Bladder cancer is a common and potentially lethal cancer and yet studied far less than other equally common malignancies. It is also the costliest malignancy to treat from diagnosis to death. Recently, several checkpoint inhibitors have been approved for metastatic disease, however, there have not been any major therapeutic break-throughs in the non-muscle invasive bladder cancer (NMIBC) setting since the advent of BCG immunotherapy couple of decades ago. Moreover, there is an urgent need for therapies in BCG-refractory NMIBC as well as for rare histologies such as squamous cell carcinoma of the bladder.
The bladder is a unique solid organ in that it can easily be accessed from the urethra and so intravesical approaches are well accepted for diagnosis and treatment. Hexaminolevulinate (HAL) blue light-based photodynamic detection of bladder cancer is an emerging standard of care diagnostic practice in the field. Conversely, photodynamic therapy using Photofrin I and II, 5-ALA, and HAL are not established therapies because they led to severe adverse events such as bladder contracture and skin photosensitivity. At the National Cancer Institute, our co-authors Dr. Peter L. Choyke and Dr. Hisataka Kobayashi had developed a targeted form of photodynamic therapy called photoimmunotherapy (PIT). In this case, an antibody specific for a cell surface protein over-expressed on the surface of tumor cells is labelled with a water-soluble photo-absorber called IRDye 700Dx. This photo-absorber gets activated by near infrared light at approximately 689 nm. Once activated, it produces a large excess of reactive oxygen species that can potentially damage cells and organelles. The antibody-IR700 complex, however, localizes to the cancer cell surface due to the antibody’s specificity, and once activated by near IR light, the reactive chemical species are limited to the plasma membranes of cancer cells and the neighboring vicinity leading to selective damage and consequently cellular death. Moreover, unlabeled dye does not accumulate in cells or tissues because it is highly water-soluble and therefore, gets extruded out of the body via urine.
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The current study is the first proof of concept study in a preclinical setting to demonstrate that PIT can destroy bladder cancer cells. We used an EGFR overexpressing bladder squamous carcinoma cell line as well as urothelial cancer cell lines to show that pan-IR700 (panitumumab (antibody specific for EGFR) labelled with IRDye 700Dx) binds specifically to bladder cancer cells and when activated by near IR light kills these cells. Treatment with antibody alone, dye alone or near IR light does not show any cell toxicity. We showed that this cell damage following pan-IR700 based PIT is very rapid and very violent leading to necrotic cell death. Furthermore, this therapy was not toxic to normal urothelial cell lines. This kind of necrotic cell death in human beings may lead to activation of the immune system with the production of immunogenic proteins, thereby leading to better clearance of tumors. In our small mammal (mice) tumor xenograft studies, some animals showed complete clearance of tumors in the presence of pan-IR700 + near IR light.
In the future, we will be combining this therapy with checkpoint inhibitors to increase the efficacy of both therapies. We hope to identify an ideal combination that we will one day evaluate in patients suffering from bladder cancer.
Written by: Piyush Kumar Agarwal, MD, Head, Bladder Cancer Section, Urologic Oncology Branch, National Cancer Institute/NIH, Bethesda, MD