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Immunotherapy for Bladder Cancer

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  • Bladder Cancer
  • Treatment Options
  • CRI's Impact
  • Clinical Trials

What Makes Immunotherapy a Promising Treatment for Bladder Cancer?

Reviewed By: Padmanee Sharma, M.D., Ph.D.
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The University of Texas MD Anderson Cancer Center, Houston, TX
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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 2017, there were an estimated 80,000 new cases diagnosed and approximately 17,000 deaths in the U.S. alone. 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.

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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. Recurrent bladder cancer is treated with combination chemotherapy regimens, including gemcitabine plus cisplatin (GC) or methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC).

There are currently six approved immunotherapy options for bladder cancer.

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 advanced bladder cancer and as a first-line treatment for patients who are ineligible for cisplatin chemotherapy
  • Avelumab (Bavencio®): targets the PD-1/PD-L1 pathway; approved for advanced bladder cancer
  • Durvalumab (ImfinziTM): targets the PD-1/PD-L1 pathway; approved for advanced bladder cancer
  • Nivolumab (Opdivo®): targets the PD-1/PD-L1 pathway; approved for advanced bladder cancer
  • Pembrolizumab (Keytruda®): targets the PD-1/PD-L1 pathway; approved for 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.

Find a bladder cancer clinical trial

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, M.D., Ph.D., and Sacha Gnjatic, Ph.D., 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, Ph.D., 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.

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Bladder Cancer Statistics

6th Most common cancer in the United States
75% More likely to affect men than women
77% Overall 5-year survival rate
1990 When bladder cancer immunotherapy was approved by FDA

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Bladder Cancer Clinical Trial Targets

Discover the different proteins, pathways, and platforms that scientists and physicians are pursuing to develop new cancer treatments. Use this information to consider your clinical trial options.

Therapies
  • Targeted Antibodies
  • Cancer Vaccines
  • Adoptive Cell Therapy
  • Immunomodulators
  • Oncolytic Virus Therapy

Targeted antibodies are proteins produced by the immune system that can be customized to target specific markers on cancer cells in order to disrupt cancerous activity, especially unrestrained growth. Antibody-drug conjugates (ADCs) are equipped with anti-cancer drugs that they can deliver to tumors. Bi-specific T cell-engaging antibodies (BiTEs) bind both cancer cells and T cells in order to help the immune system respond more quickly and effectively. Antibody targets under evaluation in bladder cancer clinical trials include:

  • EpCAM: a pathway that controls cell growth and adhesion
  • FGF/FGF-R: a pathway that controls cell growth, death, and migration
  • Nectin-4: a pathway that controls cell growth and adhesion
  • VEGF/VEGF-R: a pathway that can promote blood vessel formation in tumors

Cancer vaccines are designed to elicit an immune response against tumor-specific or tumor-associated antigens, encouraging the immune system to attack cancer cells bearing these antigens. Cancer vaccines can be made from a variety of components, including cells, proteins, DNA, viruses, bacteria, and small molecules. Cancer vaccine targets under evaluation in bladder cancer clinical trials include:

  • Personalized neoantigens: these abnormal markers arise from mutations and are expressed exclusively by tumor cells
  • Tumor-associated antigens: antigens often expressed at abnormally high levels on tumor cells and can be used to target them; also found on normal cells at lower levels

Adoptive cell therapy takes a patient’s own immune cells, expands or otherwise modifies them, and then reintroduces them to the patient, where they can seek out and eliminate cancer cells. In CAR T cell therapy, T cells are modified and equipped with chimeric antigen receptors (CARs) that enable superior anti-cancer activity. Natural killer cells (NKs) and tumor infiltrating lymphocytes (TILs) can also be enhanced and reinfused in patients. Cell-based immunotherapy targets under evaluation in bladder cancer clinical trials include:

  • MAGE antigens: the genes that produce these proteins are normally turned off in adult cells, but cancer cells can reactivate their expression, flagging them as abnormal to the immune system

Immunomodulators manipulate the “brakes” and “gas pedals” of the immune system. Checkpoint inhibitors target molecules on immune cells to unleash new or enhance existing immune responses against cancer. Cytokines regulate immune cell maturation, growth, and responsiveness. Adjuvants can stimulate pathways to provide longer protection or produce more antibodies. Immunomodulator targets under evaluation in bladder cancer clinical trials include:

  • CD137 (also known as 4-1BB): activating this co-stimulatory pathway can help promote the growth, survival, and activity of cancer-fighting T cells
  • CTLA-4: blocking this pathway can help promote expansion and diversification of cancer-fighting T cells
  • IL-2/IL-2R: activating this cytokine pathway can help promote the growth and expansion of cancer-fighting T cells
  • IDO: blocking this enzyme’s activity can help prevent cancer-fighting T cells from being suppressed
  • OX40: activating this co-stimulatory pathway can help promote T cell survival after activation
  • PD-1/PD-L1: blocking this pathway can help prevent cancer-fighting T cells from becoming “exhausted”, and can restore the activity of already-exhausted T cells
  • Toll-like receptors (TLRs): activation of these innate immune receptors can help stimulate vaccine-like responses against tumors

Oncolytic virus therapy uses modified viruses that can infect tumor cells and cause them to self-destruct. This can attract the attention of immune cells to eliminate the main tumor and potentially other tumors throughout the body. Viral platforms under evaluation in bladder cancer clinical trials include

  • Adenovirus: a family of common viruses that can cause a wide range of typically mild effects including sore throat, fatigue, and cold-like symptoms
  • Coxsackievirus: a virus that belongs to the same group as the polio virus; commonly infects young children and causes flu-like symptoms
  • Herpes simplex virus: a virus that can cause the formation of sores on the mouth and genitals
  • Vaccinia virus: the virus that was used to help vaccinate against and eliminate smallpox; rarely causes illness in humans and is associated with a rash covering the body
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Sources: ACS Facts and Figures 2017, National Cancer Institute Physician Data Query, National Cancer Institute Biological Therapies fact sheet, SEER Cancer Statistics Factsheets: Bladder Cancer, ClinicalTrials.gov, CRI documents

Updated August 2018

*Immunotherapy results may vary from patient to patient. Consult a health care professional about your treatment options.

*Immunotherapy results may vary from patient to patient.

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