In 1991, Operation Desert Storm brought the first large-scale use of missile-type bombs that carried precision guidance systems, or “smart” bombs. Since these munitions could hit targets with great accuracy, collateral damage to civilians and civilian structures was greatly reduced. Now there is a new approach using smart bomb principles to treating metastatic prostate cancer (PCa) that no longer responds to hormones or chemotherapy.
Here are the key elements of this therapy:
- PSMA – Prostate-specific membrane antigen is a normal type of protein on the surface of prostate tissue cells, but it is up to 1000 times more present on PCa cells. Thus, PSMA on cancer cells is a prostate-cancer restricted “target”
- Monoclonal antibody – Monoclonal antibodies are components of the immune system. In this case, they can be engineered to carry a toxic “payload” such as a chemotherapy molecule or radioactive particle, and then bind with PSMA on PCa cells to deliver the “payload”
- Lutetium 177 (Lu-177) – A radioactive particle that can be “attached” to a compound that cancer cells preferentially like to take in (like a child who wants candy) or “attached” to a tailored monoclonal antibody.
Here’s how the PCa “smart” bomb works when Lu-177 is bonded with a monoclonal antibody. Let’s say a patient’s PCa has spread to his bones. Special types of nuclear imaging can reveal the metastatic bone tumors, or PCa bone mets. When an intravenous injection of the monoclonal antibodies that have been loaded with particles of Lu-177 begins to travel through the bloodstream, they have a “guidance system” that leads them to the PSMA on the bone mets tumors (and to any other active PCa metastasis that was too small for imaging to detect). The monoclonal antibodies are drawn to the PSMA, and when they find it, they attach to it. There, they become a kind of key that unlocks a door into the cancer cell. Once there, the radioactivity of the Lu-177 promptly begins to work on the cell’s DNA so it loses the ability to reproduce itself and dies off.
Why Lu-177 and not some other radioactive agent? Lu-177 has a short range of radioactivity so it does little damage to healthy tissues that are adjacent to the tumor. Also, it can be picked up on imaging, so its successful location in the target can be evaluated. Finally, it has a longer half-life (the time it takes to decay) so the tumor cells are exposed longer to its effects.
This type of treatment, called radioimmunotherapy (radioactive + immune system component) using Lu-177, is available in Europe. In the U.S., however, it is still in clinical trials. There have already been promising results from earlier trials. In one Phase II efficacy study of 47 patients, where the degree of success was measured by a drop in PSA, the authors reported the following observations after a single-dose treatment with Lu-177 bonded to monoclonal antibodies: “10.6% experienced ? 50% decline in PSA, 36.2% experienced ? 30% decline, and 59.6% experienced any PSA decline following their single treatment.”[i] In addition, the therapy appeared to add months of survival that patients might not have otherwise had.
Although radioimmunotherapy with Lu-177 labeled monoclonal (as it is technically called) is promising, it is not ready for prime time. The treatment itself has blood-related side effects that seem to resolve in a satisfactory manner with or without interventions such as transfusion. Patients whose imaging results are less favorable do not do as well with the treatment. Furthermore, a recent review of the published literature on Lu-177 (Emmett et all, 2017[ii]) points out that despite the lack of immediate significant symptoms at the time of treatment, “The main safety issues are standard radiation safety precautions that are inherent in all intravenously injected, renally [kidney] excreted radionuclide therapies.” These include carefully calibrated radiation dose, and varying periods of observation. Since the Lu-177 that will be excreted in urine is still radioactive, family members must be instructed on safety at home (radiation spill). The authors particularly note that despite the intense concentration of PSMA on PCa cells, PSMA is present elsewhere in the body:
PSMA is not entirely prostate specific and is expressed in other cells including the small intestine, proximal renal [kidney] tubules and salivary glands. This means that, although the expression of PSMA on these cells is significantly reduced compared to prostate cancer cells, there is a radiation dose delivered to these target organs when PSMA is used as a target for radionuclide therapy. This has an impact on both the side effect profile of PSMA?targeted therapy, and on the safe dose of radiotherapy that can be delivered to the patient without causing significant radiation damage to non?target organs.
We have much to learn as clinical trials progress. Lu-177 radioimmunotherapy is not being considered as a therapy for men with localized PCa, though some researchers are undoubtedly interested in the potential for “smart” bomb-type targeted therapies to be used against small foci of disease, including aggressive disease, still contained in the gland. For now, Lu-177 delivery systems are limited to PCa patients with metastatic disease that no longer responds to any other conventional therapy. Still, like so many other treatments in clinical trial, Lu-177 holds the hope of a brighter day for men with metastatic PCa.
[i] Tagawa ST, Milowsky MI, Morris M, Vallabhajosula S et al. Phase II study of Lutetium-177-labeled anti-prostate-specific membrane antigen monoclonal antibody J591 for metastatic castration-resistant prostate cancer. Clin Cancer Res. 2013 Sep 15;19(18):5182-91.
[ii] Emmett L, Willowson K, Violet J, Shin J et al. Lutetium 177 PSMA radionuclide therapy for men with prostate cancer: a review of the current literature and discussion of practical aspects of therapy. J Med Radiat Sci. 2017 Mar;64(1):52-60.