cells at the initial site but also results in the development of systemic antitumor immunity.
Dr. Inman is currently validating and expanding upon these exciting results. If these studies are successful, SIMPHONY could be easily translated into early phase clinical trials. A phase I trial is a particular reality since a PD-L1 inhibitor similar to what is used in SIMPHONY is already FDA-approved for use in humans with BlCa. Similarly, because gold nanoparticles are generally considered to be nontoxic, Dr. Inman believes that using the GNS in humans should be safe. There is great hope that SIMPHONY could be a much needed new treatment option that would reduce the cost of BlCa treatment and improve survivor quality of life.
 National Cancer Institute Division of Cancer Control and Population Sciences, Surveillance Research Program, Surveillance, Epidemiology, and End Results Program (SEER) Data, Cancer Stat Facts: Bladder Cancer (https://seer.cancer.gov/statfacts/html/urinb.html)
Last updated Tuesday, September 29, 2020