Immunotherapies for Advanced Bladder Cancers

Cancer MicroscopeImmunotherapy is a very encouraging approach for treating bladder cancers and other tumors arising from the renal pelvis and ureters. There are a number of different types of bladder cancer immunotherapies currently available:

1. Atezolizumab (brand name Tecentriq) is an FDA-approved immunotherapy for urothelial carcinoma, the most common form of bladder cancer. Atezolizumab is an immune checkpoint blockade or “checkpoint inhibitor.” It selectively binds to cancer cells based on the presence of PD-L1, a protein on the tumor surface.

PD-L1 is more strongly expressed on certain types of tumors, including urothelial cancers arising from the bladder, renal pelvis, and ureters. PD-L1 prevents the body’s immune system from being able to recognize the cancer and attack it. It had been more than two decades since the FDA approved a new bladder cancer treatment.

Atezolizumab is only approved for urothelial carcinoma that has grown or recurred after previous chemotherapy, and we offer this treatment at Weill Cornell Medicine. We are also currently testing another PD-L1 checkpoint inhibitor alone or in combination with another immune checkpoint antibody versus standard chemotherapy through an open phase III clinical trial.

2. Ramucirumab is a monoclonal antibody that binds to the Vascular Endothelial Growth Factor (VEGF) receptor-2. This is a receptor found predominantly on blood vessels. Angiogenesis is a process where vessels grow to feed tumors and blocking this pathway can be helpful at stopping the growth of these vessels, particularly in combination with chemotherapy. We previously completed a randomized phase III trial which demonstrated that patients who got docetaxel (Taxotere) chemotherapy plus ramicurimab had more than twice the tumor shrinkage and double the time until tumor growth compared to docetaxel chemo alone; This study was recently published in the Journal of Clinical Oncology. Based upon our results, we recently opened a phase III trial using this drug in combination with chemotherapy. People who have already received chemotherapy, and those who have received chemo followed by atezolizumab or other checkpoint inhibitors are eligible for this clinical trial.

3. IMMU-132 (also known as Sacituzumab Govitecan) is an antibody drug conjugate that leverages the capability of monoclonal antibodies to attach to specific targets on cancer cells. By attaching a drug to the monoclonal antibodies, treatments are able to “hitch a ride” into the cancer cells.

This treatment is a potential good treatment fit for adults with metastatic bladder cancers who have not responded to chemotherapy or who have relapsed after chemotherapy or PL-1/PD-L1 checkpoint inhibitor immune treatment.

Initial positive results in the phase I trial led to a phase II clinical trial that is currently open to enrollment. Learn more about how this drug works in the body and get more information about our open IMMU-132 clinical trial by checking out our recent blog post, “Doing Better on Behalf of Bladder Cancer Patients.”

4. REGN2810 is a monoclonal antibody – a type of protein that works by blocking the programmed death receptor 1 (PD-1), a cell receptor on immune cells that is involved in preventing the immune cells from destroying other cells. Through our open clinical trial, patients with bladder and other urothelial cancers who have received prior treatment with checkpoint inhibitors (such as atezolizumab) can get the combination of the REGN2810 drug with immune boosters.

FDA Approves New Immunotherapy for Bladder Cancer

Cancer LabFor the first time in more than 20 years, today the FDA granted approval to a new treatment for urothelial carcinoma, the most common form of bladder cancer.

Tecentriq, also known as atezolizumab, is an immune checkpoint blockade or inhibitor that selectively binds to cancer cells based on the presence of PD-L1, a protein on the tumor surface. This is the first PD-L1 inhibitor that has been approved by the FDA for any disease.

PD-L1 is more strongly expressed on certain types of tumors, including urothelial cancers arising from the bladder, renal pelvis, and ureters. PD-L1 prevents the body’s immune system from being able to recognize the cancer and attack it, but PD-L1 inhibitors help the body to “see” the cancer and use the immune system to fight it.

This treatment has shown promise for platinum-resistant metastatic urothelial carcinoma – an advanced cancer that does not respond to traditional chemotherapies and which so far has very few other effective therapies.

In the study that ultimately led to atezolizumab’s approval by the FDA, it was shown to be effective at helping unleash the power of the immune system to recognize and attack these tumor cells.

The patients who responded positively to this treatment can do well on it for a long time. This is sometimes referred to as having a “durable response.” Few side effects were seen with this drug and they were mild. Severe side effects were rare and tied to too much immune activity. These study results first led to the FDA granting atezolizumab priority review designation in March 2016 to put it on the fast track for full FDA approval.

Additionally, in this study the investigators identified a correlation between mutational load and response to the drug. This means that when there was a higher concentration of proteins that could be recognized by the body, there was more sensitivity to this immunotherapy.

At Weill Cornell Medicine, we have been involved in the development of several types of immunotherapy and are at the forefront of developing ways to better determine which patients are most likely to respond to treatment. We are conducting research on how mutations and the “mutational load” can lead to the formation of neoantigens and the impact these neoantigens have on immunotherapy response in order to identify the patients most likely to benefit from this therapy.

We’re very excited to be able to offer Tecentriq/atezolizumab to our patients and encourage you to inquire about whether it’s a good fit for you. Additionally, we continue our research with immunotherapy and monoclonal antibodies for patients with urothelial cancer. One open clinical trial is testing whether a single checkpoint inhibitor (targeted at PD-L1) or dual checkpoint inhibitor (targeted at both PD-L1 and CTLA4 – a protein on the T-cell) is more effective against tumors compared with chemotherapy.

Marking their Territory: Using Cell Markers to Find Cancer and Stop its Spread

Cancer Cell Markers and AntibodyA key way to detect cancer cells in the body is to find “markers” on the cancer cells that don’t exist in healthy cells. For prostate cancer, we use a marker called the prostate specific membrane antigen (PSMA). PSMA is a protein on the cell surface of most prostate cancer cells, but it is not usually present elsewhere in the body. As a result, we’re able to use PSMA in order to track the presence of prostate cancer tumor growth and metastasis. At AACR 2016, the Weill Cornell Medicine (WCM) and Meyer Cancer Center investigators presented the results of two new studies that further hone in on the role PSMA plays in prostate cancer.

While we’ve known about the presence of PSMA for many years, we have recently discovered more about its biology and the tight relationship it has with the key driver of most prostate tumors, the androgen receptor (AR) pathway. As the AR pathway becomes more abnormal (is more dysregulated), the amount or expression of PSMA increases. This means that more aggressive tumors will have more PSMA on the cells.

How do we measure or quantify the amount of PSMA?

At the Weill Cornell Genitourinary (GU) Oncology Program, one way we do this is by using non-invasive methods to locate active tumors in prostate cancer patients. By tagging an antibody or small molecule with a particle that gives off energy, we can “see” the PSMA using imaging techniques. In this case, we can give people an injection to bring these tagged molecules into the body and then follow the “energy” the molecules are giving off with a scan that visualizes the tumors. In some cases, this approach helps us locate tumors that might otherwise be hidden.

However, we may also be able to assess the biology of tumors without a biopsy (non-invasively). To do this, we analyzed men who had undergone molecular PSMA imaging. Following infusion of the anti-PSMA monoclonal antibody J591 which was tagged with a particle, men underwent scanning. Based upon a system we previously published, we scored how bright their tumors were with the belief that brighter tumors would be more aggressive. In long-term follow up of the men who underwent imaging between 2000-2015, our hypothesis was confirmed. The men with the brighter tumors had higher rates of mortality, even among those who received the newer, better therapies. This type of non-invasive molecular imaging may assist physicians in determining prognosis, which may in turn guide therapy choices for especially aggressive cancers.

Antibodies as a Treatment Vehicle

In addition to tagging an antibody with an imaging agent, we can label J591 with a radioactive particle capable of killing the cancer cells, termed radioimmunotherapy. For more than a decade, we have delivered different versions of this therapy to patients at WCM. A phase II clinical trial published in 2013 was shown to be very successful at delivering a large, single-dose of radioimmunotherapy to patients, also showing that those patients receiving a larger dose had better response and survival (a “dose-response”). Building on the results of this trial, we hypothesized that by splitting the radiation dose and giving half initially and half two weeks later (this is called “dose fractionation”) that we would be able to ultimately deliver a higher dose of the treatment. At ASCO in 2010, we demonstrated this to be a promising approach to treatment and will be presenting a follow up expanded version of this study in June at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting.

At AACR 2016, Dr. Ana Molina presented results of a pilot study of hyperfrationated (very split doses) 177Lu-J591, which delivers the radioactive particle lutetium-177 (177Lu) to tumors via the anti-PSMA monoclonal antibody J591. In this study, small doses of the radioimmunotherapy were delivered every two weeks until blood counts started to drop, as measured by the level of white blood cells and platelets. This treatment approach allowed all patients in this small study to receive a higher total dose than could be safely delivered with a large single dose. Two patients received five and six total doses of the treatment, reflecting a range 179 – 214% higher than the single large dose. As a result, this new approach to administering this type of immunotherapy with very split dosing may have long-term merit for men with advanced prostate cancers.

Today, men with advanced prostate cancer are able to benefit from a number of new treatment options, including the common oral hormonal drugs, abiraterone and enzalutamide. These hormonal drugs help decrease the burden of the cancer, maintain or improve the quality of life, and allow men to live longer. However, none of these drugs are curative, so we still need to make advancements in the field.

This is why we continue to use what we already know about cancer “markers,” such as PSMA, and to build on this knowledge in order to better diagnose and treat prostate cancers in a way that exploits these markers and keeps the cancer at bay. We are also constantly seeking new ways to better “see” and leverage these markers, and specifically PSMA, to prevent the growth and spread of prostate cancer.

Learn more about some of our current open clinical trials exploring this approach: