Bladder cancer was the first indication for which an immunotherapy was granted approval by the Food and Drug Administration (FDA) in 1990. 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 2016, an estimated 76,960 new cases will be diagnosed and approximately 16,390 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 overall 5-year survival rate for bladder cancer is 77%, 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% 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 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 requires 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), or atezolizumab (Tecentriq), an immunotherapy that targets the PD-L1 molecule.
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.
Immunotherapy for Bladder Cancer
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.
Oncolytic Virus Therapy
Oncolytic virus therapy uses a modified virus that can cause tumor cells to self-destruct and generate a greater immune response against the cancer.
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 III study is testing CG0070 in patients with non-muscle invasive bladder cancer who have failed BCG therapy (NCT02365818).
A phase I trial of enadenotucirev, an oncolytic virus, for patients with metastatic or advanced epithelial cancers, including bladder cancer, in combination with pembrolizumab (Keytruda®) (NCT02636036).
A phase I trial of Cavatak™ in patients with non-muscle invasive bladder cancer (NCT02316171).
Checkpoint Inhibitors/Immune Modulators
A promising avenue of clinical research in bladder cancer is the use of immune checkpoint inhibitors. These treatments work by targeting molecules that serve as checks and balances in the regulation of immune responses. By blocking inhibitory molecules or, alternatively, activating stimulatory molecules, these treatments are designed to unleash or enhance pre-existing anti-cancer immune responses.
Atezolizumab (MPDL3280A): A PD-L1 Antibody
A phase III study of atezolizumab as adjuvant therapy in patients with PD-L1-positive, high-risk muscle invasive bladder cancer after surgery to remove all or part of the bladder (NCT02450331).
A phase II preoperative study of atezolizumab in patients with transitional cell cancer of the bladder (NCT02662309).
A phase I/II study of atezolizumab in patients with advanced cancer, including bladder cancer, in combination with varlilumab (CDX-1127), an anti-CD27 antibody (NCT02543645).
A phase I trial for patients previously treated for metastatic bladder cancer (NCT01375842).
A phase I study of CPI-444, which targets the adenosine-A2A receptor that suppresses the anti-tumor activity of immune cells, +/- atezolizumab for patients with advanced cancer, including bladder cancer (NCT02655822).
Atezolizumab (MPDL3280A) was given “Breakthrough Therapy” designation from the FDA for bladder cancer in June 2014.
CRI Impact: 1996-1999 CRI fellow Bryan A. Irving, Ph.D., joined Genentech in 2001, and led studies that culminated in the generation of MPDL3280A, an anti-PD-L1 antibody, that is showing promise against multiple tumor types.
Durvalumab (MEDI4736): A PD-L1 Antibody +/- Tremelimumab: A CTLA-4 Antibody
A phase III trial of durvalumab +/- tremelimumab for patients with bladder cancer (NCT02516241).
A phase II trial of durvalumab, tremelimumab, or the combination for patients with advanced tumors, including bladder cancer (NCT02527434).
A phase I/II trial of durvalumab, tremelimumab, and Poly-ICLC, a Toll-like receptor 3 agonist, in patients with advanced, measurable cancers, including bladder cancer (NCT02643303).
Nivolumab (Opdivo®): A PD-1 Antibody +/- Ipilimumab (Yervoy®): A CTLA-4 Antibody
A phase II trial of nivolumab +/- ipilimumab in patients with bladder cancer (NCT02553642).
A phase I/II trial of nivolumab +/- ipilimumab for patients with several different types of cancers, including bladder cancer (NCT01928394).
A phase I trial of nivolumab +/- ipilimumab in combination with cabozantinib, a cMet and VEGFR2 inhibitor, in patients with advanced or metastatic bladder cancer (NCT02496208).
Pembrolizumab (Keytruda®, MK-3475): A PD-1 Antibody
A phase II trial for patients with high-risk non-muscle invasive bladder cancer (NCT02625961).
A phase II trial after initial chemotherapy for patients with metastatic bladder cancer (NCT02500121).
A phase II trial for patients with advanced urothelial cancer (NCT02335424).
A phase I/II trial for patients with advanced cancer, including bladder cancer, combined with PLX3397, a tyrosine kinase inhibitor of KIT, CSF1R, and FLT3 (NCT02452424).
A phase I trial for patients with metastatic or advanced epithelial cancers, including bladder cancer, in combination with enadenotucirev, an oncolytic virus (NCT02636036).
A phase I trial for patients with high-risk superficial bladder cancer, combined with BCG (NCT02324582).
A phase I trial plus chemotherapy for patients with recurrent or stage 3-4 bladder cancer (NCT02437370).
A phase I trial for patients with transitional cell cancer of the urothelium, in combination with ramucirumab (Cyramza®), a VEGFR2 inhibitor (NCT02443324).
A phase I study to test MGD009, a B7-H3 x CD3 DART protein, in patients with unresectable or metastatic B7-H3-expressing cancer, including bladder cancer (NCT02628535).
A phase I trial of AMG 228, a GITR antibody, for patients with solid tumors, including bladder cancer (NCT02437916).
Adoptive Cell Therapy
Another avenue of immunotherapy for bladder cancer is adoptive T cell transfer. In this approach, T cells are removed from a patient, genetically modified or treated with chemicals to enhance their activity, and then re-introduced into the patient with the goal of improving the immune system’s anti-cancer response.
A phase I study of T cells engineered to recognize the NY-ESO-1, MAGE-A4, PRAME, survivin, and SSX markers in patients with solid tumors, including bladder cancer (NCT02239861).
Monoclonal antibodies are molecules, generated in the lab, that target specific antigens on tumors.
A phase III trial of ramucirumab (Cyramza®) plus chemotherapy for patients with urothelial cancer (NCT02426125).
A phase II trial of B-701, an anti-FGFR3 antibody, for patients with locally advanced or metastatic bladder cancer (NCT02401542).
A phase I trial of MK-6018, targeting CEA, for patients with select advanced or recurrent cancers, including bladder cancer (NCT02346955).
A phase I trial testing HuMax®, an antibody-drug conjugate targeting tissue factor, in patients with solid tumors, including bladder cancer (NCT02552121).
Cytokines are messenger molecules that help control the growth and activity of immune system cells. Monoclonal antibodies are molecules, generated in the lab, that target specific antigens on tumors.
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. By linking IL-2 to the antibody, ALT-801 can target IL-2 to cancer cells. A phase I/II trial are testing ALT-801 in combination with gemcitabine in patients with non-muscle invasive bladder cancer who have failed BCG therapy (NCT01625260).
Adjuvants are substances that are either used alone or combined with other immunotherapies to boost the immune response. Some adjuvant immunotherapies use ligands—molecules that bind to proteins such as receptors—to help control the immune response. These ligands can be either stimulating (agonists) or blocking (antagonists).
A phase I/II trial of VPM1002BC, a genetically improved version of BCG, in patients with recurrent non-muscle invasive bladder cancer (NCT02371447).
It was Lloyd J. Old, in partnership with Baruj Benacerraf and Donald Clarke, who demonstrated that 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.
CRI Impact: “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 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
Updated March 2016
Sources: ACS Facts and Figures 2016, National Cancer Institute Physician Data Query, National Cancer Institute Biological Therapies fact sheet, SEER Cancer Statistics Factsheets: Bladder Cancer, ClinicalTrials.gov, CRI documents
[i] Morales A. Treatment of carcinoma in situ of the bladder with BCG. Cancer Immunol Immunother 1980; 9: 69-72.
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