Dr. Scott Tagawa Video (Text Version)
Title of Talk: Anti-Prostate Specific Membrane Antigen-based Radioimmunotherapy for Castrate Resistant Prostate Cancer
It’s a real pleasure to introduce to you Scott Tagawa from the—from Cornell University and from the New York Presbyterian Hospital. Scott is an Assistant Professor in both Medicine and Urology there and is also the Medical Director of Genitourinary Oncology Research Program. His research has involved similar to what you’ve heard earlier today, really that kind of clinical and translational investigations in genitourinary cancers.
He’s—he’s gotten a number of awards even though he’s relatively young in the field and has been supported by a number of these early mechanisms that you’ve heard of for funding. He’s both received the Chiron Immunotherapy Research Fellowship Award, a Young Investigator Award from the Prostate Cancer Foundation, and awards from the American Society of Clinical Oncology as well. He is originally from the University of South Carolina where he—I’m sorry Southern California where he received his medical degree and completed his Residency and Fellowship there as well. So it’s really my pleasure to welcome Scott to the microphone.
Scott Tagawa, Assistant Professor of Medicine and Urology, Medical Director of Genitourinary Oncology Research Program, Division of Hematology and Medical Oncology, Department of Medicine, West Cornell Medical College
Thank you Dan and excuse me, I’d like to thank the meeting organizers for the opportunity to present our group’s data. I also wanted to take this opportunity just to mention how much I’ve enjoyed this meeting. This is the fourth day as—as exciting as every other day to me, and in part, because like other meetings I’ve had the opportunity to interact with some of my colleagues and particularly this meeting with my—my new colleagues and—and I count all the consumers really as colleagues as we are true partners in this fight against prostate cancer. So I thank you for attending.
What I’m going to talk about is our—our work specifically in anti-PMSA radio immunotherapy. We—we have a group that has been focused in PMSA research ranging from diagnostics to therapeutics. I’m specifically going to speak about radio immunotherapy and I’ll explain exactly what that means in a moment.
So I want to thank Dan and Sam and a number of other investigators earlier for really talking about PSMA. So I won't have to go too far in-depth but I want to make a couple points that were partly made before and I’m going to emphasize it a little bit differently here. So as was mentioned before, prostate-specific membrane antigen or PSMA is expressed on the cell surface of essentially all prostate cancer cells. Initially as published in pathology studies—it was all cells and now we know that’s not 100% true but it’s the vast majority of cells and actually especially when we get to later stage diseases. There—there might even be a million per cell.
It’s also expressed to a lower degree in other tissues as was mentioned. What I’m going to talk about is—is our monoclonal antibody research and for practical purposes those sites of other expression don’t have access to the monoclonal antibody which allows us to—to target what we want to target which are the prostate cancer cells. And as was mentioned, PSMA is also expressed on the neo-vasculature of solid tumors; that’s a talk for another time.
So I have a couple of slides and I really don’t want to minimize this; really this is a true bench-to-bedside phenomenon and I only have a couple of slides on the bench part and really we’ll—we’ll get to the bedside part which—which for me is my laboratory, the—the clinic. Initially there—there was or is a monoclonal antibody against PSMA, 7011 or capromab. There’s an approved scan called capromab pendetide scan; some of you may know that as ProstaScint. The problem with—with that antibody is that it attaches to the internal domain of PSMA and therefore it cannot bind to viable cells, the live cells. It relies on some dead cells in the tumor and [vacillates] that way. So Neil Bander and his group came up with four antibodies against the external domain of which J591 was the leading clinical candidate. What these all have in common is they bind to the external domain of PSMA allowing them to bind viable cancer cells and upon binding, the complex is rapidly internalized.
PSMA is then—is re-circulated to the cell surface whereas the antibody stays in the—in the cell.
Now this is a cartoon of an antibody and—and Chuck Drake a couple days ago showed a—a true picture of an antibody, but just to—to visualize what we were able to do is to infuse—this is just J591. It attaches to PSMA; it’s internalized. In another set of preclinical data in essentially three successive DoD grants—[Shankar] is here somewhere—what we’ve been able to do is attach different what we call effective molecules to J591; in this case radioactive particles or radionuclides. And [Shankar] had a poster presentation as well as an oral presentation yesterday that—that detailed some of this work, so I’m going to go ahead and go forward. But essentially what we were able to do is to—to find prostate cancer cells, the J591 antibody, take that radionuclide to the prostate cancer cell and that’s internalized.
So that work led to two Phase 1 clinical trials; both were in men with metastatic castration-resistant prostate cancer. One utilized yttrium 90, radiolabeled J591; the other lutetium 177 radiolabeled J591 and in some ways what these dose escalation studies were able to do was to demonstrate number one that it was safe. We came up with the primary end points which was determining the dose limit toxicity and maximum tolerated dose to figure out what doses are—are safe to go forward in therapeutic studies and we confirmed and, I’ll show you a picture in a minute, that we were able to accurately target sites of metastases.
And there was—there were some evidence of efficacy even though some of these patients received relatively low doses. This is an example of—the middle two images are radio-labeled J591—whereas the outer images—our—are standard bone scans. And essentially what you can see is that all of the sites that are visible on bone scan light up or are targeted by radiolabeled J591 and in fact you can—you can make out that some of the sites actually we pick up sites that are not necessarily seen on—on standard bone scans. Now that is not always true but this is an example of what can be seen.
So that led to a Phase 2 trial of lutetium radiolabeled J591 and I’m going to come to why we chose lutetium over—over yttrium. In the Phase 1 study, the maximal tolerated dose in what was—in what we would recommend for Phase 2 studies was 70 mCi/m2. Because overall there’s relatively limited experience with radio-immunotherapy in general for prostate cancer, the FDA said hold on; we’re going to start with a little bit of a lower dose. But we—we enrolled a total of 32 patients; quite simply they received a single infusion of lutetium radiolabeled J591, had a scan a week later, and they were followed. Primary point is—was response.
It was a fairly typical patient population for these—these types of trials although we did not require chemotherapy. That’s been a—a common question; slightly more than half received one to five lines of previous chemotherapy but that wasn’t a requirement. And you can—you can see the—the baseline demographics here. This is a—a waterfall plot. Now I haven't seen too many of these so I’ll walk you through this a little bit. Each one of these bars represents a single patient. If the—if that bar goes up, that man’s PSA went up and if it goes down, then the PSA went down. Overall about a third of the patients experienced a 30% PSA decline, and a lot of us will use that based on some chemotherapy studies. You can get a hint if you look at the slide on the right side, they’re slightly more red compared to the left side meaning that—that—and I’ll show you some actual numbers that maybe the—the dose that we thought was the best actually is the best.
This is another picture, a little more—more color. This is a particular patient; overall the majority—94% of patients had accurate targeting of sites of metastases that were evident on scans. And on—on one side you can see a bone scan and—and kind of the middle of the J591 scan which is—which is right here and I want to use this to point out that besides sensitivity, specificity is also demonstrated. You can see on the bone scan that we’ll commonly see sites of arthritis will light up versus not in the J591 scan—images as we are targeting just the prostate cancer. This particular man you can see his PSA was rising and had a—a nice response.
In terms of toxicity, we see in general three toxicities. And I’m going to start at the top and move to the bottom and then talk about the middle. Infusion reactions; these—these are commonly seen with monoclonal antibodies. And I want to point out that we have never in any of our studies to date, at least until now, we never gave any pre-medications because we wanted to see—this is—I really sped past the preclinical work. This is a deemed immunized-antibody in the days before immunization really came into place so it shouldn’t have that much toxicity but we—we always see some toxicity. And what I mean by infusion reaction quite simply is about an hour after infusion men felt hot or cold or occasionally had some—some shaking that self-reversed or they got Tylenol and Benadryl and it went away.
Moving toward the bottom of the slide, radiolabeled J591 just cleared through the liver and it’s not surprising that we see some liver toxicity—transaminitis is—is what you might hear commercials on TV for—for Lipitor you see—you need to watch your liver and that’s what we’re talking about. About a quarter of the patients about 3 to 4 weeks after receiving the—the radiolabeled drug, their AST or ALT went up and then came back down. But really what is the major dose limiting toxicity of radio-immunotherapy in general including radiolabeled J591 is myelin stress and change in the blood counts. And you can see here that—that overall, 42% of patients had transient grade four thrombocytopenia and 27% had grade four neutropenia. And the thrombocytopenia, no one had significant bleeding but overall 28% received at least one platelet transfusion.
Now this is a little more detailed breaking down the—the two separate doses and even though the trial is not specifically designed to look at this, I do believe that there is a dose response. And what you can see is that 47% versus 13% of the—the patients receiving the—what we consider the—the recommended Phase 2 dose had at least a 30% PSA decline that P values .06 versus—and 71% versus 46% had any PSA decline.
In addition there was more toxicity as expected with—with the higher dose and even though I think we—we transfused patients a little bit too carefully, this is a number that we quote in our informed consent documents—there’s a 41% chance they might require at least one platelet transfusion. In general, the—the platelet nadir or the lowest point is about a month after the infusion and then it comes up subsequently.
So the—the conclusions that I would draw from this single Phase 2—single dose Phase 2 study is that it’s—it’s well tolerated with reversible toxicity, shows some evidence of efficacy, or good effect, and there is some—some hint of a—of a dose response.
Now because there were only 17 patients that received the—the dose that we think is true efficacious, we have expanded that with the primary end point of narrowing our confidence levels around the—the response rate. But we’re taking advantage of—of that to look at some—some biomarkers. We have never preselected any of our patients for PSMA expression. It was initially in the literature as all patients—all tumors had expression of PSA; we know that not to be true, and we know that it can be varying levels of expression.
We also know in—from post-op analyses that imaging in some ways predicts response or lack of response with poor imaging. So can we pre-select the—the patients and we’re looking at additional biomarkers including PSMA expression on—on tissue as well as on circulating tumor cells. You’ve heard some—some work on circulating tumor cells. This happens to be an image of tumor cells captured via Cell Search and for those of you know that we are—we’re working on our own capture mechanism that captures by—by PSMA rather than EPCAM, again a different talk.
So I would argue that we—we have shown evidence of efficacy but unfortunately to date the—you know from the single infusion, the longest response has—has been less than a year about 50 weeks. So how can we improve? We know that the standard chemotherapies that are there are taxanes and those act as radio-sensitizers. The problem is that radio-immunotherapy causes myelosuppression or decrease in the blood counts as do chemotherapy. How can we combine that safely? Another problem as—as has been mentioned with us and other investigators is—is lack of funding. We’re not a drug company in going forward, so the DoD gave a number of grants to Akhtar and he—he presented this—this next series of slides both in oral session yesterday and a poster session a couple days ago so I’m going to speed through this and get to the conclusion. But basically, by dose fractionation, which is used in radiation oncology all the time as you know of those who have received radiation you don’t go in typically once; you go in several days in a row or—or weeks or months in a row, and we moved forward with this—with this concept. It was a Phase 1 fractionated study, metastatic castration-resistant prostate cancer, similar toxicities as the overall—overall group. A hint of efficacy—sorry for speeding through but these slides were presented yesterday and the day before.
Another picture where—where we have some—some evidence of tumor targeting. And I’ll slow down here; this is the—the summary of the fractionated Phase 1 study. And the results are consistent with our hypothesis that we are able to give fractionated radio-immunotherapy more safely while maintaining efficacy. And to give an example, the—the safe—what we call the maximum tolerated dose was 80 mCi/m2 given in two doses of 40 plus 40. That required zero platelet transfusions versus a single dose of 70 as I showed you before—requires respectively at 41% transfusions.
Now that study enabled us to go forward with a subsequent study, which is ongoing, which is a combination study of docetaxel and prednisone with fractionated dose radio-immunotherapy with J591. This is the schema for the study; we have completed cohort two. This is a—a dual center study between us and the University of North Carolina. And that study is moving forward.
Now what I’ve shown you in terms of the efficacy or—or positive effects has really just been PSA and we—we just analyzed our—our decade of experience with radio-immunotherapy and this is the overall—this was presented by one of my research fellows 2 weeks ago. However, I do believe that this does mean that we are doing good for some of our patients. I know that talking to patients in clinic, they—they feel better; their pain goes away.
One important note to make is that we—we know from preclinical studies that—that J591 has no direct expression on PSMA expression or secretion and in analyzing our decade of—of data, PSA declines are associated with the survival benefits when we compare those that have had PSA declines without PSA declines. Other efficacies that we’ve seen is CTC count changes; it will show you in the slide, and all of the patients that have had [inaudible] that we’ve seen responses in they all have PSA drops as well. This is a slide that shows just in the more recent era we’ve been looking at changes in CTC counts and this is a slide that illustrates some of those patients. This is a particular slide of a patient that prior to J591 had a rapidly rising PSA, pretty quick nodal growth, had a single dose of radio-immunotherapy, and then 12 weeks later had nice—nice imaging.
As we’d expect those that overall—those that got yttrium 90 had more radiographic responses than with lutetium 177 and I will get to that. So this again will—will speak to one of the questions that have been answered. All of the studies to date have been in metastatic castration-resistant prostate cancer, but what we’d really like to do is move into those with micro-metastatic disease. So what we’ve done is to move forward in a—in a DoD-sponsored study in castrate rising PSA. I’m going to skip forward a little bit as I’m talking about this.
As I mentioned, yttrium 90 has a fairly long pathway so it is good for a bulk of the disease but might have more toxicity whereas what we really want to go over is smaller disease with lutetium 177. And this is an example of micro-metastatic disease that happens to be there in a bone marrow biopsy; this is a disease that’s too small to be seen on any scans but might make PSA. We know that for those men who have a rising PSA after surgery we can give radiation therapy to a subset of them, and some of them are cured. However, unfortunately the majority of them their PSA eventually rises, and that’s because of micro-metastatic disease outside of the pelvis.
So we’re taking this forward. We have a randomized trial in men with a rising PSA despite medical or surgical castration despite Lupron and men in a randomized trial 2 to 1 get radiolabeled J591 with lutetium 177 versus our control arm. And we’re looking to delay or prevent what we consider much more powerful than just PSA and that’s the onset of metastatic disease. We have a number of other secondary end points. This trial is open through limited size within the CTSA consortium and hopefully will open soon through the DoD consortium with the—the PI within the consortium, Mark [Styde].
So in—in summary, over this decade, I would submit that we have demonstrated safety and efficacy with radiolabeled J591. We’re moving forward with biomarkers and improving the therapeutic profile but—but really this—this decade of work has—has led to what we hope is really the biggest bang for the—for the buck from—from the DoD and from other funding agencies that we’d like to be able to use this technology to prevent or at least delay metastatic disease. And I’d just like to—.