Update in PSMA-Targeting for Imaging and Therapy

Prostate-specific membrane antigen (PSMA) is a protein concentrated on the surface of prostate cancer cells with limited expression on other locations in the body.  As covered previously on the blog, PSMA can be exploited for both imaging and treatment utilizing either large monoclonal antibodies or small molecule targeting agents

PSMA-targeting entails attaching a radionuclide (a particle that gives off radiation) to an antibody or small molecule designed to recognize and bind to PSMA. Research into PSMA-targeting has led to promising investigational treatments and transformed how we can detect prostate cancer. In December 2020, the U.S. Food and Drug Administration (FDA) gave limited approval for 68Ga-PSMA11 PET scans for patients with high-risk localized prostate cancer and patients with rising prostate specific antigen (PSA) levels following radiation or surgery. This form of FDA approval allowed for specific facilities in California to use this agent outside of the clinical trial environment. 68Ga-PSMA PET, which has been used elsewhere in the world without strict regulation, allows doctors to better detect recurrent and hidden prostate cancer and consequently, to choose the best type of therapy for each patient.

Weill Cornell has a dedicated team of physicians that study and interpret 68Ga-PSMA PET imaging. Numerous studies have demonstrated that 68Ga-PSMA PET is more effective than traditional scans (such as CT or MRI) in finding metastatic prostate cancer (sites where the cancer has spread elsewhere, including microscopically) and in a small head-to-head study was also better than 18F-fluciclovine (Axumin) PET/CT. There are a number of ongoing trials at Weill Cornell and elsewhere evaluating the use of PSMA targeted imaging, which currently remain the only way to obtain PSMA PET outside of California, with additional approvals of PSMA PET agents expected in the first half of 2021.

At the 2021 Genitourinary (GU) Cancers Symposium, researchers presented a head-to-head comparison of 68Ga-PSMA11 PET vs. MRI in detecting and staging localized prostate cancer (disease mainly confined within the prostate) in 74 patients. The two imaging methods had similar performance, with PSMA PET a little better for tumors outside of the prostate and MRI better for identifying tumor invasion of structures adjacent to the prostate. It may be that the combination of both methods will further enhance prostate cancer staging and a study is currently being done at WCM to evaluate this combination.

Additionally, a number of studies on PSMA-therapeutics were presented at the 2021 Genitourinary Cancers Symposium. There is an ongoing trial investigating PSMA-targeted radionuclide therapy (PSMA-TRT) with radioactive iodine in combination with the prostate cancer drug enzalutamide; radioactive iodine (Iodine-131) is conjugated to the small molecule 1095. An initial study of 10 patients receiving PSMA-directed/TGFβ-insensitive CAR-T cells (immune cells that have been engineered to recognize PSMA) demonstrated safety and efficacy. In this study, 60% of patients experienced PSA decline, ranging from 11.6 to 98.3%, and post-treatment biopsies demonstrated CAR-T cells infiltrating the tumor microenvironment. Furthermore, there is an ongoing clinical trial of a bispecific antibody (REGN5678) that connects PSMA with immune cells, which can subsequently destroy the cancer cell; this bispecific antibody is combined with a medication called cemiplimab that further strengthens the body’s immune response. 

There are multiple agents utilizing PSMA small molecules to carry the beta-emitting radionuclide lutetium-177 (177Lu) to PSMA-positive areas in the body (mostly areas of cancer spread). Updated results of a prospective head-to-head comparison of 177Lu-PSMA-617 vs. cabazitaxel (a type of chemotherapy) in 200 patients with advanced prostate cancer were presented at the 2021 Genitourinary Cancers Symposium.  In the data initially shared at ASCO 2020, the main objective was met, with more patients receiving 177Lu-PSMA-617 having PSA response compared to cabazitaxel chemotherapy.  In the updated report, patients receiving 177Lu-PSMA-617 had longer disease control (both by PSA measurements and scans), with fewer side effects and more improvements in quality-of-life. Recently, VISION, the multicenter phase III clinical trial comparing 177Lu-PSMA-617 + standard of care against standard of care alone in patients with advanced metastatic prostate cancer, has shown that patients receiving 177Lu-PSMA-617 lived longer and had longer disease control. Full results will be presented at an upcoming research conference, and we hope that this study leads to FDA approval in the future.

In general, tumors spread to other parts of the body via the bloodstream. The ability to capture these tumor cells, called circulating tumor cells (CTCs), has led to significant prognostic information along with the ability to study the cells as part of a “liquid biopsy”.  When a number of different types of therapy is able to decrease or clear CTCs from the circulation, those therapies generally make patients live longer.

Scans before and after treatment with PSMA-targeted radionuclide therapy (PSMA-TRT).

Weill Cornell researchers examined several sequential prospective clinical trials utilizing various PSMA-TRT agents. In an analysis of 116 patients, 70% treated with PSMA-TRT and with CTC counts before and after therapy had a decline in CTC counts. Some PSMA-targeting agents (i.e. the carrier molecules) may have anti-cancer effects on their own. While it appears that agents labeled with radioactive particles are more effective, some patients treated with anti-PSMA antibody J591 alone had control of CTC counts.

Alpha and beta-emitting radionuclides have different properties.  In 2020, we presented preliminary information at ASCO that a single dose of the potent alpha-emitter actinium-225 (225Ac) linked to antibody J591 (225Ac-J591) was safe, and despite lack of selection of patients with PSMA PET and prior 177Lu-PSMA therapy in the majority, 60% had PSA decline.

At the 2021 GU Cancers Symposium, investigators presented the design of WCM’s ongoing clinical trial investigating either fractionated (2) or multiple-dose (1-4 doses) of 225Ac-J591.  This study (NCT04506567) is one of many PSMA-targeted therapeutic clinical trials open at Weill Cornell Medicine and NewYork-Presbyterian Hospital.

Antibodies and Small Molecules: Two Different Tools to Target PSMA

Prostate-specific membrane antigen (PSMA) is a molecular marker present on the surface of virtually all prostate cancer cells. It can be targeted by different molecular agents that bind to PSMA. This enables a targeted approach to find and image or treat prostate cancer cells wherever they are in the body, including the cells that have escaped (metastasized) to other organs.

The most commonly used agents to target PSMA fall into two categories: small molecules (also known as peptides, ligands, or inhibitors) or antibodies (also termed monoclonal antibodies).

Small molecule- and antibody-based molecules that bind to PSMA have different physical characteristics and these have implications on the way the molecules circulate through the body.

For example, peptides and other small molecules that target PSMA are much smaller than antibodies – approximately 100-fold smaller. As a result of their small size, peptides are able to quickly travel through blood vessels and disperse throughout all body tissues – both normal and tumor – and they are also rapidly excreted by the kidney into the urine and bladder.

Conversely, the larger antibodies tend to stay within the circulating blood and flow more selectively through the larger, abnormal blood vessels within tumors than the vessels in normal tissues. Their large size also prevents them from being excreted by the kidneys. Because of these properties, peptides can penetrate tumors, as well as normal tissues, rapidly and then disappear from the body quickly, in minutes to hours; antibodies take longer to travel and enter the tumor, but this is compensated for by the longer amount of time they spend in the body (days to weeks) and their decreased likelihood to penetrate into normal tissues.

Imaging

From a diagnostic imaging perspective, small molecules are typically better, as the rapid excretion of the radiolabeled peptide quickly minimizes the radioactive background “noise” seen on a scan. Additionally, using small molecules means that patients can be injected with imaging agents and then undergo scans quickly thereafter (on the same day within 1-3 hours). Physicians can see good contrast of the cancerous cells compared to other parts of the body with this method. In comparison, patients must return approximately 3-8 days after infusion with a monoclonal antibody for scans. Some of the benefit of using small molecules is offset by the fact that they are excreted via the urine and accumulate in the urinary bladder. This may lead to an intense signal in the urinary bladder area of the scan, adjacent to the prostate gland and lymph nodes in the pelvis, thereby possibly obscuring these potential sites of tumor. On the other hand, some antibodies are taken up by the liver, obscuring visualization of that organ. Antibody fragments such as so-called “mini-bodies” (derived from the whole antibody), are half the size of a normal antibody, but still large enough so as not to be excreted in the urine, and as such, they may provide improved imaging of the prostate and the pelvic area. This is currently under investigation at Weill Cornell Medicine and NewYork-Presbyterian Hospital.

The nuances of these molecular targeting agents aside, it is clear that both peptide-, antibody or mini-body-based agents provide significantly improved targeted molecular imaging of prostate cancer compared with conventional modalities such as bone, CT, and MR scans and also have some advantages over glucose (FDG), sodium fluoride (bone), choline, or fluciclovine (FACBC) PET scans.

Treatment

From a therapeutic perspective, there are theoretical advantages to the faster tumor penetration of the smaller molecule targeting agents, but this may be offset by their quick disappearance and their ability to impact normal tissue. The longer time antibodies spend circulating in the body theoretically provides for a greater amount of the treatment agent to get internalized into the cancer cells, allowing greater uptake of the payload agent (such as a radionuclide) that is being delivered to kill the cancer cells. Additionally, some antibodies may also be engineered to generate an immune response.

Does uptake in different body areas lead to side effects?

The different characteristics of small molecules and antibodies confer advantages and disadvantages when targeting PSMA on cancer cells within the body. Because of their small size, small molecules/peptides can penetrate through the depths of the tumor very quickly, but they also readily target normal tissues that express low levels of PSMA such as the salivary glands, small intestine, and kidneys. When using as a therapeutic delivery vehicle, this might lead to dry mouth, nausea, or delayed kidney damage. Luckily, no significant kidney damage has been seen in humans to date, but the number of patients treated on prospective clinical trials remains small and follow up is short. An antibody, on the other hand, does not target salivary glands or kidneys because its larger size leads to relatively restricted access to those normal sites. However, it circulates in the body for a longer period of time including high flow through the bone marrow. Antibodies tagged with radioactive particles may therefore contribute to non-specific side effects such as temporary decreased blood counts. This is a common (expected) toxicity related to the dose and schedule of the radiolabeled antibody.

Currently, it is not known whether peptide-based or antibody-based targeted PSMA prostate cancer treatments provide better results, but both approaches offer therapeutic benefit to patients. At Weill Cornell Medicine and NewYork-Presbyterian Hospital – where we have two decades of experience pioneering prostate cancer imaging and treatment with PSMA-targeted agents – we are the only center in the world currently able to offer both types of imaging and treatment modalities and plan to combine both within individual patients. We hypothesize that will be able to use the favorable properties of each targeting agent at slightly lower than maximal doses to deliver a higher amount of therapeutic payload to tumor with less to normal organs, further improving the tumor kill : side effect ratio and have initiated a clinical trial testing this approach.


References

Phase I Trial of 177lutetium-Labeled J591, a Monoclonal Antibody to Prostate-Specific Membrane Antigen, in Patients with Androgen-Independent Prostate Cancer

Phase II Study of Lutetium-177-Labeled Anti-Prostate-Specific Membrane Antigen Monoclonal Antibody J591 for Metastatic Castration-Resistant Prostate Cancer 

 

Promising New Radioligand Treatment for Men with Metastatic Prostate Cancer Using Lutetium 177 (177Lu)

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Using small molecules, we are able to target not only the known tumors, but can also treat the unknown tumors.

Physicians and researchers at Weill Cornell Medicine have been utilizing prostate specific membrane antigen (PSMA)-directed radioisotope therapy for more than a decade. Over the years, we have shown that we could use this approach to target the vast majority of prostate cancer tumors (“hitting” essentially all known tumors and avoiding normal organs), demonstrated anti-tumor responses when the J591 antibody is linked to a radioactive particle with a large (single) treatment, and then further improved upon this treatment (while simultaneously reducing the side effects) by dose-fractionation (splitting the dose into two).

Following our lead and with the discovery of new small molecules which also specifically bind to PSMA, European physicians have begun using these compounds tagged with the same radioactive particle. The most common molecule has been termed PSMA-617. They have shown some very nice anti-tumor responses with limited side effects. However, because European laws differ from the U.S., many men are able to pay for treatment outside of the setting of rigorous, organized clinical research studies that clearly define appropriate dosing, efficacy and toxicity.

In January 2017, research was published in the Journal of Nuclear Medicine demonstrating that Lutetium 177 combined with PSMA-617 can reduce the amount of tumors in the body and lead to remission of the cancer as measured by PSA level. Twelve German hospitals reviewed their data and compiled a publication of patients with metastatic prostate cancer who received Lutetium-177 linked to PSMA-617 (177Lu-PSMA-617). Over 18 months, 145 men whose cancer grew despite standard treatments (including abiraterone and/or enzalutamide and chemotherapy) and whose tumors “lit up” on PSMA imaging were treated. While not a proper prospective research study, they were able to determine information about both anti-tumor activity and safety. Most patients who had PSA measured before and after treatment had some decline, with 40% having PSA cut at least in half following a single treatment. Blood counts dropped in less than half (usually to moderate degrees) and some developed dry mouth and/or taste changes. Severe toxicity was rare.

It is encouraging to see that there is a treatment that might lead to reduction in cancer without severe side effects, even in men who previously have received many other lines of treatment. However, both rigorous research as well as access for our patients are current issues. Therefore, we are excited to offer a clinical trial that builds upon our prior experience of anti-PSMA radioimmunotherapy while taking into account the available European data.

This study utilizes the most commonly used molecule, 177Lu-PSMA-617, in a prospective manner. Our prior research has shown that higher doses result in significantly better anti-tumor responses, so one purpose of this study is to perform dose-escalation to determine the safest and most-effective dose without increased side effects. In addition, our research demonstrated that dose-fractionation allowed higher doses with less toxicity, so our treatment schedule will deliver the total dose in 2 fractions.

We look forward to advancing science and also making these treatments available to men in the tri-state area and across the U.S., not just those who can afford to fly to Germany for treatment. At Weill Cornell Medicine and NewYork-Presbyterian, we have an excellent, multidisciplinary team that has led the world in PSMA-targeted radionuclide therapy. We will leverage our combined expertise and experience to translate the exciting knowledge base into true clinical gains for prostate cancer patients.

To learn more about the clinical trial or enroll, click here. Call us at 646-962-2072 to make an appointment or schedule a consultation.