Heating Cold Prostate Tumors with PSMA-Targeted Alpha Therapy and Pembrolizumab
Abstract
Immunotherapy is a way to exploit a person’s immune system for therapeutic purposes. In oncology, we have demonstrated some major responses with immunotherapy virtually eliminating all traces of cancer from patients and lasting for years. Prostate cancer (PC) was the first cancer to have a therapeutic vaccine approved, demonstrating proof of principle that immunotherapy could be effective. However, while this therapy (sipuleucel-T, Provenge®) does lead to a 22% improvement in length of life (survival), there is almost no response to observe and newer non-immune therapies have taken over. Newer versions of immunotherapy, called immune checkpoint inhibitors, have been successful in a number of different cancer types, including melanoma, kidney, bladder, lung, and many others. One drug called pembrolizumab (Keytruda®) is approved for 12 cancers. There have been some impressive results in men with PC, but unfortunately in only 10-20% of cases. We have learned that one way to increase the chance of responding to immunotherapy is to combine treatment types. The most common treatment type used for men with advanced PC is to target the androgen receptor pathway (loosely termed hormonal therapy). Scientific experiments show that targeting this hormonal pathway in combination with immunotherapy drugs like pembrolizumab leads to increased responses. Another way to increase responses is by adding radiation, with both laboratory and human patient examples of success. Radiation is a cornerstone in the treatment of patients with PC, including the bone-targeting radioactive drug radium-223 (Xofigo®). Although radium-223 improves both the quality and duration of the lives of men, the radioactive particle only gets near PC in bone and skips tumors outside of bone. On the other hand, targeted radionuclide therapy (TRT) attaches a radioactive isotope to an antibody or small molecule that binds only to a specific cancer-related molecule on a tumor cell (a “lock and key” scenario, where the antibody or small molecule resembles the key that will only recognize a very specific lock on the cancer cell). As it turns out, nearly all PC tumors have a specific “lock,” called prostate-specific membrane antigen (PSMA), that is absent in most other places in the body. This means a PSMA-targeted antibody drug can get to and deliver drug to PC cells anywhere in the body, including the bone, largely bypassing normal organs. Following years of study using effective but weaker radioactive particles, we are completing a trial utilizing a PSMA TRT called 225Ac-J591. This complex attaches a very powerful radioactive alpha particle (actinium-225) to a PSMA-seeking antibody (J591). This complex is now being delivered safely at high doses in clinical trials. We plan to improve the proportion of men with advanced PC responding to immunotherapy by performing a randomized trial where all men receive the combination of the immunotherapy drug pembrolizumab plus a potent hormonal therapy pill (an androgen-receptor signaling inhibitor such as enzalutamide). Half of the men will also receive a dose of 225Ac-J591. With this study design, we will be able to give all qualifying men access to two important drugs while also being able to rigorously study the effect of the addition of the PSMA-targeted alpha particle radiation. We hypothesize that we will more than double the response rate (with the addition of the third drug) and the responses to immunotherapy will be durable (lasting at least a year). In addition, we recognize that not all men benefit (and some more than others), and that we can assess the men/tumors more or less likely to benefit with a series of “biomarkers.” Participating men will provide: 1. Blood samples before/after treatment to assess immune response. We believe that those with better immune responses will derive more clinical benefit from immunotherapy. 2. Stool samples to assess part of the “microbiome,” which is the c
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010706
Entities
People
- Scott T Tagawa
Organizations
- United States Army
- Weill Cornell Medicine