PCF-funded investigator Neil Bander, M.D., Director of Urological Oncology Research at Weill Cornell and a pioneer in the study of PSMA (prostate-specific membrane antigen), developed an antibody that targets this molecule that sits on the surface of prostate cancer cells. He later characterized PSMA, and found many reasons why it is an excellent way to target prostate cancer. Results from work by Bander and others generated worldwide interest – particularly in Germany.
IN SELECT PATIENTS, RESULTS ARE ENCOURAGING
Bander made an antibody that targets PSMA and linked it to a radioisotope called lutetium-177 (Lu177), a beta emitter. With colleagues at Weill-Cornell, and with a nod from the FDA, in 2000, they began a series of prospectively designed clinical trials that showed excellent targeting of metastatic prostate cancers wherever the disease was located in the body. These treatments resulted in PSA declines and improvement of pain. At the time, however, the pharmaceutical industry was not interested in radioactive drugs and the prostate cancer field was more focused on the development of Taxotere chemotherapy.
In Germany, around 2013, physicians began using different agents, small molecules called ligands, instead of antibodies, that bind to PSMA. Some of these had been developed in the U.S. by John Babich, Ph.D. (then at Molecular Insight, Inc, now at Weill-Cornell) and Martin Pomper, M.D., Ph.D. at Johns Hopkins. The Germans tested Lu177 as well as a different radioisotope, actinium-225 (Ac225), an alpha emitter, says Bander. “Ac225 is several thousand times more potent than Lu177.” In Germany, a “compassionate use” program is frequently used to allow the use of new, previously untested therapies in patients who have exhausted all approved treatment options available. This means that, for a patient with a serious illness who understands and agrees to take the risk, doctors can try promising – but unproven – treatments outside of a formally designed clinical trial. “So, in Germany, they were able to give these radiolabeled ligands to patients on an ad hoc basis, not as part of a formally designed and specified treatment protocol. A number of centers in Germany began to make their own radiolabeled-ligands. They started treating patients and publishing the results, sometimes on just 1 or 2 patients, sometimes on small groups, sometimes on large retrospective series of patients,” in various nuclear medicine journals.
“The other thing they did,” Bander continues, “was, they would only treat patients whose cancers showed up well on PSMA-PET scans. They selected their patients, which helped them achieve high response rates.” A report of two patients treated with a PSMA ligand carrying Ac225, in particular, showed spectacular results. “To say they were dramatic would be an understatement. These two patients had already had their cancer progress despite treatment of every kind then available for prostate cancer. Everyone was blown away by those two cases.” The “before and after” images showed that widely metastatic cancer had completely disappeared. PSAs that were in the hundreds in one case or thousands in the other, became undetectable.
Those ligands became readily available in Germany, Austria, Australia, India, South Africa, and “other countries that have more liberal regulatory policies than the U.S.,” Bander says. “It generated an onslaught of publications, all showing excellent results. That’s what really ‘flipped the switch’ and got Big Pharma interested; among them, Novartis and Bayer.”
This provided a backdrop that ultimately led to the recently reported (at ASCO 2021) phase 3 trial of the ligand PSMA 617-Lu177, run by Novartis, that confirmed a significant delay in tumor progression and improved survival in patients with metastatic castrate-resistant prostate cancer.