SLIDES & TRANSCRIPTS
Saturday, December 14, 2002

Immunotherapy of Prostate Cancer

Neil Bander, M.D.

I have to start with a disclosure. The Cornell Research Foundation patents the technology that I’m talking about. It was licensed to a company called BZL Biologics, to whom I am a consultant, and about a year and a half ago was sub-licensed to Millennium Pharmaceuticals.

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This is not a diagram from an upcoming endourology textbook. It is simply to point out to you that with only 10 minutes; I'm not going to be able to get to the root of a lot of things I'm talking about. I'm just going to get to the tip of the iceberg here.

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I think most of you are familiar with PSMA, at least I hope you are. It is really an idea target. It is present on virtually all prostate cancer cells. It is expressed at very high levels. And as prostate cancers get more aggressive, there are increasing amounts of PSMA expressed. Once antibody binds to the extra cellular domain of PSMA, it becomes internalized, so any payload that is being carried by the antibody is also internalized. And a very interesting and potentially exciting area that I don't have time to talk about is the fact that PSMA is expressed by tumor vascular endothelium of all solid tumors.

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The antibody that I'm talking about is called J591. It was the first IgG antibody to the extracellular domain of PSMA. And it is the first such antibody in clinical trials. And it happens to be the first de-immunized or humanized antibody of PSMA in clinical trials. And this antibody functions as a tumor targeting vehicle that can carry a payload to disseminated sites of prostate cancer.

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This antibody really does provide a platform of many uses, either as a naked antibody to target the endogenous immunoeffector function of the patients. It can be used to deliver radioisotope for therapy, or radioisotopes for imaging, or other agents for imaging. And it can also be used with conjugated drugs to deliver those. And it can be done in either prostate cancer and in non-prostate cancers. And today we are just going to focus on a small segment of this platform.

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I'm going to jump right to the clinical trials. There are about seven clinical trials, which have either been completed or are running with this antibody at this time. At this point over 120 patients have been treated, or entered in trials I should say with this antibody, either at Cornell or more recently at Sloan-Kettering.

The two trials I'm going to focus on are these two radioimmunotherapy trials, one with Yttrium-90, and one with lutetium-177.

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These are both beta-emitting particles. That means that they have therapeutic capability. You may be more familiar with yttrium-90. That's the isotope, which is used, on an approved antibody called Zevelin for treatment of non-Hodgkin's lymphoma.

These two isotopes have different physical properties, which is why we are interested in looking at both of them. They have different half-lives. Yttrium is a little shorter than lutetium. Yttrium has a higher energy level, and therefore, a longer range. It's not clear whether a longer range is better in prostate cancer. And another interesting difference is that although yttrium-90 can't be imaged directly, because it has no gamma component, lutetium-177 does have some gamma emission, so that can be imaged directly. In any case, we thought we wanted to look at both of these particles.

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These are two independent phase I trials, classic objectives looking at toxicity, defining the maximum tolerated dose of the isotope. We were particularly interested in determining how well we could target the disseminated prostate cancer. We obviously wanted to look at whether the antibody was immunogenic, or whether we would be able to use it in repeat doses. And as a secondary objective in these phase I trials we were looking at response as well.

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It's pretty standard eligibility in the phase I trial. All the patients had progressing metastatic prostate cancer. And although it was not required, we did restrict entry primarily to patients who were already hormone-dependent. I don't have time to go into all the other eligibility criteria.

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The design was pretty straightforward. One Day 0 patients got the radio-labeled antibody. In the case of yttrium, since we couldn't directly image yttrium, a week before their yttrium dose they got an indium-111 dose of antibody. That's the same isotope that is used for prostacint.

Subsequent to their doses they got imaged about four or five times so we could track the targeting of the antibody.

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The yttrium-90 trial is completed; 29 patients were entered. The lutetium-177 trial, which started later, has entered 25 patients, and is still enrolling.

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I won't go through all the demographics, which you can read up here. Suffice it to say that all but one of the patients was hormone refractory. That one patient could not tolerate hormonal therapy, and more than a third of the patients had already failed chemotherapy. These were patients, as you will see, with significantly advanced disease, and generally large tumor burdens.

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Let me spend a couple of minutes on targeting, because this really is the core principle of this approach. If we can successfully target disseminated prostate cancer with this antibody, we can delivery whether it's radioisotopes or cytotoxic agents, successfully.

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The take home message with respect to antibody targeting with the J591 antibody is that we can target both bone and soft tissue disease. We have virtually 100 percent success. That is, in every patient where we see disease on conventional scans, we can see those sites on the antibody scan.

This is consistent with immunopathology studies that have demonstrated that 100 percent of prostate cancers are PSMA positive. None of these patients are selected prior to entry for PSMA expression. And we see no significant normal tissue targeting by the antibody.

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As anticipated, with radio immunotherapy, the dose limiting toxicity is hematological. We have defined the yttrium-90 MTD as being approximately 17.5 millicuries per meter squared. This is very similar to what you see with Zevelin. We have not yet reached the MTD with lutetium. There are essentially no other side effects from the therapy.

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This is the first immunized antibody in the clinic. The immunization is next generation humanization. Again, I don't have time to go into the details of that technique.

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Suffice it to say in over 100 patients, the antibody is not immunogenic, which raises the possibility of multiple dose therapy.

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Let me just conclude by saying PSMA is an ideal target for prostate, and probably other cancers as well. The J591 antibody is specific to the extracellular domain of prostate cancer cells. The antibody is de-immunized enough and non-immunogenic.

This antibody can be used as a targeting vehicle for imaging agents or chemotherapeutic agents, or radiotherapeutic agents, or even to target the endogenous immune effectors function of the host.

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We get targeting with virtually 100 percent accuracy. It's extremely well tolerated. With radioimmunotherapy the DLT is hematologic, as would be expected. We have demonstrated that multiple doses are well tolerated.

And although tumor responses are a secondary endpoint in phase I trials, we have seen several major biochemical and measurable responses in the context of these studies. This antibody may be useful in vascular-toxic therapy of other solid tumors.

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There are trials going on now with naked antibody in both prostate cancer and other cancers. The radio therapeutic antibody I showed you, the yttrium-90, will shortly go into a multi-center phase II trial. We are continuing to conclude the lutetium trial, and earlier this month a cytotoxic antibody conjugate trial started at two institutions.

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Just to acknowledge all of my co-workers and funding.

Thank you very much.

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