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.

Targeting Prostate-Specific Membrane Antigen (PSMA)

Our team is at the forefront of utilizing prostate-specific membrane antigen (PSMA)-targeted therapies in the treatment of prostate cancer.

PSMA is a protein on the surface of prostate cancer cells that enables a targeted approach to locate and image or treat these cells wherever they are in the body, even those that have escaped (metastasized) to other organs. We are able to target PSMA using different types of drugs, including small molecules and antibodies.

Targeting Prostate-Specific Membrane Antigen (PSMA)

Learn more about how we use antibodies and small molecules to target PSMA.

For examples of our work in action, browse open prostate cancer clinical trials at Weill Cornell Medicine and NewYork-Presbyterian.

2018 in Review: Advancements and Accomplishments

From delivering exceptional care in the clinic, to presenting at scientific conferences and publishing research in high-impact medical journals, our Genitourinary (GU) Oncology Program had an exceptionally busy 2018. We continue to work diligently to develop new and more effective therapies to treat advanced prostate, bladder and kidney cancers, while educating the community about cutting-edge advancements in the field.

As we look back on 2018, we wish to share a brief update of our research and accomplishments. Here’s what our team has been up to over the past year.

New Faces
Most recently, we were proud to welcome Dr. Cora Sternberg, a global thought-leader in the GU oncology space, to our team. Dr. Sternberg will facilitate the continued growth and development of clinical and translational research programs in GU malignancies, as well as serve as Clinical Director of the Englander Institute for Precision Medicine (EIPM) to develop strategies to incorporate genomic sequencing and precision medicine within our Program and across Weill Cornell Medicine and NewYork-Presbyterian.


New Events
More than 200 prostate cancer patients and loved ones attended our inaugural New York City Prostate Cancer Summit, a multi-institutional collaboration between Weill Cornell Medicine, NewYork-Presbyterian Hospital, Columbia University Irving Medical Center and Memorial Sloan Kettering Cancer Center. This educational and advocacy event featured presentations and panel discussions from local medical experts and national advocacy leaders, with topics including nutrition, screening, coping and anxiety, immunotherapy and much more. Our second annual Summit is slated for September 2019 during Prostate Cancer Awareness Month. Stay tuned for details.


New Research Developments

Prostate Cancer

• Based upon our prior work with fractionated dosing of our radiolabeled antibody 177Lu-J591, we performed the world’s first phase 1 dose-escalation trial of 177Lu-PSMA-617 without finding any dose-limiting toxicity (no major side effects despite higher and higher doses), presenting the initial results at the European Society for Medical Oncology (ESMO) 2018 Congress. The phase II portion of the trial is ongoing. We are also leading the first trial combining two different targeting agents (J591 and PSMA-617) designed to deliver more radiation to tumors and less to other organs.

•  Alpha particles are several thousand-fold more potent than beta-emitters such as 177 Lu. We are completing the phase 1 dose-escalation portion of the world’s first-ever clinical trial utilizing a powerful alpha particle (225Ac) directed almost exclusively at prostate cancer cells by linking it with our J591 antibody, which avoids salivary glands.

• As prostate-specific membrane antigen (PSMA) targeting enters “prime time,” the United States Department of Defense (DOD) has recognized our significant contributions to this evolving field with a grant that will allow us to research optimal patient selection for PSMA-targeted radionuclide therapy and assess the treatment’s immune effects.

• Thanks to developing technology utilizing circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA), we are able to draw information about a patient’s tumor via a simple blood test. In our findings published by the American Association for Cancer Research (AACR) Clinical Cancer Research journal, we analyzed the relationship between chemotherapy treatment and expression of androgen receptor (AR) variants in CTCs of men with metastatic prostate cancer.

• We led a phase II clinical trial through the Prostate Cancer Clinical Trials Consortium (PCCTC) and discovered that an aggressive subset of disease called neuroendocrine prostate cancer (NEPC) is driven by a gene with an associated target known as aurora kinase. Further investigation into targeting of the gene may help us to refine therapy for this difficult-to-treat patient population. Our findings were published as a cover story in Clinical Cancer Research. 

• Working with collaborators and funded by the Prostate Cancer Foundation (PCF), we have developed unique genomics sequencing methodology called PCF SELECT that allows us to identify actionable mutations in men with advanced prostate cancer.

Kidney Cancer

• The number of United States Food and Drug Administration (FDA)-approved drugs for patients with advanced kidney cancer continues to grow. Dr. Ana Molina leads our team in offering clinical trials focused on novel targeted agents, combination treatments, and risk-directed therapies for various subtypes of kidney cancer.

• Working together with the Englander Institute for Precision Medicine, we are evaluating genetic signatures from patient tumor specimens and developing organoids that can be used to test novel pathways and tailor treatment to each individual patient.

• Laboratory studies of our in vivo kidney cancer models have resulted in discoveries regarding the metabolism of the disease. Understanding the role of the mitochondria (a cell’s power generator) in kidney cancer is leading us to novel therapeutic approaches to block tumors from growing and spreading.

Bladder Cancer

• Five immune therapies are now FDA-approved for people with advanced bladder cancer. We continue research to improve upon these agents by combining them with targeted therapeutics with the potential to replace chemotherapy. Collaboration with EIPM will help us to identify tumors most likely to benefit from these treatments.

• Dr. Bishoy Faltas and his lab team are focused on understanding the role of a specific family of proteins that cause mutations (genetic errors) that may be the underlying cause of bladder cancer. This research will enable us to develop new treatments to target the newly-identified genes that drive the disease.

• Based upon Dr. Faltas’ prior high-impact Nature Genetics publication that identified the genetic mechanisms by which bladder cancers become resistant to chemotherapy and new drug targets, we are launching an innovative new clinical trial utilizing a targeted drug that inhibits bladder cancer growth, the first time this type of drug is being tested in bladder cancer.

• We are conducting clinical trials of two antibody-drug conjugates (sacituzumab govitecan and enfortumab vedotin) designed to deliver potent chemotherapy-like toxins preferentially to cancer cells. This type of therapy is anticipated to become one of the standard approaches to bladder cancer treatment.

Precision Medicine

• Using samples of patient tumors (drawn via needle biopsy), we can create small 3-D tumor representations known as organoids that mimic the way that cancer cells grow within the body and respond to treatment. Our team has worked to develop this exciting new form of precision medicine, which is especially significant for rare cancers with a lack of preclinical models available for study.

We are moving closer to our ultimate goal of curing genitourinary cancers and look forward to continued progress in the years ahead.