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 almost 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 

 

Liquid Biopsies in Prostate Cancer: Ready for Prime Time?

Beltran and Lab
(From L to R) Dr. Himisha Beltran, Dr. Raymond Pastore and Dr. Bishoy Faltas

Recent studies in advanced prostate cancer have identified emerging treatment targets and mechanisms of treatment resistance. At the 2017 European Society of Medical Oncology (ESMO) Annual Meeting, Dr. Himisha Beltran chaired and moderated a session evaluating the use of liquid biopsies – blood tests used to glean information about tumors – as a useful clinical tool for prostate cancer management.

While there are no formal guidelines on who, when, how and what to test for in prostate cancer, Dr. Beltran’s expertise provided important guidance to the global oncology community on this topic, as the prospect that a blood test might reveal many insights about the cancer and the tumor makeup has led oncologists to feel excited. Several steps are still needed for broad clinical implementation.

As tumors grow, some of their cells may enter into the bloodstream. These cells are known as circulating tumor cells (CTCs) and travel throughout the body along with fragments of tumor cell DNA known as circulating tumor DNA (ctDNA). Compared with traditional biopsies which extract tissue directly from the tumor, liquid biopsies offer a less invasive way for doctors to detect molecular biomarkers and learn more about what’s going on with someone’s cancer. Liquid biopsies can also better capture tumor heterogeneity, as CTCs and ctDNA can provide a window into the entire tumor (and metastatic sites), compared with a traditional biopsy in which typically only one part of the tumor is sampled. Thus, with a simple blood test, doctors can potentially access a more comprehensive view of an individual’s cancer, which can then help them determine the best treatment for that person. Blood testing can also be more easily repeated throughout the course of treatment in order to monitor disease changes in response to therapy, so liquid biopsy offers ways to detect treatment resistance and resistance mutations early on and throughout the course of the disease.

Red Blood Cells

There is an emerging role for molecular testing in advanced prostate cancer since this information can better inform treatment decisions involving targeted therapies, such as PARP inhibitors, platinum-based chemotherapy, and immunotherapies. Liquid biopsies such as ctDNA may provide information about the genomic alterations present in the cancer, which can be used to help predict how people might respond to certain therapies.

Through liquid biopsies, physicians and researchers can also better detect signs of therapy resistance that may be emerging. For example, if a patient has a gene amplification or mutation detected in ctDNA that involves the androgen receptor (AR) gene, or AR splice variants expressed in CTCs, this may indicate that potent AR-targeted therapies may be less likely to work. This is because the cancer cells may develop various ways to reactivate androgen receptor signaling by acquiring extra copies of the AR gene (gene amplification), activating AR mutations, and/or AR splice variants (such as the AR-V7 variant), all of which result in downstream over-activity of the AR-pathway. Knowing this information up front may spare people from the side effects from a treatment likely to be ineffective. Current research is focused on developing more effective AR pathway inhibitors in this setting. CTCs may also identify other features of the cancer such as localization of the AR in response to taxanes as observed in the TAXYNERGY trial, tumor heterogeneity, and expression of emerging therapeutic targets.

Through a grant from the Prostate Cancer Foundation (PCF), Dr. Beltran and colleagues at WCM are working as part of an international consortium to develop, validate, and implement a ctDNA platform for prostate cancer. This targeted genomic sequencing test, called PCF SELECT, identifies tumor mutations in ctDNA from metastatic prostate cancer patients to guide treatment selection based on precision medicine. It is currently undergoing centralized development, and the long-term goal is that this ctDNA test will be widely used by the clinical prostate cancer community for precision medicine applications.

While liquid biopsies do have promise for these indications and can help guide decisions on the most appropriate treatments for prostate cancer patients, it is important that both patients and clinicians understand the advantages and limitations of available and emerging technologies. Undergoing treatment at a center of excellence that contributes to research on emerging trends allows individuals the opportunity to be among the first to access cutting-edge technologies that may benefit them.

 

ESMO 2017: Day 2 Recap

IMG_3948The second day of ESMO included the oral genitourinary (GU) oncology session that focused on renal cell (kidney) and urothelial (bladder) carcinoma.

Several years ago, the SWITCH study evaluated the sequence of sunitinib and sorafenib showing similar overall progression free survival and overall survival regardless of the order by which each drug was utilized. At ESMO 2017, results of the SWITCH-II trial were presented. This study tested the sequence of pazopanib and sorafenib in patients with advanced RCC of any histology (i.e. clear cell or non-clear cell).  The study sought to enroll 544 patients, but stopped after 377 patients due to slow accrual. Only half of the patients remained on study and switched to their assigned drug after tumor growth on drug #1. Overall, while the study didn’t complete planned accrual, there was a trend for improved progression-free and overall survival for the pazopanib → sorafenib sequence.

Historically when most patients were treated with cytokines (IL-2 and interferon), two randomized trials by U.S. and European cooperative groups showed that in the setting of metastatic kidney disease, patients live longer by first removing the kidney mass and then treating with interferon rather than treating with interferon without removal of the kidney. Since the introduction of new therapies in late 2005 which have higher rates of tumor shrinkage and longer lifespans for patients, it is unknown if patients should still have their kidney tumor removed prior to drug therapy.

IMG_3954In the EORTC 30073 SURTIME trial, European investigators decided to try to assess whether tumors remained under control longer and patients lived longer if surgery was performed first or if patients initiated sunitinib for 3 cycles prior to cytoreductive nephrectomy. Because enrollment was slow, the study design was changed to assess the percent of patients that were free of tumor progression at 28 weeks. Ninety-nine patients were randomized to immediate versus delayed surgery, most with large kidney tumors and intermediate-risk cancer. Overall there was no difference in the percent with cancer progression at 28 weeks with either approach.  With the caveat of a small study, there were trends for longer survival and less surgical complications in those with delayed surgery. While the amended study is not able to prove that delayed surgery is the better approach, it gives comfort for those physicians/patients that the choice to initiate medical therapy and then re-evaluate for surgery is acceptable. We await the results of the larger CARMENA study that is testing surgery followed by drug versus drug alone (with no surgery) to see if removal of the primary kidney tumor is necessary.

Additionally, two early-phase studies of novel drug combinations of immunotherapy + targeted therapy were presented. In a phase I study led by the NCI, the safety of the combinations of cabozantinib/nivolumab and cabozantinib/nivolumab/ipilimumab were tested in patients with a number of different treatment-refractory tumor types, especially urothelial and other types of bladder cancers. Overall, both combinations were deemed to be safe and are moving forward in a phase III trial. However, many toxicities did occur and most patients needed to reduce the dose of at least one drug so these combinations should only be used in a clinical trial setting.

IMG_3958The phase II portion of a phase I/II study testing the combination of lenvatinib + pembrolizumab. The initial (phase 1) portion of the study presented at ESMO 2016 determined the safe dose in patients with different types of tumors (mostly RCC). This year, new results were presented with 22 additional patients added to the 8 previously treated on the phase I portion. Overall, there was an impressive tumor response rate of 63%, with 83% significant tumor shrinkage in those patients treated in the 1st line setting. This combination is also being tested in a phase III study for patients with advanced RCC which will soon be opening at Weill Cornell Medicine and NewYork-Presbyterian.

Missed our Day 1 Recap of ESMO 2017? Check it out here.