EFFORTS TO REDUCE SIDE EFFECTS
So, with all this published success, is there a downside to radioligands? Just like the use of magic in fairy tales – they come with a price. The radioligands target the salivary glands, where there is a small amount of PSMA produced. Beta particles such as Lu177, as used in the Novartis compound, generally cause only minor salivary gland toxicity. But, “since alpha particles are at least 1,000 times more potent than beta particles,” says Bander, “when you put the alpha particle on the ligand, it targets the salivary glands and the tear glands, and they get destroyed.” Now, you might be thinking, losing my salivary glands is a small price to pay for progress against prostate cancer. But Bander would suggest that you think very carefully about this. “When you destroy the salivary glands, the result is absence of saliva, a persistently dry mouth, inability to taste, difficulty swallowing, and tooth decay and loss. Affected patients report that it’s a pretty miserable existence. So that has proven to be a major impediment to using the small ligands to target the alpha particles: even though you can get promising tumor responses with the alpha particle, it can be intolerable for the patient.”
Is there any way to avoid the salivary gland toxicity? As it turns out, there is. “While the small molecule ligand targets the salivary and lacrimal (tear) glands, antibodies do not,” says Bander. “Antibodies are much larger molecules than the ligands.” With the small ligands, the radioisotope “can easily pass through normal tissue barriers. But, when you deliver the radioisotope by use of the antibody, we see no targeting of the salivary or lacrimal glands.”
In fact, “we recently completed a trial at Weill Cornell using our J591 antibody to target the alpha particle, Ac225. Based on an interim analysis, we have seen minor salivary gland toxicity in 6 of 27 patients, 5 of whom had previously been treated with the small ligand. We found that the antibody-targeted alpha particle was well tolerated and very effective against the prostate cancer, even in patients who had previously progressed after treatment with the ligand-Lu177.” This is a PCF-funded phase 1 trial.
Another key difference between the antibody and ligand: “The ligand is excreted from the body through the kidney and bladder,” says Bander, and there is a risk of kidney toxicity. “It has not yet been a significant problem, although there have been a few reports of kidney toxicity from the ligand with an alpha particle on it, and it may take a while to develop. With the antibody, the path of excretion is through the liver, so the kidney is less likely to be subject to damage from the alpha particle. The liver is pretty resistant to radiation.”
A COMPLEMENTARY APPROACH
So… no to alpha particle-labeled ligands, then? Not so fast, says Bander. “Here at Cornell, we have data that suggests the best way to target prostate cancer is actually using a dual-targeted combination of the antibody and the ligand. Our data show that with the dual-targeted combination, we can deliver a substantially higher dose to the tumor without increasing side effects.” This is due to the different ways that these targeting agents behave in the body. Dual targeting also allows us to use both the beta and the alpha emitters simultaneously, and our research shows this combination of alpha and beta isotopes to be very complementary. Ultimately, the dual-targeting approach, with both antibody and small ligand, provides a substantial increase in the dose to the tumor without additive toxicity. At Cornell, we are beginning to treat mCRPC patients with the ligand-Lu177 plus the antibody-Ac225. Our laboratory data and our understanding of the biology of how these agents interact suggests a substantial benefit to this dual targeting/dual isotope approach. The ability to substantially increase the dose to the tumor offers, I think, significant potential benefit for improved survival.”
25 YEARS OF PERSPECTIVE – AND COUNTING
This is what Bander envisioned 25 years ago, when he first began investigating PSMA. “It’s rewarding to finally see my expectations starting to reach fruition, and it’s going to get a lot better,” he says. At the 2019 ASCO international oncology meeting, a session on PSMA “filled a 4,000-seat auditorium. I was joking that a few years earlier, we could have had that meeting in my hotel room and there would have been room for housekeeping! It’s just like somebody flipped a switch. Leveraging the ability to target PSMA for imaging and treatment is in the process of dramatically changing everything about how we approach prostate cancer – it will change how patients are diagnosed, how they’re monitored and how they’re treated. If serial PSMA imaging can be shown to reflect tumor response, it has the potential to be used in the development of all prostate cancer drugs going forward to provide rapid insight into drug efficacy. That will make new drug development in this disease much more rapid and efficient. It’s a game-changer. I’m confident that the best is yet to come.”
Read the other parts in the Targeting PSMA series:
Part 1: Amazing Potential
Part 2: Making it Happen
Part 3: Dramatic Success
