Lutetium 177 Radioimmunotherapy Clinical Trial Open for Men with Rising PSA Levels

We have an open clinical trial using radioimmunotherapy for men who have been diagnosed with prostate cancer, and whose PSAs are rising despite initial hormonal therapy but have no evidence of metastatic disease on scans (no tumors seen on CT/MRI and bone scan). This clinical trial is investigating whether attaching Lutetium 177 with the monoclonal antibody J591 (177Lu-J591) can delay or prevent the disease progression to overt metastatic disease in men with “biochemical progression”.

J591 can recognize a protein antigen known as PSMA (also known as anti-prostate-specific membrane antigen) that is present on the surface of nearly all prostate cancer tumors and circulating tumor cells.

The targeted treatment in this trial uses J591 as a delivery vehicle for the radioactive treatment (Lutetium 177) to be delivered directly to the prostate cancer cells that may be hiding or circulating in the body (for example in lymph nodes, the blood stream or the bones).

The Lutetium 177-J591 treatment approach may be ideal for men who are experiencing rising PSA levels after primary prostate cancer treatment and early hormonal therapy, but whose bone and CT scans remain negative. Even though we can’t detect the presence of cancer on these traditional imaging scans, we know from prior research that these men have what we call “micro-metastatic” disease, meaning that the prostate cancer cells are increasing throughout the body because otherwise PSA levels would not be so high or increasing at such a rapid rate. Unfortunately, even with traditional hormonal manipulation, metastases become evident in these men after months. Although we have treated many men with overt metastatic prostate cancer and demonstrated anti-tumor responses, we have also shown that we are able to target these micro-metastatic sites (tumors that are too small to be seen on CT or bone scan), and the properties of 177-Lu make it more optimal for tumors that are too small to be seen on conventional imaging.

Many patients fall in this category in a broad sense and usually these men feel completely fine. Approximately 50,000 new men per year in the U.S. suffer a biochemical relapse (rising PSA after surgery or radiation) and some of these men will have further PSA rises despite the most common type or hormonal therapy, which are injections to bring down testosterone levels. The goal is to intervene earlier on in order to bring more men to cure and suppress the disease from further progression and metastases.

Men in this phase II study will be randomized and all patients will receive oral hormonal therapy as part of treatment which also serves to boost their PSMA level (i.e. increase the number of “locks” per tumor cell). Since PSMA is the target for 177Lu-J591, radioimmunotherapy increased expression of PSMA can lead to more targeting of the otherwise invisible tumor cells. Two-thirds of patients will receive 177Lu-J591 at the highest tolerated dose that improved outcomes based on our prior study and the remaining one-third will get J591 with a diagnostic isotope (111Indium). The isotope 111-Indium (abbreviated 111In) is also an energetic radioactive particle, but it does not generally give off enough energy to kill cancer cells while still allowing researchers to take more detailed pictures of where the prostate cancer is located in the body.

Our goal is to ultimately cure the men who fall in this category by eradicating microscopic deposits of cancer, and the Weill Cornell Genitourinary Oncology team is available for patient consultations and to speak with physicians who are interested in referring patients to this trial, which is available at a number of sites across the country.

Learn more about how this treatment works in this article and video:

Using Radiation, Radioimmunotherapy and Radioactive Isotopes such as Lutetium 177 to Treat Prostate Cancer

Radiation is a mainstay in the treatment of prostate cancer. In men with localized prostate cancer (confined to the prostate gland), using radiation can help cure the cancer. In men with advanced disease, radiation can improve survival and help to manage pain.

Radiation can be delivered a variety of different ways. For example, there are external beams that can be used to deliver radiation from an external machine into the prostate, radioactive “seeds” that can be implanted, or ways to inject special radioactive isotopes directly into the bloodstream.

In the United States (U.S.), there are older FDA-approved treatments utilizing radioactive isotopes for men with prostate cancer that has spread to the bones to decrease pain, called samarium-153 (brand name Quadramet) and strontium-89 (Metastron). More recently, a bone-targeted alpha particle called radium-223 (brand name Xofigo®) was approved because it leads to longer overall survival in men with symptomatic metastatic castration-resistant bone metastases. These bone-targeted radioisotopes have been useful because prostate cancer commonly spreads to bone. However, those drugs cannot treat other sites of tumors such as in the prostate, lymph nodes, or lung.

We are also able to use parts of the immune system as a way to deliver radioactive particles or other targeted cancer treatments to the prostate cancer. We have engineered very specific monoclonal antibodies and molecules that will bind only to PSMA, leading to the opportunity for “molecularly targeted” radiotherapy for prostate cancer. When we combine immunotherapy with monoclonal antibodies with radioactive isotopes, we call the treatment approach radioimmunotherapy. Radioimmunotherapy involves attaching a radioactive isotope (such as Lutetium 177) to a cancer-targeting antibody or small molecule that binds only to a specific cancer-related molecule on a tumor cell. This is similar to a “lock and key” scenario, where the antibody or molecule serves as a key that will only recognize a very specific lock (the cancer-related molecule). In prostate cancer, nearly all cells have a specific “lock” that lives on the surface of each cell called prostate-specific membrane antigen (PSMA).

j591_psmaFor nearly 15 years, we have been utilizing a monoclonal antibody known as J591, which is a version of a specific key that will only recognize and enter cells with the specific lock PSMA. We successfully utilized this antibody tagged with small radioactive particles to either visualize or treat prostate cancer tumors within the prostate, bone, lymph nodes, and other sites in the body. Our initial studies demonstrated safety and signaled anti-tumor efficacy. In addition, we showed that the antibody went to virtually all sites of tumors (sometimes discovering new ones) and did not target other normal organs (with the exception of the liver which helps clear the drug from the body). Subsequently, our larger studies have shown responses in larger numbers of patients. In Europe, physicians picked up on our results and Lutetium 177 (also known as Lu-177, 177-Lu or 177 Lutetium) has become a very popular radioactive particle that can be directed to prostate cancer via PSMA. It has been used to kill prostate cancer cells and treat hundreds of prostate cancer patients. This commonly-used approach uses a small molecule which recognizes PSMA to deliver Lu-177 to prostate cancer cells (termed radioligand therapy or radioimmunotherapy therapy).

Lutetium-177 PSMA therapy is associated with a good prostate cancer response and many men travel from all over the world to Europe in order to access this treatment. In the U.S. it is only available via clinical trials, and for more than 10 years, Weill Cornell Medicine and NewYork-Presbyterian have been one of the few centers in the U.S. to offer Lutetium 177 and other targeted treatments using radioactive particles.

Learn more about how this treatment works in this video:

Immunotherapy and Prostate Cancer: What You Should Know

Cancer CureImmunotherapy, broadly defined as using the body’s own immune system to fight cancer, is one of the most exciting developments in cancer care. In oncology, for some patients using an immunotherapy treatment approach has resulted in some deep and prolonged responses.

The field of genitourinary (GU) oncology one was of the first sub-specialty areas to utilize immunotherapy and compared to many other tumor types, GU oncology has been using it for the longest amount of time — particularly for kidney (renal) and bladder cancers. There have been more recent advances across the board in immunotherapy, including the approval of atezolizumab by the FDA for bladder and urothelial cancers, marking the first new treatment for that tumor type in nearly three decades. Additionally, in select patients who have advanced urothelial cancer that has not responded to platinum-based chemotherapy, adding immunotherapy with pembrolizumab to the treatment regimen improved survival.

In the modern treatment era, prostate cancer was one of the first cancers to show a survival advantage with immunotherapy, specifically sipuleucel-T. Also known by the brand name Provenge, sipuleucel-T stimulates the immune system to seek out cancer cells and attack them. It represents the first therapeutic cancer vaccine in any cancer (treatment-focused as opposed to prevention-focused), and is FDA-approved for men with metastatic hormonal-resistant prostate cancer (mCRPC). Unfortunately, not all men respond to this treatment. At Weill Cornell Medicine and NewYork-Presbyterian, we are looking to improve responses to sipuleucel-T with our Newlink-sponsored study of sipuleucel-T followed by indoximod/placebo. In addition, since it is difficult to tell which patients are the best fit for this treatment and which ones are responding to sipuleucel-T, we continue collaborations with other researchers to work on developing blood tests to find biomarkers to help men in the future.

Additionally, recent data from the 2016 European Society of Medical Oncology (ESMO) annual meeting demonstrated promising results for using pembrolizumab (also called Keytruda) in metastatic hormonal resistant prostate cancer. This immunotherapy that works by inhibiting the PD-1 pathway and has been recently approved in other tumor types, such as melanoma and lung cancer. An initial study of the drug across different tumor types was highlighted at the ESMO meeting with significant responses in a proportion of men with prostate cancer whose cancers grew despite essentially all known therapies. In addition, a study influenced by and subsequently performed by different groups of WCM collaborators demonstrated that five men with progressive metastatic castration-resistant prostate cancer had major responses to this immune therapy, with PSA’s dropping by more than 99% and tumors greatly shrinking on scans. While all types of immunotherapy can lead to serious side effects, the treatment was generally very well-tolerated with minor side effects.

We are continuing the work to further define the subsets of men with advanced prostate cancer who can benefit from immunotherapy and we have a newly opened study of pembrolizumab for men with mCRPC. In this study, three groups of men will receive open-label (i.e. no placebo) pembrolizumab to test efficacy as measured by tumor shrinkage. We will also assess PSA changes and duration of tumor response, as well as biomarkers to help us determine in the future which men will receive the greatest benefit from this treatment.

Another promising immunotherapy-based prostate cancer treatment uses the monoclonal antibody (mAb) J591. J591 can recognize a protein antigen known as PSMA (also known as anti-prostate-specific membrane antigen) that is expressed on virtually all prostate cancer cells, and more heavily expressed in men with treatment-resistant metastatic forms of the disease. At the recent ESMO conference, we presented two clinical trials of J591 immunotherapy that are currently in progress here at Weill Cornell Medicine and NewYork-Presbyterian. One is for men with advanced prostate cancer and high (unfavorable) circulating tumor cell (CTC) count and the other delivers two doses of J591 prior to prostatectomy for men with intermediate and high risk prostate cancer. These trials are based upon the prior track record of this antibody in men with prostate cancer, including the fact that in initial pilot studies, men with advanced prostate cancer and a high number of CTCs had a decrease in tumor cell counts after J591. In addition, a prior study of J591 in combination with low-dose interkeukin-2 (IL-2) indicated that men with biochemically recurrent prostate cancer (rising PSA) did not develop metastatic disease as would have been expected without this intervention, and those with metastatic castration-resistant prostate cancer lived significantly longer than expected.

We also continue to utilize antibodies to deliver chemotherapy or radioactive particles to tumor cells with the intent of sparing normal cells. Three of these types of immunotherapy studies are currently enrolling for men with advanced prostate cancer, with others in development.

  • IMMU-132: This compound consists of a drug attached to an antibody which recognizes Trop2, a target that is over-expressed on prostate cancer cells. The antibody carries SN38, the active ingredient in irinotecan, which has shown prior responses in solid tumors. The drug has shown promising activity in breast and bladder cancer and is now being studied in prostate cancer.
  • Rovalpituzumab Tesirine “Rova-T” in Delta-Like Protein 3 (DLL3)-Expressing Advanced Solid Tumors: Our research has demonstrated that neuroendocrine prostate cancer (NEPC), one of the most aggressive and treatment-resistant prostate cancer subtypes, highly expresses DLL3. Rova-T uses an antibody to hone in on cells with DLL3 and take along a potent toxin to target those specific cells.
  • 177Lu-J591 + ketoconazole: In this clinical trial, J591 is radiolabeled with 177Lutetium, (177Lu) in order to deliver the drug directly to the prostate cancer cells. It is given in combination with an oral hormonal therapy drug which both attacks prostate cancer and at the same time, increases expression of PSMA, which is recognized by J591, leading to more targeting of the otherwise invisible tumor cells.