Dr. Saul Priceman is an assistant research professor in the T-Cell Immunotherapy Program at City of Hope in Duarte, California. His expertise is in T-cell biology and cancer immunotherapy. He’s currently developing chimeric antigen receptor (CAR)-based T-cell immunotherapy primarily for breast, prostate, and pancreatic cancers.
Prostatepedia spoke to him about CAR T-cell therapy for prostate cancer.
Over the last few decades a paradigm-shifting idea has emerged: from before you’re even born until the day you die, you probably get hundreds of cancers. It’s just that your immune system blocks that cancer from growing so that you don’t ever become symptomatic. The cancer you deal with is the one cancer that gets around your immune system and grows. That idea was intriguing to me. Your immune system plays an essential role in your body’s ability to fight everything. It’s the reason why we can live 100 years without succumbing to a plethora of different things that can attack your body, including cancer.
Would you call cancer in general a failing of the immune system?
Dr. Priceman: Not really. Cancer is really many different things that occur in sequence, or simultaneously, that are likely the root cause. I wouldn’t claim that cancer is one thing. But I certainly think cancer is an immune disorder. In a lot of cancers, including prostate cancer, viruses can play an important role in the initiation of that cancer. Cervical cancer, for example, is nearly 100% virus-mediated. So whether your cancer is virus-mediated or not, the immune system plays an essential role in the initiation and progression of that cancer.
I was interested in that idea, but it seemed as if almost nobody else was really interested in this when I got to UCLA.
I went to a virus gene therapy lab and asked the principal investigator of that lab if I could study the immune system and cancer. She said, “I don’t know anything about that, Saul, but I’ll support whatever you do.” For the next four and a half years, I did just that. Together, we made an impact.
I then went to City of Hope National Medical Center, which was pioneering tumor immunology and immunotherapies. I ended up studying how the immune system affected autoimmune disease, obesity, insulin resistance, and cancer in my postdoctoral work. I did well in that area.
And then I realized T-cells are “it.” If you are going to fight an infection properly, or fight cancer properly, you have to engage the T-cells. T-cells are a specific type of immune cell, that are often called the soldiers of our immune system—the fighters that rid us of infections or cancer. I moved into another group at City of Hope to develop chimeric antigen receptor (CAR) T-cell therapy for cancer. The T-cell receptor is a protein on the T-cell that engages another immune cell, a virally infected cell, or a cancer cell to ask: “Who are you? What are you doing here?” If that other cell is not doing the right thing, the T-cell kills it. That process is messed up in cancer. That group was engineering those T-cells to recognize cancer cells as a threat. I got very interested, and that is what I do now. I develop, with a large group of researchers, CAR T-cell therapy for multiple cancers, including prostate.
Where are we in the development of CAR T-cell therapy for prostate cancer?
Dr. Priceman: CAR T-cells are FDA approved for two diseases, which just happened in the latter part of this year. We have CD19-directed CAR T-cells for a B-cell malignancy, whether that is lymphoma or leukemia. These reengineered T-cells go after cells that express the protein CD19, which is expressed on the vast majority of B-cell leukemias or lymphomas. This therapy is now putting patients that are refractory to multiple lines of other therapies in complete remissions, an almost unheard of feat, and changing the landscape of treatment options for these patients.
At City of Hope, we also have clinical experience treating gliomas or glioblastomas that are aggressive brain cancers with similar CAR T-cells. We locally deliver CAR T-cells to the brain for those patients. We’re first in the world injecting CAR T-cells intraventricularly, which is a specific route of delivery that will bathe the central nervous system with those CAR T-cells, so we can attack multifocal brain disease instead of just one site—but still regionally localized in the brain.
Four years ago, with Prostate Cancer Foundation funding, we started to ask, “Couldn’t we get these same responses in prostate cancer?” They gave us a million dollars and two years to make that a reality. We actually just published a paper in OncoImmunology this month on the development of a prostate cancer-specific CAR T-cell. We are going through the regulatory process now and will hopefully start our clinical trial by mid 2018.
How exactly does the approach differ in prostate cancer?
Dr. Priceman: The target protein is very different. It’s overexpressed in prostate cancer in the majority of patients. One of the benefits of targeting our CAR T-cells to this protein is that it is also expressed in pancreatic, bladder, and other solid cancers. We’re trying it first in prostate cancer, but we also think that we can make an impact in these other diseases eventually. The target is called prostate stem cell antigen, but that is a little misleading because it is expressed in some non-prostate cancers.