Immunotherapy:
For Bladder Cancer

What Makes Immunotherapy for Bladder Cancer a Promising Treatment?

Reviewed by:

Sangeeta Goswami, MD, PhD
The University of Texas MD Anderson Cancer Center

Immunotherapy for bladder cancer has a long history, including the first FDA-approved immunotherapy treatment (BCG) in 1990.

Bladder cancer is the sixth most common cancer in the United States and ninth most common worldwide. Most bladder cancers begin in transitional epithelial cells that make up the inner lining of the bladder. As these tumors grow, they can invade the surrounding connective tissue and muscle. In advanced disease, tumors spread beyond the bladder to nearby lymph nodes or pelvic organs or metastasize to more distant organs, such as the lungs, liver, or bone.

Cancers of the bladder make up about 5% of new U.S. cancer cases each year, mostly in older people. In 2023, there will be an estimated 82,000 new cases diagnosed and approximately 17,000 deaths in the U.S. alone. In 2017, roughly 550,000 new cases and 200,000 deaths due to bladder cancer globally. Men are more likely than women to be affected by bladder cancer—about 75% of new cases and deaths are in men—but the reasons for this gender difference are not clear. Because their disease is likely to recur, or come back, patients with bladder cancer must undergo surveillance for an extended period.

When considered by stage, the 5-year relative survival rates for patients with tumors restricted to the inner layer of the bladder or those with disease localized to the bladder are 96% and 70%, respectively. The rates drop to 34% for those with disease that has spread locally beyond the bladder and to 5% for patients with distant metastases.

Although most newly-diagnosed bladder cancers have not invaded the muscle layer, patients with high-grade (abnormal) tumors have a significant risk of dying from their cancers. Tumor recurrence is also a major concern even for patients with low-grade disease and requires extensive follow-up. Better treatments, such as novel immunotherapies, might reduce recurrence rates and improve the survival of patients with bladder cancer.

Bladder Cancer Treatment Options

Most cases of bladder cancer are caught relatively early, and are treatable with immunotherapy. Traditional treatments for bladder cancer include surgery and chemotherapy.

For patients with bladder cancer that has not invaded muscle tissue, treatment consists of surgical removal of the tumor followed by one dose of chemotherapy, usually mitomycin C, within the bladder (so called intravesical chemotherapy). After recovering from surgery, patients with a lower risk of disease progression may undergo surveillance or additional intravesical chemotherapy. Patients with moderate- to high-grade disease often receive intravesical immunotherapy with a weakened, live bacterium, bacillus Calmette-Guérin (BCG). BCG was the first FDA-approved immunotherapy and helps reduce the risk of bladder cancer recurrence by stimulating an immune response that targets the bacteria as well as any nearby bladder cancer cells. Approximately 70% of bladder cancer patients go into remission after BCG therapy.

Standard treatment for patients with bladder cancer that has invaded muscle tissue includes cisplatin-based chemotherapy followed by surgical removal of the bladder or radiation therapy and concomitant chemotherapy. A section of patients with high risk features can receive immunotherapy after surgery to prevent recurrence. Recurrent bladder cancer is treated with combination chemotherapy regimens, including gemcitabine plus cisplatin (GC) or methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC), immunotherapy and targeted therapy.

Immunotherapy is class of treatments that take advantage of a person’s own immune system to help kill cancer cells. 

Targeted Antibodies

• Enfortumab vedotin (Padcev®): an antibody-drug conjugate that targets the Nectin-4 pathway and delivers toxic drugs to tumors; approved for subsets of patients with advanced bladder cancer
• Sacituzumab govitecan (Trodelvy®): an antibody-drug conjugate that targets the TROP-2 pathway; approved for subsets of patients with advanced bladder

Cancer Vaccines

• Bacillus Calmette-Guérin (BCG): uses weakened bacteria to stimulate the immune system; approved for early-stage bladder cancer

Immunomodulators

• Atezolizumab (Tecentriq®): targets the PD-1/PD-L1 pathway; approved for subsets of patients with advanced urothelial carcinoma
• Avelumab (Bavencio®): targets the PD-1/PD-L1 pathway; approved for subsets of patients with advanced bladder cancer, including as first-line maintenance therapy after chemotherapy”
• Dostarlimab (Jemperli): a checkpoint inhibitor that targets the PD-1/PD-L1 pathway; approved for subsets of patients with advanced bladder cancer that has DNA mismatch repair deficiency (dMMR)
• Nivolumab (Opdivo®): targets the PD-1/PD-L1 pathway; approved for subsets of patients with advanced bladder cancer
• Pembrolizumab (Keytruda®): targets the PD-1/PD-L1 pathway; approved for subsets of patients with advanced bladder cancer

Immunotherapy has significantly reduced the risk of recurrence for bladder cancer while also increasing the percentage of patients who see a complete response post-surgery. Investigational bladder cancer immunotherapies—those that “train” the body’s immune system to recognize bladder cancer cells—have the potential to further improve outcomes for patients with this disease.

CRI’s Impact in Bladder Cancer

Thanks to groundbreaking advancements in immunology research and clinical trials, immunotherapy has become one of the most promising bladder cancer treatments of our time.

Lloyd J. Old, in partnership with Baruj Benacerraf and Donald Clarke, demonstrated in 1959 that BCG, the tuberculosis vaccine, could inhibit tumor growth in mice. In subsequent years, CRI funded Alvaro Morales of Queens University in Canada, who, in 1980, demonstrated that BCG is effective in the prevention of recurrence of non-muscle invasive bladder cancer in human patients. The FDA approved the use of BCG for superficial bladder cancer in 1990.

“In the early 70s my rejection by the National Cancer Institute of Canada to test BCG on superficial bladder tumors included the reviewer comment ‘BCG is not only ineffective and dangerous but a throwback from the stone age of tumor immunology.’ If I hadn’t subsequently applied to and been approved for a grant from CRI, BCG might never have become the standard therapy for the treatment and prevention of early stage bladder cancer.”

Alvaro Morales

Other CRI-funded research into bladder cancer includes:

• Through her Clinical Team Grant, Nina Bhardwaj, MD, PhD, and Sacha Gnjatic, PhD, are investigating the relationship between checkpoint immunotherapy, chemotherapy, and mutations in advanced bladder cancer, to guide vaccine development and inform combination treatment approaches.
• Monica M. Olcina, PhD, a postdoctoral fellow at Stanford University School of Medicine, is exploring how we might address radiation therapy toxicities without compromising the treatment itself.

New and developing bladder cancer immunotherapies have the potential to reduce recurrence rates and improve survival rates for patients with bladder cancer. You can explore CRI’s current research into bladder cancer in our funding directory.