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 

 

ESMO 2017: Day 1 Recap

ESMO LOGOThe 2017 European Society for Medical Oncology (ESMO) annual meeting has officially kicked off and our team has joined approximately 25,000 cancer researchers from around the world to present and discuss the latest cancer research.

Welcome to ESMO 2017_SignWe’ve outlined some key highlights from the first day of the conference below.

For men with newly diagnosed “hormone sensitive” high risk / advanced prostate cancer, several recent studies have changed the standard of care. Data from the CHAARTED, STAMPEDE, and LATITUDE studies that investigated the addition of docetaxel or abiraterone and low dose prednisone to standard androgen deprivation therapy (ADT) for men with advanced prostate cancer has led to significantly longer and better lives. Updates to this data were presented at ESMO 2017.

The STAMPEDE study included an overlapping period where some men were randomized to ADT + docetaxel chemotherapy and others were randomized to ADT + abiraterone/prednisone. It was comforting to know that whether men received either chemotherapy with docetaxel for 6 cycles or abiraterone and prednisone continuously for at least 2 years that they lived significantly longer compared to men receiving the old standard of ADT alone.

The interesting comparison presented at ESMO 2017 was that men who took abiraterone had longer time to cancer progression (mostly assessed by rising PSA). There were similar overall survival outcomes with either initial treatment strategy. As expected, the types of side effects were different depending upon the type of treatment, but severe toxicity was equally common with either type of treatment.

For the first time, “patient reported outcomes” assessing symptoms and quality of life on the LATITUDE study (including men with high-risk metastatic disease treated with ADT + abiraterone/prednisone or ADT + placebos) were presented. In addition to living significantly longer and having major delays in cancer growth, men taking ADT + abiraterone/prednisone had better pain control and were less likely to have reductions in quality of life, particularly after the initial 4 months on treatment.

Prostate-specific membrane antigen (PSMA) is a protein that is on the cell surface of most prostate cancers and can be used as a treatment target since it is not present many other places in the body. At Weill Cornell Medicine and NewYork-Presbyterian, we have been targeting this protein with radioactive particles for more than a decade. Other institutions have also more recently begun using this approach. Over the past several years, there have been many patients receiving this type of therapy in Europe who may have benefitted from this treatment, but no real prospective clinical trials have been performed. Australian researchers presented data at ESMO in which they enrolled and treated 30 men whose tumors “lit up” on PSMA-PET scans with 177Lu-PSMA-617 in a clinical trial. Patients received up to 4 cycles of therapy. Most patients experienced a significant decrease in PSA, some had tumors shrink on scans, and severe side effects were limited.

We have previously published on the (initially) surprisingly high frequency of inherited “germline” alterations in men with advanced prostate cancer. A Spanish group performed a prospective study of 419 men and found that about 9% had alterations in genes that affect the body’s ability to repair damaged DNA. Among the 6.2% with the most common alterations – BRCA2, ATM, and BRCA1  — overall survival was not significantly shorter compared to men without these genetic mutations. However, when examining just the most common BRCA2 gene, men did not live as long. Whether or not these inherited DNA alterations were present, men could respond to approved therapeutic agents, so if clinical trials are not available men should be encouraged to take standard hormonal or chemotherapy.

ASCO 2017: Genitourinary (GU) Oncology Highlights

ASCO Logo PhotoEach year, the American Society of Clinical Oncology (ASCO) Annual Meeting brings together more than 30,000 oncology professionals. At this year’s meeting in Chicago, physicians and scientists presented the latest research findings in an effort to bring the best cancer treatments to patients across the United States and the world. We’ve outlined some of the genitourinary (GU) oncology highlights, broken down by disease type.

At this year’s meeting, there was also some important research presented related to communication, quality of life and survival. In a study that involved patients with GU cancers, as well as those with other types of tumors, patients were randomized to two groups: 1) a control group of standard care 2) a group to utilize a web-based patient-reported outcome questionnaire between visits. Results from any answers completed in the online system were sent to the treatment team in real time. In this study, the patients that were randomized to the online questionnaire group experienced better quality of life. In addition, these patients lived longer, with a 17% improvement in survival simply by using the online tracker reporting symptoms to their treatment team between visits. While the study was only conducted at a single institution, it underscores the importance of communicating and relaying any symptoms to your treatment team members responsible for your medical care (generally physicians, nurses and advanced practitioners).

Prostate Cancer:

The results from two large phase 3 clinical trials will lead to a change in the standard of care treatment for men with advanced prostate cancer. The LATITUDE and STAMPEDE trials investigated the addition of abiraterone and low dose prednisone to standard androgen deprivation therapy (ADT) for men with advanced prostate cancer. Similar to the unprecedented results presented at ASCO in 2014 (CHAARTED) and 2015 (STAMPEDE) with the use of docetaxel chemotherapy, a major improvement in overall survival was demonstrated, improving length of life by nearly 40%. The results from these studies will provide an additional treatment option for men presenting with advanced prostate cancer.

For men with metastatic castration-resistant prostate cancer (mCRPC), a randomized phase 2 trial demonstrated no significant differences in the efficacy, or effectiveness, of abiraterone or enzalutamide, two of the leading treatments for prostate cancer that is resistant to hormonal therapy. This research finding was consistent with most clinicians’ belief that either drug may be utilized, allowing physician and patient choice. Importantly, the study incorporated a number of interesting biomarkers using circulating tumor cell (CTC) DNA from a liquid biopsy, and the data gleaned from the DNA revealed prognostic insights about disease aggressiveness and biology. Another study showed a lack of utility to continue enzalutamide after disease progression, confirming the current practice of switching treatments after cancer growth.

Interesting data using the PARP inhibitor veliparib was presented. In a randomized phase 2 trial, the combination of veliparib and abiraterone was not better than abiraterone alone overall, but for tumors with DNA damage repair defects, there was a difference. This adds to the anticipation of results from the many ongoing randomized trials that are testing PARP inhibitors in molecularly selected patients.

Additional data was presented on genomic signatures from prostate tissue, which in combination with clinical data, are more powerful in indicating prognosis in men who receive treatment for clinically localized (low stage / early) prostate cancer.

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Dr. Himisha Beltran

Prostate cancer acquires resistance to systemic treatment as a result of tumor evolution and selection, but repeat biopsies to study how cancers evolve are challenging, invasive, and may be confounded by tumor heterogeneity. Dr. Himisha Beltran evaluated a non-invasive approach: whole exome sequencing of circulating tumor DNA in the blood. Additional data utilizing circulating tumor cell (CTC) counts as an early indicator of response may speed drug development. Clinical trials are currently evaluating measuring circulating tumor cell counts as a biomarker for whether or not treatments are working. This may be a better indicator than measuring levels of prostate specific antigen (PSA), the current indicator for response.

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Dr. Scott Tagawa presents an update on the 177Lu-PSMA-617 clinical trial for men with metastatic prostate cancer.

Dr. Scott Tagawa presented a trial-in-progress update about the clinical trial he is leading at Weill Cornell Medicine and NewYork-Presbyterian utilizing the small molecule lutetium 177Lu-PSMA-617 to target prostate-specific membrane antigen (PSMA). PSMA is a protein abundantly expressed in 85-90 percent of metastatic prostate cancer cells, and this is the first U.S. trial of its kind. Learn more about this radionuclide therapy-based clinical trial and the eligibility criteria.

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Dr. Loredana Puca

Additionally, there were many research updates presented in the area of neuroendocrine prostate cancer (NEPC), an aggressive subtype of prostate cancer that is resistant to many traditional treatment types. Dr. Loredana Puca received a Merit Award from the Conquer Cancer Foundation for her research examining the potential use of antibody-drug conjugate rovalpituzumab tesirine for treatment of NEPC. View the abstract and learn more about our open clinical trial using this antibody-drug conjugate. Dr. Himisha Beltran highlighted the significance of the loss of tumor suppressor ZFP36 in prostate cancer patients.

Prostate cancer was the first tumor type to have a cancer vaccine (sipuleucel-T) lead to longer survival, but the drug’s activity may be limited on its own. In a randomized phase 2 trial, receiving sipuleucel-T in combination with indoximod – a drug with the potential to improve immune response – kept the cancer at bay more than twice as long compared to those who received sipuleucel-T plus a placebo. This was an exciting research update showing promise for patients with prostate cancer.

New research using tumor and liquid (blood-based) biopsies demonstrated that a majority of tumors and circulating tumor cells in men with metastatic castration-resistant prostate cancer express a protein called Trop-2, justifying a targeted treatment approach. With this knowledge, we are now evaluating the safety and efficacy of IMMU-132, an immunotherapy-based drug that targets Trop-2, in an open clinical trial for men with prostate cancer.

Bladder Cancer and Other Urothelial Cancers:

ASCO_Bishoy Faltas_Talk
Dr. Bishoy Faltas presents on “Unlocking the Genome: Insights Into Risk and Response in Bladder Cancer” at the ASCO 2017 Clinical Science Symposium.

Dr. Bishoy Faltas was invited to present at the ASCO Clinical Science Symposium entitled “Expanding the Actionable Landscape: Bladder Cancer Genomics — Unlocking the Genome: Insights Into Risk and Response in Bladder Cancer.”

During this session, Dr. Faltas discussed the genomics of urothelial cancer, and highlighted the latest research describing new data on the frequency of inherited (germline) mutations as well as tumor (somatic) genomics and relationship to response to chemotherapy and immunotherapy. Patients with “upper tract” urothelial cancer (tumors arising in the kidney or ureter) in particular have a higher chance of harboring an inherited mutation. Different genomic alterations in the tumors may be separated into groups that are associated with better responses to chemotherapy and immunotherapy. This is becoming more clinically relevant as we can test for these genes and the number of treatment options is expanding.

Additionally, updated results of the KEYNOTE-045 study confirmed the overall survival benefit of the anti-PD1 immune checkpoint inhibitor pembrolizumab (Keytruda) compared to second-line chemotherapy in patients with prior platinum-based chemotherapy. Importantly, this was the first head-to-head trial to demonstrate the superiority of immunotherapy over chemotherapy in urothelial cancer.

Dr. Scott Tagawa contributed to the investigation of a novel oral targeted chemotherapeutic agent called RX-3117 in advanced bladder cancer patients. Learn more about our open clinical trial with RX-3117.

Kidney Cancer (Renal Cell Carcinoma):

Several different combination studies for the treatment of advanced renal cell carcinoma (RCC) were presented at the 2017 ASCO Annual Meeting. While some studies demonstrated promising response data, significant toxicity of some combinations underscored the importance of clinical trials and the recommendation to avoid combinations outside of the research setting, which is regulated and in which these types of side effects can be monitored. Several randomized phase III trials testing combination therapy are ongoing with results anticipated to lead to changes in standard of care.

Unfortunately, despite imaging that indicates no evidence of cancer metastases (spread), many patients are not cured with surgery alone. Treatment of many cancers incorporate the use of systemic (medical) therapy in addition to surgery to increase cure rates. For the most part, this strategy has not been overwhelmingly successful in the setting of renal cell carcinoma (RCC). Unfortunately, another “negative” phase III trial showed that the addition of pazopanib (Votrient) to surgery did not improve cure rates for patients with RCC. Additional data was presented utilizing either clinical or genomic biomarkers that may assist physicians in choosing patients that might benefit from the addition of the oral drugs following surgery. We continue to await the results of additional completed studies and some currently enrolling studies utilizing immunotherapy before/after surgery.