Conversations With Prostate Cancer Experts

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Join A CAR T-Cell Therapy Trial For Prostate Cancer

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.

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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.

Can you walk us through the details of the trial?

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.

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CAR T-Cell Therapy For Prostate Cancer

Dr. Susan Slovin is a medical oncologist specializing in prostate cancer immunology at Memorial Sloan Kettering Cancer Center in New York City.

Prostatepedia spoke with her recently about immunotherapy for prostate cancer.

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Dr. Susan Slovin: My career goes back probably 40 years when immunotherapy meant that you tried to devise a variety of different platforms to influence the human immune response so that it recognizes and fights cancer. We didn’t have the same level of sophistication in understanding the inner mechanisms of the immune system we do now, and frankly, in the 1970s, we were just identifying that there were two cells that governed the immune system, B- and T-cells. The world, unfortunately, has become checkpoint-centric much to my dismay. I believe that people think that checkpoint inhibitors are synonymous with immunotherapy. There are other immune treatments that continue to be investigated, but may not be easily exportable into clinical practice due to their uniqueness and complexity in development. This is, in fact, the case with CAR T-cell therapy. CAR T-cells (chimeric antigen receptor T-cells) are another platform whereby we engineer a patient’s immune T-lymphocytes (a white blood cell that is known to fight the cancer cell) to treat their cancer. We’ve been focusing on patients with metastatic prostate cancer to the lymph nodes and/or bone tissue who have failed other therapies but have not had chemotherapy before. They essentially have had multiple hormonal therapies.

We are using the body’s immune system in a different way than checkpoint inhibitors.

The body has two cell types: first, we have B-cells, which produce antibodies. Antibodies are proteins in the blood that fight infection or recognize molecules that don’t belong there. And second, there are T-cells, which are white cells involved in immune surveillance and tumor cell killing. In other words, they scavenge the body looking for molecules that don’t belong. Molecules that don’t belong include foreign cells, bacteria, and viruses. And, remember that cells also go to the bathroom and they leave behind waste products that may be foreign to the immune surveillance cells. These cell products, along with cells that die as a result of radiation or chemotherapy, provide novel antigens or molecules that may never have been seen before by the immune system and may invoke the immune system to respond and protect the body.

The immune system does not react against things that don’t pose threats to it. But the use of CAR cells takes advantage of the fact that T-cells are the largest cell population in the body and that they are the ones involved in effecting an anti-cancer response.

T-cells are part of the CAR therapy approach called adoptive cell transfer. It’s a little different from what’s been done with Provenge (sipuleucel-T), which is, ironically, the first autologous (self-derived) immune cell product used for the treatment of a solid tumor for prostate cancer. What’s ironic about that is that here we are in the world of prostate cancer for which we have an approved immune-based therapy but which appears to be minimally responsive to the more widely and successfully used checkpoint inhibitors.

Unlike Provenge (sipuleucel-T), which stimulates the patient’s dendritic (antigen-presenting) cells, adoptive cell transfer uses only a particular population of the patient’s immune cells to treat their cancer, mainly their T-cells.

CARs are approved in two indications: acute lymphocytic leukemia and lymphoma, but as yet have not been demonstrated to have antitumor efficacy in solid tumors. They are formed by engineering T-cell receptors, which graft a molecule with particular specificity onto an immune effector cell (T-cell). Typically, these receptors are used to graft the specificity of a monoclonal antibody onto a T-cell (for example prostate-specific membrane antigen [PSMA]) with transfer of their coding sequence facilitated by retroviral vectors. The receptors are called chimeric because they are composed of parts from different sources. The upshot is to be able to develop an “armored CAR,” that allows the T-cell to seek out cells that express that same molecule and therefore will ultimately engage the cancer cell that expresses the molecule and kills it via a variety of mechanisms. These include the recruitment of other cell populations and soluble serum factors such as cytokines. In toto, these cell populations also signal to one another to seek and destroy what may be considered foreign to the body. While there are limitations to the technology, we take the T-cell and change or engineer its receptor to express other molecules that recognize a wide range of proteins on the cancer cell. As such, when the T-cell receptor notices that protein, it will immediately follow the cancer cell and bring with it the remaining part of the T-cell to try to affect the cancer.

You can put anything on the surface of that T-cell, any particular kind of molecule, and use it to identify the cancer cells that harbor that molecule.

In prostate cancer, we have PSMA, a molecule that is overexpressed on the surface of prostate cancer cells as they become more resistant to therapy. Our group has used PSMA as a focal point for CAR therapy. We’ve been learning a lot about how to use these cells. It’s a very costly enterprise, and it has not proven perfect yet in the world of prostate cancer. We were able to complete a 12-patient trial looking at CAR T-cells’ ability to track to cancer cells with PSMA on their surface. We know that these CAR cells can migrate to the cancer cells and persist at the site of disease, but they can be unstable and not proliferate sufficiently to continue to interact with the cancer.

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