Of the estimated 80,470 new cases of bladder cancer diagnosed in the U.S. in 2019, the vast majority – about 70 percent – are caught at an early stage: non-muscle invasive disease, with cancer limited to the epithelium, the tissue lining the bladder. The standard first-line treatment is transurethral resection of the bladder tumor, followed by immunotherapy: bathing the bladder with intravesical bacillus Calmette-Guerin (BCG), a modified form of tuberculosis bacteria.
“Initially, it’s effective,” says medical oncologist Noah Hahn, M.D. However, adds urologist Max Kates, M.D., “while up to 35 percent of patients have long-term, sustained remissions with intravesical BCG, as many as 60 percent of patients will have a recurrence of cancer within two years. Ultimately, 40 percent of these high-risk patients will progress to muscle-invasive stages and require radical cystectomy, surgical removal of the bladder.” That many patients do not have a long-term response is one issue with BCG; another is a basic problem of supply. “We have had continuing supply issues and shortages in getting BCG,” says Kates, “due to the fact that there is currently only one manufacturer.”
“Clinical outcomes of the GEMDOCE combination were promising, approaching 50 percent recurrence-free survival at two years when used with monthly maintenance.”
A better approach? Kates and colleagues have begun investigating a combination of two chemotherapy drugs, gemcitabine and docetaxel (GEMDOCE), delivered directly in the bladder – in the same way that BCG is instilled – for newly diagnosed bladder cancer patients. In previously published work at the Brady, as part of a multi-institutional study, Kates and Trinity Bivalacqua, M.D., Ph.D., evaluated patients who were given GEMDOCE when bladder tumors recurred after BCG. “Clinical outcomes of the GEMDOCE combination were promising,” says Kates, “approaching 50 percent recurrence-free survival at two years when used with monthly maintenance.” Based on these promising results, Kates has opened a Phase 2 clinical trial to evaluate this combination for newly diagnosed patients who have not had previous BCG. “We will also be looking for a biomarker that can predict response to GEMDOCE, which would help us guide newly diagnosed patients either to intravesical chemotherapy or BCG immunotherapy, based on their tumor biology.” More information on this clinical trial can be found here.
Molecular characterization of CIS: Hahn recently presented insights on the key drivers of tumor and immune cell biology in patients with a specific type of non-muscle invasive bladder cancer, called carcinoma in-situ (CIS), at the International Bladder Cancer Network’s Annual Meeting. Significant work by a Brady-led team of investigators on urothelial CIS and adaptive immune resistance to intravesical BCG in non-muscle invasive bladder cancer was published recently in Applied Immunohistochemistry Molecular Morphology. The team included Kara Lombardo, Max Kates, Woonyoung Choi, Trinity Bivalacqua, Andres Matoso, and others.
“The scant size of these tumors has presented challenges to unraveling tumor and immune cell biology unique to CIS patients,” Hahn says. But with the help of sophisticated technology, he and colleagues have made unprecedented inroads in understanding gene expression in these patients. In a study with HTG Molecular Diagnostics, using that company’s 1,392-gene Precision Immuno-Oncology RNA-based platform, the team was able to perform comprehensive profiling of gene expression in tissue from 43 out of 50 CIS patients.
Even more exciting: “We identified unique immune gene expression signatures found only in patients with CIS,” says Hahn. Next, the team plans to investigate whether these new CIS signatures are associated with response to BCG and other forms of bladder cancer immune therapy.