Theranostics: New Targets, New Atoms
SESSION 1: Theranostics: New Targets, New Atoms
Moderator:
Michael Hofman (Peter MacCallum Cancer Centre)
Prostate Cancer Theranostics: What’s Hot in 2025?
Michael Hofman (Peter MacCallum Cancer Centre)
Terbium-161 PSMA: Does Auger Strike a Perfect Balance of Beta and Alpha?
James Buteau (Peter MacCallum Cancer Centre)
View the Transcript Below:
Theranostics: New Targets, New Atoms
Howard Soule, PhD [00:00:01] So without further ado, we will open our scientific sessions here in Carlsbad, California today. Professor Hofman, who needs no introduction, but nuclear medicine physician par excellence from the Peter McCallum Cancer Institute in Melbourne, Australia, will lead this section on radioligand therapy. Michael, welcome.
Michael Hofman, MBBS [00:00:32] Thank you so much, Howard and Andrea. It’s a real honor to chair and present in the opening session. We’re titled New Targets, New Atoms, and we’ve got a stellar line up. I’m going to start by giving you a bit of a highlights of what’s happened in this area in 2025. And then the remainder of the speakers are really gonna move on to the new targets, new atoms. The main theme of my talk is gonna be what’s been happening with lutetium PSMA. So, I’m gonna be talking about what’s hot in 2025 and it’s mainly on lutetium PSMA as a prelude to the new atoms and new targets that James and the other speakers will be talking on. As I said, we’ve just celebrated the 10th anniversary of our first dose. This is the birthday cake being made in the hot cells just a couple days ago. Radio chemists are multi-talented. I’d be interested to see, Jason, if you can do this in your lab. But although we started 10 years ago, the story started much, much earlier. In fact, in 1987, with the identification of the first antibodies against PSMA. And you can see from this wonderful review that Andrea wrote in Journal of Nuclear Medicine that PCF have really been there from the very beginning, and it’s quite a long history. So, if you’re interested in learning about the history, do pull out that article. We’re talking about theranostics, which is a play on the word. Half of it is Thera, the therapy, and Nostics is diagnostics. So, we’re using radioactively labeled peptides in this case for both PET-CT imaging and then we just change the radioactive substance from an imaging to a therapy and then, we can essentially see what we treat. Now, this is actually one of the first patients we treated exactly 10 years ago. He had extensive bone, adrenal and lung metastases and after three doses of treatment, he had a complete response. I can tell you, I was quite naive at this time. I didn’t know a lot about prostate cancer. I wondered if we had cured him. Which was obviously not the case, because we see recurrence in really 100% of these advanced cases. This patient’s wife was an oncology nurse, and she was so impressed with this response, she tried to get some media attention, and she wrote before the treatment, he was on heavy medications to cope with his bone pain, and he spent most of the day asleep. He was weak without hope and within a week of the treatment he was up and cleaning the garage without painkillers. And as a former oncology nurse, she’d never seen anything work like this before. So, when we look at this image of our eight best responders, they’re not just images, but there’s a patient behind every scan. And these patients really had impressive symptomatic responses. And being such a well-tolerated treatment without much side effects, even the patients who aren’t responding generally don’t have too much of a decrement in quality of life. Around five years ago, thanks to funding from the PCF, we established a Center of Excellence in our center. And in the rest of the talk, I’m gonna highlight some of the things we’ve been able to achieve with this funding that we’re very grateful for. You can see a real explosion of radionuclide therapy in our center. Last year, we gave over 1,200 cycles of treatment, and the dark blue at the top is terbium-161, which you can see growing rapidly in the last year or so. The big news of this year was an announcement by the FDA that Pluvicto was now approved pre-chemotherapy in patients where it was considered appropriate to delay taxane-based chemotherapy, and I understand in the US that more than 50% of treatments given today are indeed in this pre- chemotherapy setting. I presented this slide last year, and at that time there were five randomized controlled trials of PSMA. Wound forward one year, and there are another six randomized control trials that have read out this year alone, so let’s deep dive on a few of them. Our focus at Peter Mac, through our Center of Excellence, has been on trying combinations. We think lutetium monotherapy is probably not the best way forward, and you can see we’ve tried combinations with hormone, chemotherapy, immunotherapy, PARP inhibitors, multiple radioligands with different targets, surgery, and external beam radiation. And some of these have read out, but we’re gonna get a lot more data over the next few years. Now for us, the year started at ASC OGU with Louise Emmett presenting updated results from the ENZA-p trial. This was an Australian randomized control trial that randomized 162 participants to either Enzalutamide or Lutetium in combination with Enzalutamide in a population that had a high risk of failure. This was a very neat trial because we’re utilizing this upregulation phenomenon that occurs. You can see day one and day 15, the scan looks like it’s getting worse, but the PSA is actually dropping and the enzalutamide’s probably resulting in upregulations of the receptor. We then jump in with the lutetium, and we get the benefit of that. This patient having a complete response at 20 months after only two cycles of lutetium PSMA. Now what Louise presented at ASCO GU was survival with longer follow-up. And surprisingly, for this small phase two trial, there was a significant survival advantage, 34 months versus 26 months, favoring the addition of lutetium. And not only were the patients living longer, but they were living better because quality of life was significantly improved with the addition lutetium. In a second Lancet Oncology publication from the ENZA-p trial this year alone, we also published the quantitative PET imaging biomarker analysis. And what we can see is that the total tumor volume, which is a volume around all the tumors done in an automated fashion on PET, was prognostic for survival. So, patients with higher tumor burdens did worse, which is what you might expect. However, it was predictive for response for lutetium. So, patients with higher tumor burdens seem to be the ones that were benefiting by adding in additional lutetium. In the middle of the year, at ASCO 2025, there was a dedicated session on radioligand therapy in prostate cancer for the first time ever in a very big hole that you can see here. Dr. Sandhu presented the results of the ANZUP EVOLUTION Trial, a small, randomized trial of lutetium PSMA-617 compared to lutetium combined with IPI-NIVO, so a CTLA-4 and a PD-1 inhibitor. And there was a significant prolongation of RPFS, radiographic progression-free survival, with the addition of immunotherapy. However, the difference was not huge but did reach significance. There were, however, significantly more adverse effects with immunotherapy, as we would expect. So, 76% of patients having a G3, [G]4 toxicity, compared to only 26% with lutetium monotherapy. Now, from my perspective, I wonder if this combination is too toxic for everyone. However, there is a lot of biomarkers embedded in this trial that Dr Sandhu is analyzing, and I wonder if we can predict using ctDNA, PET or other biomarkers, which are the small number of patients that really seem to get prolonged benefits from the addition of immunotherapy. We’ve also had longer follow-up from our therapy study. This was the first randomized trial run in Australia, lutetium PSMA-617 compared to Cabazitaxel. And we took ctDNA at baseline and at times of progression. And Ed Kwan in the Vancouver lab, led by Alex Wyatt, analyzed these samples. And it was published in Nature Medicine and presented at ASCO. And Ed’s actually giving a talk on this in a couple of days’ time, so I’m gonna leave it to him to present the enormous volume of data that came out of this study. Unfortunately, 7 a.m. On Saturday, but we expect to see all of you there, but you can see just an incredible, rich data set and we have identified some putative, predictive and prognostic biomarkers. This is a patient who had six cycles of lutetium PSMA-617 on the therapy trial and then had an additional 14 cycles afterwards over a five-year period, so 20 cycles in total. The patient’s renal function was completely normal after 20 cycles despite a cumulative dose to the kidney of 55 gray, which is more than twice the external beam dose limits, and it tells us that we shouldn’t extrapolate these EBRT dose limits to radiopharmaceutical therapy. And this patient actually had cabazitaxel after 20 cycles of treatment, and you can see he did very well despite having a large burden of tumor to start with. With almost 10 years of experience at Peter Mac, we are starting to see potentially some second neoplasms after lutetium therapy. We’ve looked at 381 patients and five developed MDS, which appeared to be related to treatment, making an incidence of around 1.3%. This is one such patient who participated in the therapy study. And what we were able to do, since we collected ctDNA before treatment, is have a look. And in fact, there was a specific mutation identified, which was a marker of clonal hematopoiesis that was present prior to the lutetium therapy. And then expanded or became worse. So, it seems that some people may have a predisposition to MDS, and when you throw in large amounts of radiation, you may accelerate their development. With that in mind, Asli Munzur from the Vancouver group looked at the therapy data set, where we were able to really go back in time, since we had plasma frozen prior to treatment and then at time of progression. We were able compare lutetium versus cabazitaxel. And in fact, the rate of emergent clonal hematopoiesis, which is a potential biomarker for MDS, was significantly greater in the lutetium arm, 62% compared to 40%. And moreover, we were able to identify a specific mutation, PPM1D, that seemed to be the putative cause. And now I haven’t come here from Melbourne, I’ve actually come via Berlin, the ESMO European Oncology meeting. And this is the presidential session. Where the PSMA addition trial was presented by Scott Tagawa. And rather than showing you the results, I’m gonna leave it to Oliver Sartor, who’s doing an encore presentation of this on Friday. But this is the first trial of Lutetium PSMA-617 in men with newly diagnosed hormone sensitive disease, phase three trial, so potentially practice changing results. And you can also see a commentary on PSMA edition that I did together with Declan Murphy on GU Cast, where we really deep dive into these results in a little bit more detail. Earlier this year, we saw some stunning results of the PEACE-3 trial. Now this is a trial using Radium-223, an alpha-seeking, bone-targeted radioligand, and when this was added to Enzalutamide in a phase three randomized control trial, it led to an improvement in overall survival, hazard ratio 0.69, overall survival 35, compared to 42 months, and really reinvigorating potentially what is the role for radium in the lutetium PSMA era. And it timed really well with our AlphaBet trial that we just presented a few days ago at ESMO, that co-published in Lancet Oncology. And this was a phase two trial where we gave a cocktail of lutetium PSMA-I&T plus radium-223. And you can see the results in our poster session to deep dive that James Buteau will show later on. But here is an example of a patient who has a PSMA negative bone metastasis, that’s FDG-positive, bone scan positive, so that when we target using both lutetium and radium, we’re potentially targeting both the PSMA-positive and PSMA-negative sites. And I think in the future, this type of nuanced imaging biomarker work may be the way forward to really select the right treatment for the right patient at the right time. Also, at ESMO, we saw the updated results of the LuPARP trial, a PCF Challenge Award supported trial, right up to 10 different dose cohorts, and we selected dose nine, which is 300 milligrams of olaparib BD, day minus four to day 18, so a pulse of olaparib with each cycle of lutetium, rather than a continuous dose of olaparib. That seemed to be a little bit more toxic. And in this phase two trial, the PSA 90 response at 52% is really quite striking. So, I think this is a combination that worthies further consideration. At ESMO, we also saw the results of this intriguing study from Kim Chi, a cooperative group trial out of Canada, where patients were randomized to either lutetium followed by docetaxel, or the flip-flop, docetaxel followed by lutetium. It’s really only cooperative group trials that seem to answer some of these fundamental key questions, and the results were really striking. Although the responses were better when lutetium was given prior to docetaxel, the overall survival actually favored giving docetaxel first, followed by lutetium with a hazard ratio of 1.64, which was statistically significant, so really interesting results to think more about. And, lastly, We saw some early results in patients with oligometastatic disease. This is the LUNAR trial led out of UCLA by Jeremy Calais and Dr. Kishan, presented also at ASTRO. Patients with up to five bone metastases were randomized to either two cycles of lutetium, PSMA-I&T, followed by stereotactic radiotherapy or stereotactic radiotherapy alone. And the aim was to delay commencement of hormone treatment, which is a really patient-friendly endpoint, and this was comprehensively achieved, 14 months with SABR monotherapy compared to 24 months with the addition of only two cycles of lutetium. So, this is only a phase two trial, but these results look really promising. We were lucky enough to receive a 2022 Tactical Award together with UCLA, UCSF and Essen. Our goal was to spearhead the development of next-generation radioligand therapy. Using two platforms. One, a new chemistry platform for peptide discovery, and two, using lead-212 as an alpha emitter, which we think has advantages compared to actinium-225, particularly for peptide-based theranostics given the half-life of lead, which is 12 hours, compared to actinium of 10 days, which potentially just a bit too long for peptide theranostics and other potential advantages. At ESMO, we also saw the TheraPb trial, read out some early results. This is a trial sponsored by AdvanCell using lead-212 PSMA in a dose escalation design. And some really early promising results with a PSA50 response rate of 80%, very good responses on resist, in fact, a 100% objective response rate in the 60 valuable patients. And a few nice case examples, such as this patient. Who has a 99% reduction in PSA at six months. So, lead-212 is unique because it’s a generator produced radioisotope, unlike lutetium which is coming out of a nuclear reactor. So, this is potentially scalable and distributed around the world and then labeled locally to really scale up what may be a very promising way to do alpha theranostics. Lastly, I’d like to change text in the last minute and just talk about this really nice article published in the Journal of Nuclear Medicine, a little bit geeky. It was a new PSMA ligand for PET imaging. But this group labeled it in both mouse, pig, dog, monkey and human. And you can just see how different the bio-distribution is in each different animal. So, in the monkey there’s diffuse marrow uptake. In the dog there’s high lung uptake, in the pig there’s heart uptake and in the human there’s liver spleen uptake. And this really nicely highlights to me the need to move into humans very early on and not play too long in animals. And one way we’re gonna do this at Peter Mac is by using a new technology, total body PET scanners. So standard PET scans around 30 centimeters, the body moves and you do that about five times, you stitch those together and it takes about 15 minutes to do a PET scan. On a total body device, like the one we’re installing in Peter Mac, which was just being installed last week. This is me in the loading deck, unloading the new PET scanner and a snapshot down the 1.2-meter detector range. We can now scan the entire body in one go, which means we can actually do a scan in around one minute and do dynamic imaging, see how the tracer moves around the whole body over a period of time, which I think is going to be extraordinary for new tracer development. With that, I’d like to invite everyone to attend the meeting that we have every second year, together with the Prostate Cancer Foundation, which is ProsTIC26, September 3-5. Take any burning questions, although if I’m over time, we could also move on to the next talk.
Unknown [00:18:35] Great, Michael, can I ask one question? That was one hell of a whistlestop tour. And along the way, you mentioned MDS. I think you said 1.2% in therapy. Your thoughts on when we use RLTs early in the disease, is this gonna go up? What should we be telling patients?
Michael Hofman, MBBS [00:18:53] Yeah, so it was not 1.3 from therapy, but 1.3 from all the treatments we’ve done at Peter Mac, all the trials, all the off-trial. And I think it can only go up with time because you discover more cases. And before prostate cancer, I was a bit of a lutetium-dotatate neuroendocrine person and we used to consent patients for 1% incidents of MDS and it’s now well-known with lutetium-dotatate that it’s somewhere in the five to 8% range, which is actually quite high. However, Somatostatin receptors are expressed on hematologic progenitor stem cells. So, I think the incidence will be lower with PSMA. I’m not sure what the final number will be. Maybe it’ll be about 2%, 3%. This is a low number, but it’s not insignificant. And most patients that develop MDS actually die from MDS, not prostate cancer or neuroendocrine tumor. So, it is something to be mindful of as we bring it earlier and earlier. If you’ve got 10, 15 years to live, You don’t want to die of MDS in year three or four, even if the incidence is very low. But it does seem that there may be some biomarkers that powerfully predict which patients are at risk, and potentially we can use that to avoid lutetium as an early or first line treatment maybe in those patients in the future. So, let me introduce James Buteau. James Buteau is a nuclear medicine physician who works out at Peter Mac with us. He’s just completed a PhD, and one of the main topics of his PhD was this first in human trial of terbium-161 PSMA, which was presented at ASCO this year and published in Lancet Oncology. And he’s gonna start by talking about, I think this ticks the new atoms box. Over to James.
James Buteau, MD, PhD [00:20:42] New atoms. All right, I was hoping I wouldn’t see our slide deck appearing now. So, I’ll be presenting on terbium PSMA-161, our experience. I don’t have any conflicts of interests personally. PCF YI of 2023, and we did have some institutional funding for this trial. The VIOLET trial, the first results were presented at ASCO this year in 2025 by Michael and they were co-published in Lancet Oncology. So, it was very exciting results, first in human, using a terbium-161 across any cancer type. I think this is the key summary. If you want to have a look at one slide to understand, this really summarizes it best. You can see here the 12 best responders who had a greater than 90% reduction from baseline. And these are the SPECT scans. So, after each cycle, we take a scan and you can see cycle one to the last one that they had next to them. All of the cancer is contoured in purple. As they had remarkable responses, no dose limiting toxicities was very encouraging and we escalated to the highest dose of 7.4. All right. So, essentially, the rationale is that we know that lutetium-PSMA is very effective. We can treat in a very targeted manner, so it’s liquid radiation, goes to prostate cancer, and gives very few side effects as it doesn’t give much to normal tissues. And we know we can also treat time and time again. We’ve treated patients well beyond six, up to 12, even 20 at Peter Mac. Generally, the duration of response shortens and eventually there is resistance. Even when we don’t see anything left, we know that there are micro metastases lurking around. And when you think about it, lutetium-177 delivers radiation around one millimeter where it binds. So even if it can target those micro metastases, that radiation just bounces around normal tissues. Mostly, it doesn’t strike many of the remaining micro metastases. Beta radiation is a little bit like throwing marbles at DNA, you throw lots of them, it’s going to cause lots of damage. So, they can go further, less energy. Alphas are much stronger than the heavy hitters, they just tear through. Bit like throwing a bowling ball at DNA, and it’s going to just rip it apart. They don’t go as far. And Auger and conversion electrons are like that sweet zone in between where it’s very energetic, it goes a very short range. So, we want to investigate this additional type of radiation. We know that terbium-161 is very similar to lutetium-177, so it does have lots of crossfire, lots of beta radiation. But has these additional Auger electrons and conversion electrons that stay within, smaller than the range of a cancer cell, so usually within 500 nanometers, so we can really boost radiation within those cells. And when you compare it, it’s actually quite eerie how similar they are. You can see here the main characteristics, lutetium in the middle, I guess and terbium to the left. They have very similar half-lives, slightly longer. This is in days, a little bit longer for terbium. A little bit more energy of the beta radiation that’s emitted, so 154 for terbium, but not big differences. This all adds up when you look at the physical half-life of the isotope. So, it’s between 35 and 40% more radiation from those beta electrons simply due to those two reasons. And you’ll see that there are abundant conversion in Auger electrons for terbium. There are some with lutetium, but many times more. This is about 10% for lutetium and 25% with terbium. And you’ll notice that there’s much more, there’s the range just below. There’s much energy from those conversion electrons. They go a bit further. They have more chances of striking the DNA, whereas the Auger electrons can also, but they don’t go as far. Conveniently enough, there’s also emitted x-rays so we can do this post-therapy imaging quite well just using some high-resolution, low-energy collimators instead. So, there’s lots of pre-clinical work, mainly from Cristina Müller’s group, to back our trial. There were lots of in-cell and in-mice analyzes. And these were in, oh sorry, I was looking at the wrong slide. And you can see that there’s much greater tumor growth suppression when giving lutetium to the left versus terbium-161. It had very similar kinetics, bi-distribution, and retention in cells in those models as well. And this was looked at with PSMA-617 as well as I&T. But essentially, you’ll see the next slide as multicolor simulations. And we looked at the difference of radiation to the nucleus for lutetium-177 versus terbium- 161. And you can see it was many times fold, you’ll see in a minute, greater for terbium-161, regardless of where it was distributed. So, they looked at single cells and small cells micro metastases, two layers of 16 cells, and they looked at depending on where the position was, it was about, if it was on the cell surface, cytoplasm or within the nucleus. And essentially, so this was our hypothesis. We wanted to see if terbium-161 was safe and effective in humans. So, this is where we decided to design the VIOLET trial. It’s a single center trial, phase one, two, and we had a dose escalation. We don’t know what’s the best dose to be using. So, we tried 4.4, which is roughly six gigs of Terbium-161, no, sorry, Lutetium-177. So, this was the, yeah, just you can see in red, it’s a lot higher than lutetium, looks much better for radiation to nucleus, which is what I was saying, and this is just a pretty image. So basically, yeah, Phase 1, 2 trial and very similar criteria, high uptake on PSMA-PET, no discordance, 30 to 36 patients. So, it was dose escalation with a three plus three designs. We had three dose doubles. We were treating with six cycles every six weeks. Those three dose levels that are there, the highest is roughly 10 of lutetium, just accounting for the beta. And all of it was produced on site with the isotope kit, so it worked very smoothly. Here are the objectives, so the co-primary objectives were for the maximum tolerated or administered dose and safety, and these were the dose limiting toxicities. We had multiple secondary objectives, some of them are still being collected, but I’ll be presenting some of the results for these as well. So essentially, we screened 33 patients, three were not eligible, and this is in the context of, you know, a very high-volume center where we can already kind of pre-screen and filter those patients out. So, three of them had low PSMA or discordance. So, 30 recruited, there were three dose levels, and then we expanded the highest one. So, 70% or 21% of the patients received all six cycles, a few of them did not. Mostly one of them, he died from an unrelated medical condition, and the others were from unequivocal progression. Baseline characteristics here, I think the main thing I want to draw attention to, they were allowed to be chemo-naive if they weren’t medically suitable, as we had about a third of those. Some were post-cabazitaxel, they all had RPs, and these are the PET characteristics. I can’t not present them, loving these biomarkers so much. But they weren’t favored necessarily, so you had high SUVmean in roughly a quarter of patients, a little bit less than in therapy. We had SUVmeans across the spectrum, FTG volumes as well, and predominantly with bone mets. So, there weren’t any dose-limiting toxicities, and it was a very encouraging safety profile, even if you have this higher type of radiation. There were only two grade three events, no grade four, no treatment-related deaths, and you can see that those grade three ones were lymphocytopenia in one patient, which isn’t really significant, and one patient had severe pain. He was hospitalized for two days, had to get some ketamine, and was due to a flare of pain that was obstructing the UV junction. So that only occurred once, then subsequently, so very favorable safety profile. There were no dose reductions due to safety, and there were no dose delays either because of severe cytopenias, for example. Promising PSA responses, you can see here the 30 patients. 70% of them got a greater than 50% response. And 40% of them had a greater than 90% response, so very encouraging. And here is the PFS, the Kaplan-Meyer for PSA-PFS and RPFS, so quite prolonged RPFS. It was very encouraging at 11.1 months for RPFS we still are collecting data for OS and. And this is radiation-absorbed dose. So, this is one of the patients, you can see to the left the PSMA PET at baseline, where you can see all of the cancer is very, very dark. The first spec that he had was done at three time points. So, for the dose escalation, the, all of patients had three timepoints to get some very accurate dosimetry and to be able to model for the other patients or using terbium in general. So, the three time-points at four, 24, 96 hours. And then we can put that all together in medical physics to do voxel-based dosimetry. You can see the dose map to the left. What you’ll notice is that there’s very, very high retention in the cancer. It’s very red, as you can see to the right, or very dark in those three middle images. And the salivary glands, the kidneys, all of that just washes out very quickly, as you can notice. So, it’s a very similar pattern to the lutetium. We don’t expect higher toxicity for that reason. It’s a beautiful image. I’ll just leave it there for a minute. All right, and this is the normal organ dosimetry, so it was well in line with what, it’s quite variable, I guess, depends how things are calculated, but it was quite similar to lutetium. And finally, so yeah, and that’s it. So, it was a very exciting trial, very exciting to publish this year, first in human across all tumor types. The recruitment was completed eight months ahead of schedule, so it’s really smooth logistics, bearing in mind that it came all the way from Israel, into the U.S. It came all the way back to Australia, to Melbourne, and it was all produced on site, so very smoothly. The logistics themselves are very similar to lutetium. They’re both what’s called lanthanides, so they’re both in the same chemical group. They have similar chemical properties, so you can almost just transition Terbium-161 into whatever you’re using for lutetium. So, the radiochemical, the radiopharmacy process was all validated on-site. We used the kits from my isotope. It worked super smoothly. For radio protection, it’s also quite similar. So, there aren’t any additional measures. There’s not higher energy, for example, of X-rays that are coming out of the body that could limit that we can see with other alphas, for examples. So, it’s something that could be easy, maybe better. That could be quite easy to just slot in. Limitations, it is a single cohort. Tried to look, is it better? Are there any signals? But obviously you can’t compare with other trials. We would need an RCT to understand this. We don’t have blood or Auger electron dosimetry. We had to develop some models for microdosimetry in that context. And we only explored up to 7.4 gigs. So, and that was just the maximum administered dose. So, following these results, we did expand to 9.5. So, recruitment has completed and patients are receiving treatments. There’s the large, I think this provides really robust data to inform larger trials. With terbium-161 across any other tumor types, particularly for mCRPC. And I think we have to think about designing other spaces where terbium could be used to its full potential. It can target micro metastases quite well, so could it be better early on, you know, pre-curative intent radical prostatectomy or radiation? Could it be used in oligomets? I think those are lots of spaces that are interesting to explore and for other cancer types as well. So essentially, first in human use of Terbium-161 across all human types, very low toxicity rate, very promising activity. It’s great to be in nuclear medicine. I’d like to thank a huge number of people. Thank you to PCF for the funding support as a YI also. Isotopia who provided the Terbium-161 and the kits. As well as some funding for the expansion, and particularly Professors Michael Hofman and Arun Azad, co-supervisors for my PhD, and just thank you for all of the vision around this. And finally, we named the trial after Dr. John Violet, who’s a radiation oncologist, who was quite passionate about Auger electrons. He went to lots of conferences around the world with maybe, I don’t know, 10, 15 people going, and he had passed away during the pandemic, So it was in honor of him. Thank you. I’ll take any questions.
Michael Hofman, MBBS [00:34:26] Yeah, if anyone has any questions, please come up to the microphone and James will answer them.
Felipe Eltit, PhD [00:34:29] Hello, I’m Felipe from UBC and Vancouver Prostate Center. Congrats, nice, really nice talk and awesome results. Sorry, my question comes more from radiotherapeutic ignorance. My knowledge, or to my understanding, the DNA damage through radiotherapy was by the regeneration of oxidation species around the DNA, but you talk about direct damage. I don’t know, what do you know about that? Maybe you’re not the right person to ask, but what do you know?
James Buteau, MD, PhD [00:35:01] I mean, you can have different types of damage. You have direct and indirect. If you create free radicals around, you can also break the cell membrane as well. You can cause damage directly to the DNA. I can’t go really into the deep detail of how radiation will cause it in that context, but yeah, I think all of that adds up.
Mike Morris, MD [00:35:30] Great talk, James. It was really a pleasure hearing these data. I think probably it occurs to a lot of us that we now live in a world of real abundance, right? We have lead, titanium, lutetium, and now terbium. So how do you see a way of efficiently sorting through this so that we can focus our energies on what is going to most likely be successful? Because there’s no way that we can do big studies on all of the now tracers and radioligands, etc. The list is very long. What’s the path forward for us?
James Buteau, MD, PhD [00:36:12] That’s a really great question. I think lutetium-177 won’t be phased out. I think it’s such a great treatment. It works so well on many people. Terbium-161, I think perhaps it’s using it. So, we are analyzing other biomarkers with ctDNA and PET scans. So, I think the best appropriate use could be also targeting for patients who may have high FDG volume, low PSMA SUVmean, where we know they won’t respond as well to lutetium, or could better with terbium-161. And I guess it’s probably similar with alphas. There’s probably a role with, like, can we, I think for, like true radio resistance that they’re progressing on treatment with lutetium or terbium, that’s probably the most interesting space to use alphas that, you know, might have more toxicity, like actinium. Then there’s the whole idea of cocktails. Like, are there patients with so much heterogeneity can use other targets and other atoms together to try to target all of that. So, I think, yeah, it’s probably quite a long discussion, but yeah.
Mike Morris, MD [00:37:20] It’s a hard question. Thanks so much, James.
James Buteau, MD, PhD [00:37:22] Thanks.
Mike Morris, MD [00:37:22] Great presentation.
Michael Hofman, MBBS [00:37:25] I think we’ll take one more question, and then we might move on to the next talk just in the interests of time.
Sumit Subudhi, MD, PhD [00:37:29] Alright James, excellent talk. Sumit Subudhi from MD Anderson. So, the question I have is, you know, chemotherapy, when we develop that, it’s always looking for the maximum tolerated dose and then moving forward with that. With radiation therapy, radioligand therapy, we know it can affect the tumor microenvironment. And so is maximum tolerative dose the best approach to choosing what we should move forward with.
James Buteau, MD, PhD [00:37:54] Yeah, I don’t know if we’ll actually hit an MTD, like you can probably go quite high and it’ll be very well tolerated. So, I think that you don’t, yeah, I don’t have a clear answer what’s going to be the best dose for this. It’s probably quite efficient. Even in those lower dose cohorts, it was reasonably efficient. Now we have a bigger expansion of 12 patients at 9.5, so I think that might help understand if there are any signals of a difference. And then seeing the late side effects. So, we know that it can cause some late renal toxicity in a very small number who get MDS, so it was about 1.3%. So, I think, yeah, how to use it at the lowest efficient dose.
Sumit Subudhi, MD, PhD [00:38:39] Well, I was thinking you could use on-treatment biopsies, because that’s what we’re doing with immunotherapy, to help see if we’re getting the biological activity that we want, right? Sometimes the maximum tolerate dose is not the best biological.
James Buteau, MD, PhD [00:38:53] And there might be other ways. We do have the advantage of SPECT, which is kind of an indirect biopsy. You can see how the tumor, the cancer is melting away. So perhaps we can even reduce those doses even more as treatment is responding. I don’t know. Yeah, Thank you.
Michael Hofman, MBBS [00:39:09] Thanks, James. We might move on to the next speaker. It’s going to be Professor Jason Lewis. He’s a professor of radiochemistry from Memorial Sloan Kettering, used to be the head of radiochemistry, but now he’s the deputy director of the whole of MSKCC, and he’s going talk to us about some of the data from his TACTICAL award, titled Novel Theranostic Agents for Neuroendocrine Prostate Cancer. Thank you, Jason.
Jason Lewis, PhD [00:39:41] Thank you, Mike. So unlike Mike’s amazing slides, my slides can’t match how good his look. But if my radio chemists were making a cake in a hot cell, it would be at least three tiers, not just one. But heaven forbid, we’re not competitive at all. So, one disclosure related to the talk is the fact that we do have some new DLL3 antibodies that we now have at MSK. This is the original team that was for the TACTICAL grant. And we’ve had two new additions in terms of sites, Yale University as well as Meng Zhang at Emory University. But the PCF support for this work through the TACTICAL has been immeasurable in terms of what we’ve learned about the disease and what we’re continuing to learn about the disease and what can learn about new targets and also how to exploit them. It all started off, now I know this is about prostate, I know it’s difficult to understand but there are other cancers than prostate. It all started off in small cell lung cancer Charlie Rudin. Who led a trial for small cell lung cancer using an ADC. The ADC was SC16. It failed phase three because the drug conjugate part of the antibody had terrible off-target toxicities. We, in the theranostics world, can repurpose the antibody without the ADC on, and we can turn it into an imaging agent and a therapeutic agent, as you’ve heard also previously, by switching out that isotope from an imaging agent to a therapeutic one. We started off by imaging with this antibody. The translational pathway was very straightforward. This is a case of small cell lung cancer where you can see all the disease is localized in the liver. Very soon after we started this, Misha published this superb paper. There was this. Okay, that’s where we are now. As we know that neuroendocrine prostate cancer is a growing disease. It’s because of the trans differentiation or potential treatment-induced trans differentiation of prostate adenocarcinoma. This disease is deadly. It is resistant to therapy. It has a survival of less than one year. And currently, there’s no FDA-approved agents for this, namely because the AR, the PSA, or the PSMA negativity of this disease. Misha, in her program in Boston, was able to do a rapid autopsy program where she showed beautifully that in the castrate-resistant prostate cancer neuroendocrine patients, that the time of death, the biopsy of the metastasis showed very large expression of DLL3 compared with the primary tumor. And of course, the same tissue is also AR-negative. So, we had in hand this antibody, SE16, that allows us to look at the expression of the DLL3. So, working with Yu Chen and his group, And the organoid models, the most obvious thing then was to see does this also work in NEPC models in mice, and it did beautifully. To Mike’s point earlier, getting to humans makes sense quickly because, of course, it looks good in the mouse because there’s no expression of DLL3 actually in a mouse. So, if you put a positive tumor in there, it’s going to light it up. The other advantage, of, course, with NEPC, even though it is a very aggressive disease, it is exceptionally resistant, sorry, is actually sensitive to radiation. So, if they then switch this out for lutetium with this antibody, we can get a complete and deep, durable response in all the mouse models we looked at, because the one thing that NEPC has going for it is its radio sensitivity. Because we already had this in patients, again, we support the PCF. We were then able to put this into our neuroendocrine prostate cancer patients. Here is one example. On the right-hand side is the FDG in the patient. On the left-hand is the DLL3 imaging agent, And you can see that there’s two metastasis there which have been lit up out of that entire population of disease that was highlighted by FDG. It’s not saying it’s missed anything, what it’s telling you out of the 70 plus metastases on the right-hand side, those two are the NEPC ones because there’s heterogeneity with the entire patient. But now we know where they are and now, they can be biopsied and another example here you can compare that the DLL3 picked out more in this patient than PSMA PET, but then we have option also to go and do an image kind of biopsy, get material. And in fact, prove that this was DLL3-positive disease. We know that there’s this heterogeneity present. We know, we’ve seen in many patients, they can have PSA-positive, negative legions, as well as DLL3-positives-negatives. Sometimes they both light up, sometimes they’re different. And of course, this is something that Misha, again, is looking at in terms of this heterogeneity that exists and trying to get a better handle on what we’re seeing, not just in animal models, but of course ultimately in patients. Now we have this at hand in tissues. Misha and Samir have also been looking at additional aspects of this. And they’ve been doing ASCL1 knockout and notch signaling activation and they’ve shown that suppresses the DLL3. I am a radiochemist, so bear with me as I try and attempt to talk about biology. But on the top left-hand corner, you can see that in the DLL3 low, which is also the ASCL1 low disease, in the Beltran cohort, the one thing that seems to be expressed in all of these is this KMT2C gene, not an easiest one to say, and on the right-hand side you can see that the DLL3 expression is there, in fact, in neuroendocrine in the violin plot, but the KMT2C expression is somewhat more homogeneous across all those different cohorts, allowing, again, this is perhaps another targetable gene that’s now going to be associated with DLL3 and allows additional therapeutics towards that. And what Meng has done is shown in a gene-wide CRISPR knockout screen, she’s identified both positive and negative regulators of DLL3 expression. And the important thing about this and how she separated this, you can see on the bottom plot on the left-hand side that from the DLL3 and DLL high expression, they are sorted into very two distinct groups. Those which have positive regulators of DLL3 are generally enriched in the transcription and translational regulation pathways, but those which have negative regulators of DLL3 are enriched in not signaling neuronal functions and microtubule regulation. So, this also allows another way to have targeted drugs, and she’s doing this right now, where she’s using drugs to hopefully enrich and increase the DLL3 expression, and if you’re going to target it, then that might give you more target to go for. The other thing also now that we’ve got this hand on DLL3, it’s not just getting an image, but it’s also doing other things with it, and one of the things that’s actually happening recently in our hands is its use in neuroendocrine neoplasms. It turns out that poorly differentiated neuroendocrine carcinomas in the esophagus, hepatobiliary, colorectal, and pancreatic also have an increase of DLL3 expression. So, this is a patient that again got the DLL3 image, but in this case, the patient had had, this was a gallbladder cancer, had already progressed in carboplatin, etoposide, so on and so forth, and was then given a T-cell engager for DLL3. And then was image post that with the DLL3 imaging agent, and you could still highlight up the tumors. So even though you’ve got a drug going in there targeting the DLL3, you can still image it, perhaps suggesting you haven’t put enough drug onto the target. So just because we’re now able to delineate this target, we can use it to see, is the drug hitting its target? Is it saturating its target, and is the target responding? So, I think that’s the next level of imaging we have to go to. And if it’s not gonna work with a T cell engager, like in this patient, then we need to think about doing lutetium. And this certainly has also been compared with things like Lutathera. Or NetSpot, should I say, that’s used in these same pancreatic neuroendocrine carcinomas. And you can see that it gives you very, again, distinct different images compared with the standard of care, NetSpot, in these tumors. We also want to make sure that if we’re spending time getting all this information on DLL3, there are also other diseases which are in desperate need of help. And one of those would be neuroblastoma. So, in an RNA sequencing cohort of 390 pediatric patients. It demonstrated very clearly in this neuroblastoma patient, there was also high expression of DLL3. And this patient here was a 21-year-old male who had had neuroblastoma for many years and had failed many, many diseases. And he was, again, compared to his imaging with MIB-SPECT. And you can see the superiority of the DLL3 PET compared with the MIBG SPECT, which is actually difficult to get now at high specific activity. And you can see that in his relapsed neuroblastoma that there’s a lot of bony diffuse metastasis. So, as we’re developing this new target, I guess DLL3 is kind of the flavor of the day right now, so it may not be as new as some others. It also shows you that once we have this and we have those drugs, whether they be T-cell engages or lutetium versions or terbium versions, that we actually have a whole cohort of patients that could potentially benefit from this target. We also have, though, run into the issue that the SC16 is owned by a company, and they’ve just buried it. They don’t want anything to do with it. So, we now have our own next generation of DLL3 targeting antibodies, and we’re working on minibodies and cisbodies now. Not much success. The main antibody is still the same. And this is one example here where the new antibodies, which we’re currently going through the translational pathway, in all our cases have actually shown superiority to the SC16. So, we actually think we have another antibody that is going to be really good to deploy in a situation that should hopefully improve both image quality and also response when we turn it into a lutetium or other radionuclide therapy. I was asked to give an update to the TACTICAL, but I also want to make sure that this isn’t the only target that’s an NEPC. So, a previous fellow of mine, Freddy Escorcia, and his team here have been looking at GP3 in neuroendocrine prostate cancer, and I had no idea there were these transitions because Freddy only sent me the slides yesterday. But the group at Duke first reported that GPC3 was in neuroendocrine prostate cancer. You can see in the right-hand side, one more transition, yeah, on the bottom right- hand side you can see the enrichment there of GPC3 is probably higher, at least in this cohort, than that of DLL3 in the neuroendocrine prostate population. Freddy and the group went on then to image this in mouse models of NEPC, showing superiority in terms of image quality, it lit up tumors extremely well. And then they then went on to do a series of therapeutic studies using actinium. And again, because of the radio sensitivity of neuroendocrine prostate cancer, got extremely profound and long durable responses with the actinium. I haven’t had a chance to chat with Freddy, but I think had he actually done with lutetium, he would have actually got the same response because of that sensitivity. So that’s basically a bit of a whirlwind there. I hope that I’ve caught us up on some time. And I just wanna say thank you to you for your attention and also to the funders for the money. Thank you to the team for the work and I’ll be happy to answer any questions. Thank you. And I have a slightly wrong slide deck, too, so I winged it a little bit, but that’s okay. I know, I was trying to catch this up, but nobody else has any questions. But if you have any biology questions, Misha is here, as is Zhang Meng, and they’d be both very happy to answer anything about the biology of these systems.
Michael Hofman, MBBS [00:51:14] Or if you have any terbium questions as well, follow on, feel free as well.
Jason Lewis, PhD [00:51:19] Thank you.
Michael Hofman, MBBS [00:51:24] We’ll move on to the last speaker in this session, and then we will have question time again. So, if you think of a question for Jason, please yell out. But I’m pleased to invite Professor Suzanne Lapi, who’s a radiochemist. She runs a cyclotron at the University of Alabama at Birmingham. We were discussing before, we call her the empress of radiochemistry. She’s played with just about every different radioisotope known to man that we could potentially use in humans. I think it’s the first time she’s been to a PCF scientific retreat. So welcome Suzanne and we’re very honored to have you here and learn about matched theranostic pairs.
Suzanne Lapi, PhD [00:52:18] So thank you very much for the kind introduction and the chance to say a little bit about new isotopes and match theranostic pairs. Just some disclosures. So, we’ve heard a lot about theranostics and we’re gonna talk a little about theranostics in chemistry. We’ve heard about different radio metals, there’s all kinds of new targets and there’s different vectors for theranostic applications. But we need to think a little bit about the coordination chemistry. Because we need to match the chemistry with the isotope that we’re actually attaching to the targeting agent. Because very small chemistry and these structural variations in the compounds can lead to pretty dramatic biology variations. And so, thinking about how can we customize transition metal or F-block metal isotopes to increase the efficacy of the tracer, in some cases we may be able to get elementally matched pairs. And so, I just show here. On the left-hand side, you can see a structure. This is a DOTA complex with gallium and with indium. And you can even though these are both plus three transition metals, the coordination structure is quite different. Just by changing the radio metal in a peptide, we can also see dramatic changes in binding affinity. And so, you can really get orders of magnitude differences in binding affinity simply by changing out the radio metal. So, at UAB we have a cyclotron facility and one of our main focuses is isotope production. And so, I show here a list of different isotopes. You can see they’re different transition metals or F block metals. And we’re basically trying to investigate making different radio metals that are useful for medical imaging by irradiating different target materials. So, I show here also an image of our cyclotron, affectionately called blue, and then the layout of our Cyclotron Facility. We distribute these different isotopes all over the world. We have multistate pharmacists, pharmacy, and manufacturing licenses that allow us to distribute these radiopharmaceuticals and radioisotopes into adjoining states and more and more worldwide into different countries. We have different certified shipping containers, and our staff is trained to distribute zirconium-89 and lead-203 and other isotopes throughout the country and internationally for clinical trials as well as for basic science. We’re also a member of the Department of Energy University Isotope Network and this is for distribution of cobalt-55, vanadium-48, manganese-52, and lead-203. And this means that if you’re ordering radioisotopes from the Department of Energy, you may get a box that says University of Alabama at Birmingham on it because we are a manufacturer for the Department Of Energy. So, one of the elementally matched theranostic pairs that’s been well studied is the copper 64-67 pair. And this is the idea that we can make elementally-matched or chemically identical compounds for imaging and therapy. So, copper 64 has a half-life of 12 hours. It’s a positron emitter and produced by radiation of nickel targets. It’s available from us, the University of Wisconsin, Washington Universities, and many other states. And routine production, we can do this pretty well. We can produce several curies. In one run, we irradiate 80 microamps on a 30-degree slanted target. And I just show here, this is actually what the targets look like. So, we’re radiating quite small target material. So, this is about 100 milligrams of nickel-64 that is electroplated on that gold backing that you see there on the left. Copper-67 has been around. It’s the elementally matched therapy pair for copper-64. It has a half-life of 2.6 days and is available through only a handful of suppliers. But that’s growing rapidly. There are multiple routes of production, but really the photonuclear route on zinc shows the most promise, and many of you may be familiar with the copper-67 SAR-bisPSMA trials that are ongoing now. But we’re interested in expanding the toolbox, and so another interesting elementally matched theranostic pair is lead-203 and lead-212. So, you heard a little bit about lead-212. It’s an emerging generator-produced alpha emitter. It has a very short half-life and really couples well with peptides and other small molecules. And I show the parent material and the generator concept on the left-hand side. Just to reiterate sort of the importance of the isotope, in the center I show some data from Mike Schultz’s Viewpoint pharmaceuticals that show the differences in bio-distribution with copper-64 as compared to lead-203. And so, on the left-hand side, you see at 24-hours the compound shows a tumor to kidney ratio of one and a tumor uptake of 8% ID per gram. The other graph shows the same compound, exactly the same compounds, same chelator, labeled with lead-203, showing a tumor-to-kidney ratio of six, tumor uptake of 12% ID per gram, and kidney uptake 2% ID per gram. So, if we’re going to think about using these compounds in a patient-specific fashion, we need to really think about how are we going to make imaging compounds that are really well matched with the therapy. And then I also just show some of you, that was mentioned before, the recent ESMO data just showing the efficacy of lead-212 targeted therapy. So how do we go about making lead-203? Okay, so it’s all fine and dandy, we want to make this new isotope. Firstly, we have to think about, well, what target material are we going to irradiate to make it? And we started thinking about using this thallium-205 p, 3n reaction to give you lead-203. This reaction is a nice reaction because we can electroplate thallium targets. This is what I’m showing here. So, we develop our own in-house electroplating system and show that we can electroplate this isotopically enriched thallium both on copper or gold backings. And this was actually published a few years ago in JNUC Med and was actually part of the thesis project of one of my graduate students. She went on to then develop a purification strategy. So, we have a two-column strategy where we’re dissolving those thallium target materials and then they go through two separate columns to give you lead as lead chloride. This took us several iterations. The initial stuff that we made actually was tested by our friends at Memorial Sloan Kettering and was shown not to be super reactive. So, it’s really an iterative approach trying to figure out how we get these isotopes in high purity so that we can actually do the radio labeling. And then we’re now expanding and scaling up our production. I show here the recovery of those two columns. So, we’re basically doing larger and larger batches. We’re now irradiating targets for eight hours, twice a week, to give about 300 millicurie batches every few days. We’ve done a lot with radiochemistry and imaging. And so, I show, here, just the SPECT imaging. We’ve heard a lot about the quality of PET images over SPECT images. When you think about doing dedicated SPECT imaging, especially if the isotope really matches well with your therapeutic isotope, you can get very high-quality SPECT images. And this was taken on our new state-of-the-art small animal SPECTs camera, basically showing that we can get resolution down to about one millimeter. And then now we’re supporting about four different clinical trials where we’re actually using lead-203 and trying to understand the pharmacokinetics of new lead-212 targeted radiopharmaceuticals. But what about the F block? This is the periodic table just as a reminder. So, I talk a lot about the transition metals in the middle that are kind of D block and P block. You know, we talk about lead and other isotopes, but a lot of the really cool stuff that we’re hearing today is all with chemistry on the bottom. So, we’ve heard about lutetium, of course, is sort of the mainstay of our targeted radio therapeutics. Actinium is really exciting. And then of course terbium-161, we just heard a great talk about that isotope as well. And so, thinking about how can we have imaging isotopes that are really similar to things that are in those F block. And so, if we look around at the PET imaging isotopes, there are some lanthanum isotopes that emit positrons, but they’re actually very difficult to produce and they’re quite short lived and hard to produce in high purity. There are two very nice PET isotopes. This is lanthanum-134 and praseodymium 140. They emit positron in a high branching ratio. But unfortunately, they have very short half-lives. So, you can see there, half-life of 6.5 minutes, half- life of 3.4 minutes. And so, if I say to my student, oh, take a target and go and irradiate it and do the separation and label some compounds and do animal studies with a half-live of six minutes, even our group that’s a little bit crazy is gonna say, well, that’s gonna be difficult. Fortunately, both of these isotopes have very nice parent isotopes that can be used for radiochemistry and kind of as an in vivo generator concept. So, for example, cerium-134 has been explored, has a 3.2-day half-life, and decays to lanthanum-134. And then we’ve been really looking at neodymium-140 that has a 3.4-day half-life and decays to praseodymium- 140. And so, this is this in vivo-generator concept where you can basically coordinate your long-lived parent isotope, attach it to your targeting vector. It goes where it wants to go, and then it emits this very short-lived daughter isotope that emits your imaging PET signal. And so, this in vivo generator concept has only been explored kind of relatively recently. So, we set about trying to make neodymium-140. It’s a nice nuclear reaction on praseodymium-141. This is a P2N reaction I show here. This is the cross-section or the probability of the reaction at different proton energies. And so, this is really well suited for our machine, which is about 24 MEV protons. Mangi Lal Godara started looking at, well, can we make this isotope and then how do we separate it from the praseodymium target material? And so, I show here, this is the solid target station. We simply could buy small pieces of praseodymium foils and put them in this tantalum backing. We irradiate them for several hours and then dissolve the praseodymium foil and then proceeded to do the separation. The separation is quite tricky because these are adjacent lanthanides. And so, the chemistry of the praseodymium is very similar to the chemistry of neodymium-140. Nevertheless, we were able to get reasonable separation with about 25% recovery and enough to start looking at the radiochemistry of the neodymium- 140. We’re starting to look at the different coordination chemistry, so looking at complexation to make compounds that are similar to the actinium compounds and other F block elements, so I just show here. We’re doing some studies with Macropa and with DOTA, and then also doing some phantom imaging in order to understand how far we can go with imaging of the neodymium-140. So that’s a little bit about what we’re working on these days. It’s a very exciting time to be a radiochemist and a molecular imaging scientist in this field. There’s a lot going on. So, they play an important role in medicine and many other areas of science. And really, if we think carefully, we have this wonderful variety of half-lives, different imaging characteristics, different chemistries that lead to this unique toolbox that lets us develop new nuclear medicine imaging and therapeutic agents. Of course, this is a collaborative activity. Development and use of these agents require collaborations between chemists, biologists, physicists, physicians, and technologists. We’re always welcome to new collaborations and visitors to our center. If I didn’t mention your favorite isotope, please come talk to me at one of the breaks and we’ll see what we can do. This is my acknowledgments and some of the data from our collaborative activity and then my wonderful group who does a lot of the work and I’m happy to take any questions. Thank you. Yes.
Adam Dicker, MD, PhD, FASTRO, FASCO [01:04:49] So, thank you, Adam Dicker, Jefferson. So presumably the reason to have these pairs is to have a higher signal to noise, as opposed to just imaging with the therapeutic at a much lower dose?
Suzanne Lapi, PhD [01:05:04] Absolutely, so the idea is to make an isotope that has better imaging characteristics than just imaging with SPECT post-therapy. The other thing that this lends us is a better capability to analyze the PK of those different compounds in pre-clinical models before we go and do the therapeutic.
Adam Dicker, MD, PhD, FASTRO, FASCO [01:05:21] And can you continue that thought that right now there’s this notion that your SUV uptake determines therapeutic efficacy?
Suzanne Lapi, PhD [01:05:33] Yeah.
Adam Dicker, MD, PhD, FASTRO, FASCO [01:05:34] So does that still hold?
Suzanne Lapi, PhD [01:05:36] So actually, we’ve shown that if you, the closer it matches, the better the therapeutic efficacy. And so, I think the better we can understand the distribution of the therapeutic, either pre-therapy administration or post, the better, we can understand that. And I think it also depends on the tumor type, the heterogeneity of the tumor, off-target uptake, and I could go on and on…
Adam Dicker, MD, PhD, FASTRO, FASCO [01:05:59] Thank you.
Suzanne Lapi, PhD [01:05:59] But I think the closer we can match, the better tools we have to understand that.
Felipe Eltit, PhD [01:06:09] Hello, I’m from Chile, and Chile is the largest producer of copper in the world, so I want you to use copper. My question is, in a chemical way, copper is the smallest atom of the ones you show, so logically you can fit more load in a smaller space and weight and volume. So, what’s the downside of copper in life? It seems to be the smaller, more stable nuclei, lighter.
Suzanne Lapi, PhD [01:06:37] It really depends on the chemistry of the targeted imaging agent. And so, in some of these cases, when we’re thinking about alpha therapy, copper doesn’t have an alpha emitter. So, if we’re, yeah, I know, if only nature had provided us with something better. I think it really depends on, you know, what therapeutic you’re trying to develop your targeting agent for and the paired imaging construct. But I love copper-64 and copper-67. Please try and work on ways to make higher amounts of copper-67, which I think is more of a problem.
Kenneth Pienta, MD [01:07:15] Great, great talk, thank you. For those of us who don’t understand any of this, could you explain when you need a generator versus a cyclotron and maybe how much that’s going to push our ability to give therapies in the future?
Suzanne Lapi, PhD [01:07:34] Absolutely. So, you know, it just really depends on the decay properties of your isotope and the best way to make it. So, we can make different isotopes on a cyclotron and some isotopes we can make with a cyclotron or with a generator. Just so happens that lead-212 is available through very, very, very long-lived parent isotopes so it makes more sense to get it from a generator it just, there’s sort of pathways that we can make these different isotopes and I think It also depends on the half-life because at some point, you know, logistics and getting the final product radiopharmaceutical with this nine hour half-life, you know to all your patients is gonna be the challenge.
Michael Hofman, MBBS [01:08:17] But there are three ways to make radioactive substances. Nuclear reactor, we forgot nuclear reactors. Generators and cyclotrons and…
Suzanne Lapi, PhD [01:08:27] And rotatrons, sorry, you know, and electron accelerators.
Speaker 10 [01:08:31] Hi, Leanne Burnham from Morehouse School of Medicine in Georgia. So hi, neighbor. And like Ken, this is also outside of my wheelhouse. But I was just thinking when you showed that slide of the international collaborations with Department of Energy, I saw there was so many great international collaborations, but it sort of skipped over the worst rates in the world, which is West Africa. I saw one collaborating center in South Africa. And I know the infrastructure has just got to be insane trying to set these things up in different parts of the world. But I’m wondering, I know Nigeria and Ghana have theranostic capabilities. Do you guys, is it possible for collaborations in that part of the?
Suzanne Lapi, PhD [01:09:08] Yeah, it is. And so really, we rely on people reaching out to us and wanting isotopes from us. And so, really, when somebody reaches out to the Department of Energy, there’s a cost involved. And so that may be a rate-limiting step for some people. But yeah, we’re happy to collaborate with most places. And we have had some discussions with Ghana before.
Unknown [01:09:30] This is a question for either Michael or for yourself. During James’s excellent talk, he talked about buying an Isotopia kit and then using that to make terbium-161. Could you say like this is a kit like a Betty Crocker cake mix kit? Like, how does this work?
Suzanne Lapi, PhD [01:09:43] So, I mean, the kit, I think he’s talking about the precursor, and so then you basically have the structure of the PSMA compound. You add in your terbium-161, zhuzh it around, and then you have your compound.
Unknown [01:09:55] And can average people do this, or is this?
Suzanne Lapi, PhD [01:09:58] Absolutely, so this is the same way that we make, and I don’t want to take away from James, this is same way we make gallium PSMA like at our institution is we have the generator, we literally elute the generator into the kit that has some chemicals in it and then we can go away.
Unknown [01:10:15] Thank you, that’s helpful.
Michael Hofman, MBBS [01:10:17] Time for one last question. Do we Howard? One last question.
Mike Morris, MD [01:10:24] Could you, with all of these really nice isotopes available where you can produce an image and treat so easily, can you explain to us the history that led us to go down the road to actinium, which seems to be none of those, in terms of ease of use, ease of production, et cetera. How do we get to where we are right now with so much drug development about something that’s so difficult?
Suzanne Lapi, PhD [01:10:52] Yeah, and I mean I think actinium came, like a lot of the push for actinium came out of the Department of Energy that really felt that they had some novel ways to move this forward, and that if we’re going to think about alpha emitters and alpha emitters that we can distribute, it really kind of met the bill. And so, I think that that’s why we have actinium. Unfortunately, the number of alpha emitters that are suitable for incorporation into targeted radiopharmaceuticals. There’s really only a handful. Even if you could magically make all the ones that exist, there’s not that many. And so, I think that’s kind of how we ended up getting here. But there is a long history, and I’m sure the Department of Energy and many industry colleagues have thoughts on how we got here. Yeah.
Mike Morris, MD [01:11:42] Thanks so much.
Michael Hofman, MBBS [01:11:44] Thank you so much, and thanks to all the speakers, and thanks to PCF Enterprise for really supporting theranostics over the last decade. I don’t think without PCF we would have got to the Pluvicto stage, so thank you to everyone for supporting this new science.