Dr. Naomi Haas is the leader of the kidney and prostate cancer programs at the University of Pennsylvania Health System in Philadelphia.
Prostatepedia spoke with her about her Phase I chimeric antigen receptor (CAR) T-cell therapy for prostate cancer clinical trial.
Dr. Naomi Haas: Patients are interested in approaches that could potentially allow them to live for very extended periods of time without a lot of side effects. The prostate cancer field has evolved very quickly. We have a lot of new agents that we didn’t have even three or four years ago.
One of the things that has come out of the University of Pennsylvania is that Dr. Carl June is doing a lot of CAR T trials in different solid tumors—including prostate cancer.
This particular immunotherapy trial we’re discussing collects patients’ T-cells and exposes them to a virus that has a target in it. We then give these cells back to the patients to train their bodies to attack the cancer.
It’s a very attractive approach. We started developing this clinical trial over five years ago. At the time, a lot of the therapies didn’t include some of these small molecule pill-type therapies that patients could take. We were interested in developing nontoxic approaches for patients that would hopefully incorporate into their immune system and would work for a really long time.
Dr. Haas: Patients first have testing to see if their cancer expresses the same kind of targets that we’re making in the CAR T trial. They have to have a biopsy of their tumor, which shows that their prostate cancer expresses a protein called prostate-specific membrane antigen. PSMA is similar to PSA, but this protein is secreted on the outside of the prostate cancer cells. It’s on the membrane, so it’s much more accessible to treatment. It might bring down cells that a PSA target might not otherwise do.
So, patients first undergo testing of their tumor. If they have at least 10% expression of PSMA, then they’re a candidate for the trial.
They then undergo a process called apheresis: an IV is put in their arm and their blood comes out into a machine. This machine removes some of the T-cells—the immune cells—from their bloodstream, but their blood is at the same time returned to the body. They’re not really losing a lot of blood. We’re just pulling some of the T-cells, the T-lymphocytes, out of their bodies.
Then we infect those T-cells with an inactivated HIV virus. This is the same virus that causes HIV, but we remove the bad stuff so that it can’t cause HIV in patients. We put two targets within this inactivated virus: PSMA and TGF-beta.
TGF-beta is an immune marker present in a lot of the lymphocytes. In prostate cancer, the lymphocytes hang out near the prostate cancer cells, so we felt that if we targeted both we would have a better chance of hitting the tumor with our target and not hitting other parts of the body that we didn’t want to harm.
Once these cells are infected with this CAR T, they are grown in culture. We make volumes of these T-lymphocytes with this antivirus with PSMA and TGF-beta in it.
The process takes about three weeks. Then we give it back to the patients through an intravenous line over about half an hour. It’s just a one-time treatment.
We then follow people very closely over a number of days, weeks, and months. We make important measurements, such as how much the T-cells expanded in the blood. We also do another tumor biopsy to see if the CAR T has reached the tumor.
We follow scans, blood tests, etc. to make sure that: 1) the patients aren’t having side effects; and 2) to see whether or not we can prove that the CAR T has incorporated into their bodies and that it’s doing its job.
We’re in the very early stages of this clinical trial. We’re looking first at a low dose of CAR T and are planning look at higher doses and then multi-doses because we think patients might need more than one dose to offer an effective therapy. We’re also looking at CAR T in combination with immune adjuvants. Sometimes we give a little dose of Cytoxan (cyclophosphamide) or a little dose of fludarabine with CAR T to make the body have an even bigger immune response.