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IMPaCT Investigator Highlights (Text Version) - Dr. Susan F. Slovin

Title: PSMA - Target T Cells for the Treatment of Castrate Metastatic Prostate Cancer

Investigator: Susan F. Slovin, M.D., Ph.D., Memorial Sloan-Kettering Cancer Center

The Department of Defense is currently funding a clinical trial that we are doing that is treating prostate cancer with a very novel immune approach. My institution is the coordinating center for a Department of Defense-sponsored approach called the Prostate Cancer Clinical Trials Consortium, which is a group of 13 institutions whose job it is to bring to the table new treatments, novel techniques for treatments, and also just to get the job done a lot faster than they could if the individual hospital was doing it alone.

We have been focusing on a novel platform whereby we take patients’ own specialized white cells called T-lymphocytes and genetically engineer them to express a molecule on their surface that will target PSMA, prostate-specific membrane antigen.

Now this molecule is not entirely specific for prostate cancer per se but as prostate cancer patients transition from being hormonally responsive to being hormonally unresponsive the expression of PSMA is increased almost 1,000-fold, which makes it a very good target for an immune type of approach.

The novelty of our T-cell is really based on the fact that we’re able to put on its surface a molecule that can specifically target PSMA. If one were to look at the T-cell receptor, which is on the T-cell surface, it has a variety of different molecules on its surface including an activating moiety called CD3. There’s also the zetachains which give activation to the T-cell receptor. So what’s been done here in our genetically engineered T-cell is that we’ve taken a portion of a monoclonal antibody that we call J591 that’s directed against prostate-specific membrane antigen. It is put onto another molecule on the surface of the T-cell and it’s anchored into the T-cell by these zetachains and what this does—it gives it activation because normally for engagement of the T-cell with a tumor cell, the T-cell has to recognize this abnormal molecule such as PSMA in the context of what we call histocompatibility antigens. And that’s a problem because not always are these antigens expressed by the tumor cell. They’re lost or some of these molecules are lost. You’re bypassing any of the issues that would prevent T-cells from recognition—recognizing the tumor. So if you’re genetically engineering a way of having the T-cells home to the molecule based on the fact that on the T-cell there’s an antibody directed against this molecule—so it’s almost like a key going into a lock. The PSMA is on the tumor cell; your T-cell is loaded and ready with an antibody against PSMA. It seeks out and hopefully will bind and hopefully will destroy.

Preclinical studies have shown that this modified or engineered T-cell in a mouse, for example, will target to the mouse’s prostate tumor. Now this tumor can be put in orthotopically, in other words put into the mouse’s own prostate human cell line, into the prostate where it grows or the mouse can receive a tumor that grows in the lung. These are all PSMA tumors.

So this is a bioluminescence assay; you can see where the tumor is when treated with a controlled T-cell that’s been genetically engineered not to express PSMA. And you see these little ugly areas here. This is the actual lung metastases, these spots, and over—over 13 days you’ll see that they go from spots to these huge masses. If you look by immunohistochemistry under the microscope, all of these are huge tumor nodules within the mouse, the same thing as here.

At the same time, if you’re using the T-cell that’s been genetically engineered in the mouse on the same day that you’re using the control, you can see that there are no metastases whatsoever. And if you’ll do immunohistochemistry of a lung biopsy or even the lung post-mortem, there’s no evidence of tumor cells showing that we actually were able to cure the mouse. Not only can we cure, but their survival is substantially improved. As you can see here, percent survival over time, these are the controls, these are the mice that were—had their tumors eradicated and their—their life expectancy is much, much greater.

So this has been proof of principle; this has been reproducible for different kinds of animal models and that’s the rationale for going forward in patients with metastatic prostate cancer. These patients have measurable disease. We know that their tumor cells express PSMA; it’s a nontoxic therapy and we should be able to trace these cells to areas in the patient’s body where we know there’s actually radiographic evidence of cancer.

So using the T-cells as an approach is really something that has been a long sought after goal because we know that T-cells have always played a role in cancer recognition and killing. The problem is getting them to the site and making them stay there for long periods of time and hoping that they will induce an anti-tumor effect. So we’re all very excited by this.