In an interview with Targeted Oncology, Naomi Haas, MD, discussed the role of PSMA in the treatment landscape of prostate cancer and highlighted the key findings from the phase 1 chimeric antigen receptor T-cell trial in metastatic castration resistance prostate cancer.
PSMA is an antigen expressed on the cell surface, which makes it a good target for treatment in prostate cancer, as well as renal cell carcinoma and other cancer types, but it is commonly overexpressed as castrate resistance emerges in men with prostate cancer. PSMA expression, for that reason, is more commonly observed in castration-resistant prostate cancer (CRPC), an area in which several new targeted therapies are being explored.
Some of the latest PSMA-targeted approaches under development in prostate cancer include bispecific T-cell engager (BiTE) antibodies, chimeric antigen receptor (CAR) T cells, and the lutetium studies. These are each at different stages in clinical development but appear hopeful for the treatment of this patient population. BiTE therapies can be used as repeated dosing, and they can be generated without having to make them specific. CAR T-cell therapy, on the other hand, requires waiting for the cells to expand before giving an infusion to the patient, while lutetium appears to allow for repeat dosing in select data.
All 3 remain in clinical development, but notably, the phase 3 trial of PSMA lutetium, known as the VISION study (NCT03511664), is the closest to reading out among these different clinical trials and treatment approaches. At the 27th Annual Prostate Cancer Foundation Scientific Retreat, results from a first-in-human phase 1 study were presented, which demonstrated the CART-PSMA-TGFβRd as adoptive CAR T-cell therapy as treatment of patients with metastatic CRPC was safe and feasible in combination with lymphodepleting (LD) chemotherapy.
In an interview with Targeted Oncology, Naomi Haas, MD, director, Prostate and Kidney Cancer Program, associate professor, Medicine, Hospital of the University of Pennsylvania, discussed the role of PSMA in the treatment landscape of prostate cancer and highlighted the key findings from the phase 1 CAR T cell trial in metastatic CRPC.
TARGETED ONCOLOGY: Why is PSMA such a target of interest in prostate cancer and how common is high PSMA expression in prostate cancer?
Haas: PSMA is important because first of all, it's an antigen that is expressed on the cell surface, and so for that reason, it's a good target in general, not even just for prostate cancer, but for perhaps other cancers. It's present in the neovascularization in, a variety of different cancers. In prostate cancer, it's interesting because there is overexpression of PSMA as castrate resistance emerges, so we see more PSMA expression in patients that have CRPC, as opposed to patients who have prostate cancer a little bit earlier on.
TARGETED ONCOLOGY: Why is PSMA used in the detection of disease and what makes it more or less effective?
Haas: It's pretty widely expressed in prostate tissue in cancer, and it isn't very well expressed in normal prostate or in normal tissue, so for that reason, it's a good target because you can go after it and perhaps not have as much concern about toxicity. That's 1 reason. In normal tissue, in brain cells, it's part of the neurotransmission of things, and in intestinal tissue, it helps with folate transfer. People aren't sure what its function is in prostate tissue, but be it as it may, because it's something that is very highly expressed in prostate cancer, that's where the interest arose.
TARGETED ONCOLOGY: What PMA-targeted treatments are currently in development?
Haas: In addition to prostate cancer, it's expressed in a variety of tumors, so for renal cell carcinoma, there is a bunch of PSMA imaging studies going on for clear cell renal cell. It's expressed in adenoid cystic cancer, which is like salivary duct cancer. There's evidence to some extent in breast cancer, in bladder cancer, and in non-small cell lung cancer. If you do literature searches, there's all sorts of research going on in different cancers. As far as where CAR Ts are under development, I think it's very much in the early stages for anything other than prostate cancer, but PSMA, as you know, is also being developed as BiTE therapies, and also in the PSMA lutetium studies, which are much farther ahead. What we have to do is get the imaging studies caught up with the therapeutic studies because I think if we were able to do more of those, then we could look a little bit more closely at the efficacy of any of these therapies.
TARGETED ONCOLOGY: Could you elaborate more on these therapies?
Haas: For the BiTE therapies, there are several studies ongoing. One difference in the BiTE therapies is you can you do repeated dosing, and that can be an advantage or a disadvantage. I think an advantage of the BiTE therapy is that you can generate these, and you don't have to make them specific.
The CART trials are patient-specific, so to make a CART, you have to do an apheresis on an individual patient and remove the T cells, then you have to infect the T cells with the lentivirus. You have to wait for the cells to expand, and then you can give that back as an infusion. For the BiTE therapies, they're generated more synthetically. For lutetium, they're tagged into a radioisotope, so those are the differences.
Lutetium is sort of in between because there's a little bit of data now looking at a second set of repeat dosing. Generally the spectrum is sort of CART where you think of 1 dose or maybe a second retreatment dose, the lutetium where you think 2 to 4 doses, and the BiTE therapy, in which the idea is that you might be able to give that a little bit more chronically to patients.
TARGETED ONCOLOGY: What clinical trials are ongoing in this area that are of interest right now?
Haas: The VISION trial, which was a PSMA lutetium trial, was a big phase 3 trial that I think is close to reading out, and that's probably the closest to, if that reads out in a good way, you know, then you might see that FDA approved. The BiTE therapies are still fairly early on, and BiTEs are obviously something that people aren't just doing with PSMA; they're doing it with immunotherapies and others. The CART trials are still very early on. As you know, City of Hope has 1 with stem cell antigen; we have the PSMA, and then there are another 3 CART trials in China that are also under development.
They're interesting targets because they're novel, they're not chemotherapy, they're not second-generation androgen inhibitor therapies., but I think that prostate cancer is another field where it's surprising how few therapies or kind of different directions we're going to have therapies for prostate cancer. With some of the gene fusions that have been identified, I'm surprised that there aren't targets for example being developed or maybe there are, but they're just not out there yet. We still have a long way to go with prostate cancer.
Prostate cancer remains challenging. It's behind. It's behind a lot of the other cancers because it's one where we've, until recently, have only been evaluating people with evaluable disease, and the bone microenvironment I think is still very much a challenge and prostate cancer.
TARGETED ONCOLOGY: Could you provide an overview of your presentation?
Haas: Previously there was a PSMA alone CART that was looked at Memorial Sloan Kettering, and what's novel about ours is that we have made it a PSMA CART that has a dominant negative TGFβ receptor. So why would we do that? Well, we did that because what's apparent in prostate cancer metastasis is there's a lot of infiltrates of lymphocytes, and when you characterize those, you can see that there is a strongexpression of transforming growth factor beta. Initially, this is a tumor suppressor gene, but as disease progresses, what TGFβ does is sort of fuels progression and also epithelial mesenchymal D differentiation. By adding a dominant negative there, what we're trying to do is to first bring the bring the PSMA CART closer to a more specific target, but also, using the dominant negative allows the CART to better expand.
What we did is this was a first-in-human trial in which we enrolled patients who had CRPC who had previously had at least 1 anti-androgen, so they had to have had either enzalutamide or apalutamide or abiraterone. In this trial, we required them to have a biopsy that showed PSMA expression at least 10%. We looked at several dose levels, and we started at a dose level of 1 to 3 x 10^7, which was the lower dose based on the acute leukemia trials, most of which of used 10^8. We knew that we wanted to start at a dose that was slightly lower to establish feasibility, so it was a 3 x 3 dose-escalation model. We didn't see any toxicities in the first dose level, so we only enrolled 3 patients to that level, then the second dose level looked at a tenfold higher increase, so that was 1 to 3 x 10^8 m^2 dosing alone. We treated 3 patients at that dose level and also didn't see a dose limiting toxicity, so at that point, we did a third dose level. This dose level was starting with a lymphodepletion regimen, which had also been shown to be important in the leukemia models with patients with acute leukemia. These patients were treated with 3 days of cytoxan and fludarabine to lymphodeplete their marrow, and then about 2 to 3 days later, they had an infusion. At that, we used 1 to 3 x 10^8 in that cohort.
The first patient that we treated in that cohort had pretty substantial toxicity. He had cytokine release syndrome (CRS), which was prolonged even with administration of anti-IL6 receptor antibodies and required blood pressure support for a prolonged period. Although he recovered from the CRS, he ended up with multiorgan failure and ultimately sepsis and passed away. We reconvened after that and decided that we did not want to pursue treating any other patients at that dose level. We backed down to the 1 to 3 times 10^7 dose level with the lymphodepletion regimen. We enrolled patients in that level, and I would say that what was interesting about the patient in the dose 3 cohort is that patient's PSA decreased dramatically and stayed down. His cytokine expansion was very much in the same pattern and level of expansion that had been seen in the leukemia population.
When we went to the dose minus 3 cohort, we treated these patients, and they did have some CRS but not as severe. We did continue to see declines in the PSA in this population, although it was not prolonged. We're continuing to finish that cohort. We have 3 more patients to treat in that cohort, but we're continuing to see decreases in PSA. What we've seen is stable disease as response.
The other thing that I show on the slides is that we did a quantitative PCR of CART expansion, and we did see very high CART expansion with the dose 3 cohort, and then in the minus 3, we also saw impressive expansion, although not as high as what we saw with the highest dose cohort, cohort 3. Our conclusions are that the quantitative PCR and the cytokine expression are very important and go along with CART activity. We think those are good surrogates for what you want to see in a CART. We think it's feasible.
I do think that 2 things that we're still struggling with are how to get a more durable persistence and expansion in an older patient population, where we don't want it to be too toxic. One of the other approaches, for example, is to try to do kind of fractionated dosing, and so they're at a dose level right now where they're using that 1-3 x 108 dosing, but they're giving a fraction of 70% and 30% to see if you split the dose over a period of a couple days, is that a little bit better tolerated? Other approaches people are thinking about or are using include immune checkpoint inhibitors following the CART. That's been looked at in leukemia. Another approach is giving the CART at an earlier stage of disease. There may be reason to also add in other targets because there may be evidence that with this approach that there's still escape after the initial target.
TARGETED ONCOLOGY: What do you hope attendees take away from this?
Haas: I hope that they take away that this is an approach that should continue to be explored in prostate cancer, as well as in other solid tumors, and that it is going to be more challenging because the tumor microenvironment with the stromal environment and stuff provides an additional challenge that you don't see in leukemia trials. However, I think that we're encouraged, and I think that there's still a very much an unmet need in prostate cancer to have immunotherapy trials that a patient could get in and could ultimately allow them to not continue to have to keep getting treatments.