Elizabeth Plimack: Leading the Way in Bladder Cancer Clinical Trials
Immunotherapy has been the most exciting development in bladder cancer treatment in recent years. Its introduction ended a 40-year drought during which no new therapies were available. Unfortunately, many bladder cancers can be resistant to immunotherapy.
Enter Stand Up To Cancer (SU2C), a forward-thinking organization whose sole mission is to raise funds to speed the pace of research and get new therapies to patients quickly. SU2C grants make it possible for top researchers at different cancer institutions to form collaborative clinical trials.
SU2C recently awarded a $2.9 million SU2C Catalyst Research Grant to Peter Jones, Ph.D., D.Sc., Chief Scientific Officer of Van Andel Research Institute, and Elizabeth Plimack, MD, MS, Fox Chase Cancer Center’s Chief of Division of Genitourinary Medical Oncology, to investigate whether guadecitabine (Astex Pharmaceuticals) can reverse the resistance of some bladder cancers to any prior immunotherapy checkpoint inhibitors (Tecentriq®; Genentech). The SU2C Catalyst grant supports a clinical trial which originated as part of the Van Andel Research Institute–Stand Up To Cancer Epigenetics Dream Team, a multi-institutional effort between leading cancer scientists, physicians and organizations to move promising therapies into clinical trials. The SU2C Catalyst program uses funding and materials from the pharmaceutical, biotechnology, diagnostic, and medical devices industries to rapidly explore new uses of potential compounds for cancer prevention, detection, and treatment.
The study is one of many trials designed by the bladder cancer team at Fox Chase. We spoke with Plimack about this clinical trial and its importance in advancing treatment for patients with bladder cancer.
How did you come to be awarded the SU2C Catalyst Research Grant to evaluate the potential of the epigenetic drug guadecitabine to reverse the resistance of some bladder cancers to checkpoint inhibitors?
When I was a fellow at MD Anderson, my research involved combining epigenetic therapy and immunotherapy. At the time, the best immunotherapy we had was interferon. I conducted research under the mentorship of Jean-Pierre Issa, MD. Dr. Issa had gone onto join Temple University, which facilitated our collaboration. We were both part of the VARI–SU2C Epigenetics Dream Team, which was a collaboration of top researchers at different institutions who had joined together to develop better approaches to cancer. Peter Jones and Stephen Baylin, MD, of Johns Hopkins University, were co-leaders of our team. Together with key faculty at USC, MSKCC, John’s Hopkins, and other centers around the world, the Dream Team oversaw a portfolio of ongoing clinical trials funded in part by Van Andel Research Institute. The SU2C Catalyst provided a unique opportunity, through which Genentech offered its checkpoint inhibitor Tecentriq®, specifically to be studied in combination with other treatments.
“We’re truly doing research with the top people in the field.” – Dr. Plimack
Immunotherapy with checkpoint inhibitors has been called “practice changing” for patients with advanced urothelial carcinoma. Why is that?
No new drug had been approved for advanced bladder cancer in the U.S. since 1978. During this time, we used older, established therapies, often with limited success. Bladder cancer was the first disease that the checkpoint inhibitor atezolizumab was approved for. These agents are now approved for multiple indications because they shrink tumors and help people live longer. Unfortunately, they don’t benefit everyone. That’s where our trial comes in.
How does immunotherapy work?
Cancers can make themselves invisible to the immune system, but checkpoint inhibitors interfere with that, removing the invisibility cloak. Unfortunately, checkpoint inhibitors work in only 20 percent of people with bladder cancer. These people do extremely well and live longer, healthier lives. It is the remaining 80 percent of people we want to help with this study. The study will enroll people for whom checkpoint inhibitors haven’t worked to see if we can reinvigorate the immune system’s ability to attack the cancer by adding guadecitabine.
Why is guadecitabine being evaluated to reverse resistance to the immunotherapy drug atezolizumab?
Patients whose tumors grow despite immunotherapy probably have parts of their DNA silenced. This means some antigens cannot be expressed to start the tumor rejection process. We sometimes call this phenomenon “immune escape” or refer to these tumors as “rogue tumors.” Guadecitabine can remove this silencing, so the DNA wakes up the antigens and allows checkpoint inhibitor immunotherapy to work better. Immunotherapy is a breakthrough in bladder cancer, and we want it to work for all of our patients, even those who didn’t do well on it initially.
Which patients may be best suited for this clinical trial?
Patients who want to be part of this trial at Fox Chase would need to have received unsuccessful therapy with a checkpoint inhibitor for advanced urothelial carcinoma previously, meaning that their tumor grew despite treatment. The immunotherapy should also not have caused any serious side effects. Patients who participate in a clinical trial have to be willing to invest the necessary time involved for frequent visits. Right now, the trial is only open at Fox Chase, but we expect it to open at Johns Hopkins and the University of Southern California over the next few months.
How would you explain this trial to prospective patients or family members?
We discuss the specifics of each person’s case to see whether the trial may be right for them. We explain that we have studied these drugs and believe they will work together, but we go through the pros and cons, as well as other treatment options. It is a personal decision. Many patients ask me what I would do, or what I might do for my patients. I believe in clinical trials and have seen patients live longer and live better lives because of trial therapy. We only open trials that we believe are good options for patients.
You are both a physician and a researcher. What motivated you to want to both care for patients and do cutting-edge research?
I would not be able to do as good a job taking care of my patients if I were not also involved in the science and clinical trials. Similarly, I cannot do the science as well without understanding the needs of my patients. As an example, we observed in our patients that some tumors continue to grow right through treatment, while for others we see the tumors shrink only to find rogue “escape” tumors develop and grow. This was of great interest to SU2C, as well as to all of us who take care of patients. We bring clinical observations back to the science. That interplay is what makes clinical research so important.
“Until we are curing every one of the patients in our clinics there is more work to do.” -Dr. Plimack
What do you most enjoy about working with other experts from leading research institutions?
Having a shared mission and sharing ideas across different cancers is invigorating. Being at the annual SU2C Scientific Summit in January was incredibly energizing. We approach problems from all different angles – all with the same goal of one day curing cancer. It is a privilege to engage with equally driven colleagues to find better treatments.
atezolizumab (a te zoe LIZ ue mab) A common type of immunotherapy, this checkpoint inhibitor stops cancer cells from hiding from the immune system
epigenetic changes Chemical alterations at specific places in the DNA; cancer cells can use these changes to hide from the immune system
guadecitabine (gua də sit ə bEEn) This is a drug that can stop epigenetic changes from happening
immunotherapy Treatment that uses the body’s immune system to recognize and kill cancer cells
MHC antigens Cell surface proteins that allow the immune system to recognize foreign molecules
SU2C Stand Up To Cancer’s mission is to raise money and awareness to speed the pace of research, getting new therapies to patients and saving lives now
urothelial carcinoma Cancer of the bladder and ureter