Cancer Immunotherapy

Bladder Cancer

Bladder cancer was the first indication for which an immunotherapy was granted approval by the Food and Drug Administration (FDA). Currently, there are a number of additional immune-based bladder cancer treatments in development. This page features information on bladder cancer and immunotherapy clinical trials for bladder cancer patients.

Bladder cancer is the sixth most common cancer in the United States. In 2013 an estimated 72,570 new cases will be diagnosed, representing 4.4% of all new cancers, and approximately 15,210 deaths are expected. 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.

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.


The outcome of a patient with bladder cancer depends on whether the tumor has invaded the muscle layer and on how abnormal the cancer cells appear, which is also called the tumor grade. Patients with non-muscle invasive, low-grade tumors rarely progress to more advanced disease. However, patients with high-grade tumors, even if they are non-muscle invasive at diagnosis, have a significant risk of developing advanced or metastatic disease.

Urgent Need

The overall 5-year survival rate for bladder cancer is 77.9%, and this rate has not changed significantly over the last 10 years, a period during which no new drugs for bladder cancer were approved by the FDA. 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 96.4% and 70.2%, respectively. The rates drop to 33.0% for those with disease that has spread locally beyond the bladder and to 5.4% for patients with distant metastases.

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


For patients with non-muscle invasive bladder cancer, 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 bladder cancer cells. Approximately 70% of bladder cancer patients go into remission after BCG therapy.

Standard treatment for patients with muscle invasive bladder cancer includes cisplatin-based chemotherapy followed by surgical removal of the bladder or radiation therapy and concomitant chemotherapy. Recurrent bladder cancer is treated with combination chemotherapy regimens, including gemcitabine plus cisplatin (GC) or methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC).

When are clinical trials recommended?

According to the National Cancer Institute, there are clinical trials suitable for patients with all stages of bladder cancer, and whenever possible, patients should consider participating in clinical trials designed to improve upon standard therapy.

Ongoing Trials

Immunotherapy with BCG has reduced the risk of bladder cancer recurrence and increased the percentage of patients who experience a complete response after surgery. Investigational immunotherapies that train the immune system to recognize bladder cancer cells may further improve outcomes for bladder cancer patients. Below are descriptions of ongoing immunotherapy clinical trials for patients with bladder cancer.

  • HS-410 is a therapeutic vaccine made from a human bladder cancer cell line that has been irradiated and engineered to express soluble gp96, a chaperone protein that can present multiple tumor antigens to the immune system and act as an adjuvant to enhance the immune response. A phase I/II trial sponsored by Heat Biologics testing HS-410 is currently enrolling patients with high-risk, non-muscle invasive bladder cancer who have completed surgery and intravesical BCG therapy (NCT02010203).
  • A phase I study at Roswell Park Cancer Institute is testing the DEC-205-NY-ESO-1 fusion protein vaccine with or without the biological therapy sirolimus in patients with a variety of solid tumors, including recurrent and metastatic bladder cancer. This vaccine may help build an immune response against tumor cells that express the cancer-testis antigen NY-ESO-1. The addition of sirolimus may enhance this immune response. (NCT01522820)
  • ALT-801, a product of Altor Bioscience Corporation, is a fusion of the cytokine interleukin-2 (IL-2) and an antibody that recognizes peptides on the surface of tumor cells. Treatment with IL-2 can enhance the activity of the immune system against tumors but can also cause many side effects. By linking IL-2 to the antibody, ALT-801 can target IL-2 to cancer cells. Two phase I/II trials are testing ALT-801 in combination with gemcitabine in patients with non-muscle invasive bladder cancer who have failed BCG therapy (NCT01625260) and in combination with gemcitabine and cisplatin in patients with muscle invasive bladder cancer (NCT01326871).
  • Autologous immunotherapies use a patient’s harvested immune cells, expose them to a tumor antigen outside the body, and then inject the activated cells back into the patient where they can attack cancer cells. DN24-02 is an autologous immunotherapy targeted against the cell surface receptor HER2. An ongoing phase II trial sponsored by Dendreon is testing DN24-02 against the standard of care in patients with HER2-expressing high-risk bladder cancer (NCT01353222).
  • TMX-101 is a new formulation of the immune-stimulating drug imiquimod that is optimized for intravesical treatment. A phase II study sponsored by Telormedix SA is testing TMX-101 as a treatment for patients with carcinoma in situ (CIS) of the bladder or with non-muscle invasive bladder cancer and CIS of the bladder (NCT01731652). Oncolytic viruses specifically kill cancer cells. CG0070, a product of Cold Genesys, Inc., is an oncolytic adenovirus that also expresses the immune stimulating cytokine GM-CSF to further enhance the anti-tumor immune response. A phase II/III study is testing intravesical CG0070 in patients with CIS of the bladder or with non-muscle invasive bladder cancer plus CIS of the bladder and who have failed BCG therapy (NCT01438112).
  • INSTILADRIN is an adenovirus that has been modified to prevent it from making copies of itself but can express the immune stimulating cytokine interferon-alpha. Intravesical treatment with INSTILADRIN may enhance the immune response to cancer cells in the bladder and is being tested in a phase II study sponsored by FKD Therapies in patients with non-muscle invasive bladder cancer who did not respond to or relapsed after BCG therapy (NCT01687244).

CRI Contributions

It was Lloyd J. Old, in partnership with Baruj Benacerraf and Donald Clark, who demonstrated that bacillus Calmette-Guérin (BCG), the tuberculosis vaccine, could inhibit tumor growth in mice, in 1959. 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.[i] 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 Bacillus Calmette-Guérin (BCG) on superficial bladder tumors included the reviewer comment ‘BCG is not only ineffective and dangerous but a throw back 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

ACS Facts and Figures 2013, National Cancer Institute Physician Data Query, National Cancer Institute Biological Therapies fact sheet, SEER Cancer Statistics Factsheets: Bladder Cancer,

[i] Morales A. Treatment of carcinoma in situ of the bladder with BCG. Cancer Immunol Immunother 1980; 9: 69-72.


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