AACR 2017: PSMA Update

Jaspreet Batra_AACR 2017_PSMA
Jaspreet Batra presents this research at AACR 2017

At the 2017 Annual Meeting for the Annual Association for Cancer Research (AACR), we presented research highlighting how we’re targeting PSMA – a marker on the surface of most prostate cancer cells – with radioimmunotherapy to kill cancer cells.

Radioimmunotherapy involves attaching radioactive particles to targeted immunotherapies that go directly to the cancer cells. The monoclonal antibody we use is called J591 and will bind only to PSMA. In this research, we attached the radioactive isotope actinium-225 (225Ac) to J591. We have used J591 linked with lutetium 177 (177Lu) and yttrium 90 (90Y) to treat patients in many clinical trials in the past. We believe that since 225Ac is an alpha particle emitter with much greater energy released that each individual antibody will lead to more tumor cell death. In our experimental models presented at the 2017 AACR meeting, 225Ac-J591 was not significantly more toxic than control (similar to placebo) in mice without tumors. When we treated mice with prostate cancer tumors, there was significant tumor killing following a single injection of 225Ac-J591.

Given our long history of administering radiolabeled J591 to hundreds of men in different clinical trials, we have plans to launch a phase I dose-escalation clinical trial (to determine safe doses and later look at tumor response) later this year. We and others are quite enthusiastic about this approach.

Using Alpha and Beta Radioisotopes to Kill Cancer Cells

Radionuclides, also known as radioisotopes, are particles that emit energy. The different particles they emit vary and some types emit damaging radiation (also called ionizing particles). This is a good thing when we’re using radiation as a way to kill cancer cells. The two main categories of radiation particles used to kill cancer cells are alpha and beta particles.

Several radioisotopes – using both alpha and beta particles — have been approved by the Food and Drug Administration (FDA) for clinical use in cancer treatment. Historically, bone-seeking radioisotopes were used for patients with painful tumors in the bone. For example, Strontium-89 (Metastron) and samarium-153 (Quadramet) are beta-emitters that are taken up like calcium into bone and were approved to decrease pain. More recently, the alpha-emitting agent radium-223 (Xofigo) was approved for men with metastatic castration-resistant disease that has spread to the bone. However, unlike the previous beta-emitting agents, radium-223 was FDA-approved because it leads to longer overall survival rather than just symptom relief. Radium-223 is an alpha particle that mimics calcium and is delivered and taken up by the bone cells. This generally occurs near tumor cells, and while we don’t know the exact mechanism of action, we suspect that in addition to being in close proximity to some tumor cells, this creates a less hospitable environment for the tumor cells that have spread to the bone.

Additionally, we can now utilize different targeting agents to take radionuclides directly to the tumor cells. Radioimmunotherapy or radioligand therapy involves the practice of attaching a radioactive isotope 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 resembles the key that will only recognize a very specific lock (the cancer-related molecule).

As it turns out, essentially all prostate cancer cells have a specific “lock” called prostate-specific membrane antigen (PSMA). This lock sits on the surface of each prostate cancer cell. We have engineered very specific monoclonal antibodies and molecules that will bind only to PSMA, leading to the opportunity for “molecularly targeted” (radio-)therapy.

In terms of attaching the radioactive isotopes, we can use both alpha and beta particles depending on the location and size of the tumor.Alpha vs beta radiationAlpha particles have the advantage of a very high amount of energy and a short path length. The amount of energy is high enough so that only a small number (1-10) of alpha particles lead to lethal damage to cells. An advantage of the short path length is that only the cells in close proximity to the alpha particle are destroyed, sparing other healthy and normal tissues. However, because of the short path length travelled, the alpha particle needs to be delivered into or right next to the tumor cell. In fact, even a piece of paper (or skin) is enough to block an alpha particle. Other alpha particles are being developed to be delivered as lethal payloads when attached to carrier molecules. One of these, actinium-225 (225Ac) is an alpha-emitting radionuclide that emits 4 alpha particles. In humans the 225Ac particle has been used as part of a compound linked to an antibody to treat leukemia and it also has been linked to a PSMA-recognizing peptide to treat men with late-stage prostate cancer with initial examples published last year.

Beta particles emit a lower energy, but can travel further distances. Because of their lower energy levels, more particles are required to cause lethal damage to cells.

This video provides a great overview of the process:

Additional research is needed to decipher the best radionuclides to use for which diseases in which clinical situations. We at Weill Cornell Medicine and NewYork-Presbyterian Hospital will have both alpha and beta radionuclides linked to PSMA compounds available in the clinic this year, initially with a clinical trial using 177Lu-PSMA-617, to be followed by 225Ac-J591, then the combination of 177Lu-J591 and 177Lu-PSMA-617.

AACR 2017

AACR 2017April brings more than just showers – the month kicks off with a very important cancer research conference. Tomorrow we are headed to Washington, DC for the American Association for Cancer Research (AACR) annual meeting held April 1-5, 2017.

Our team will be joining approximately 20,000 cancer researchers from across the country and around the world for this important meeting. Several physicians and scientists from Weill Cornell Medicine, NewYork-Presbyterian, and the Meyer Cancer Center again served on the scientific program committee, including our own Dr. Scott Tagawa.

We’re also proud that Dr. Bishoy Faltas was selected as an AACR NextGen Star, a competitive award that supports professional development and advancement for scientists who are early in their career. Dr. Faltas will be presenting important updates related to bladder cancer, and his NextGen Star talk will take place on Wednesday, April 5, and is titled Genomic dissection of the clonal evolution dynamics of chemotherapy-resistant urothelial carcinoma.

We have a lot to share at AACR 2017, so please check back frequently as we’ll be updating the blog regularly throughout the week.

Here are some additional highlights of what’s to come:

  • Updates regarding circulating tumor cells (CTCs) and the role of biomarkers in non-invasive diagnostics and treatments
  • How organoids may help us better treat neuroendocrine prostate cancer (NEPC)
  • The different types of radiation used to treat prostate cancer and how we’re targeting PSMA – a marker on the surface of most prostate cancer cells – with radioimmunotherapy to kill cancer cells
  • The latest updates in bladder cancer research, including updates in genomics and targeting molecular pathways