Steven Finkelstein, MD
The surface has only been scratched in the investigation of radiation and immunotherapy in combination for the treatment of patients with prostate cancer, says Steven Finkelstein, MD, of 21st Century Oncology.
“There is so much undiscovered territory with respect to this research. The fact there that are only a few clinical trails now of any significance in this area means that we need to do more work,” says Finkelstein, a Scottsdale board certified radiation oncologist, adjunct associate professor at Translational Genomic Research Institute, and executive director of the Arizona Cancer Research Alliance. “I’ve spent a career working on this topic, and only now, after 20 years, are we starting to make progress.”
While progress has been slow, the outlook is bright for the use of immunotherapy and radiation together in prostate cancer, says Finkelstein. He is currently working on a multicenter trial, which is investigating the effects of radiation therapy to augment anti-tumor responses from immunotherapy with sipuleucel-T (Provenge).
According to study investigators, the trial is “based on the assumption that cell death following radiation therapy will stimulate antitumor immunity, which could provide a more permanent solution to curing cancer and discouraging tumors from spreading throughout the body.”
The trial is still recruiting patients with metastatic castration-resistant prostate cancer (mCRPC) who will be treated with radiation therapy to 1 or more metastatic sites followed at least 28 days later by sipuleucel-T.
In an interview with OncLive
, Finkelstein explains why radiation and immunotherapy may be an effective combination. He also discusses leading immunotherapy agents in prostate cancer, and why—despite longtime popular belief—radiation is not immunosuppressive.
OncLive: What makes radiation and immunotherapy an effective combination?
: Radiation probably works similarly to anything that provides a local injury, which can cause not just DNA damage, but also other things to occur. The typical way we think radiation works is by causing double-strand DNA damage, but that is probably not the whole story. Other things probably happen.
This may include regulation of the p53 tumor suppressor genes, damage to the cellular lipid membrane, activation of various signaling pathways—which in turn can induce the up-regulation of MHC class one and class two—and cytokine release.
In general, the problem is that the immune system was never designed to fight itself. Cancer is part of the person who has it. The immune system should not attack the body, unless we can trick the body into believing that something is wrong. What radiation does is hurt and derange that tissue to the point where your body starts to clean it up.
In prostate cancer, the most effective immunotherapy treatment demonstrated thus far has been the first-of-its kind commercial approach to prostate cancer, which is sipuleucel-T. Subsequently, 5 new immunotherapy agents have come in the mCRPC space, and they all show improved overall survival.
Secondly, new drugs have made it into the marketplace, such as PD-1/PD-L1 drugs. These have had an incredible effect across the board but, so far, they are not as relevant in prostate cancer because early trials have focused on other sites.
In the past, radiotherapy has been viewed as immunosuppressive, which has precluded its use in combination with immunotherapy. How has the understanding of this changed in recent years?
Radiation therapy is used to create immunosuppression for bone marrow transplants. When that is done, the entire person is radiated. In those cases, the entire bone marrow gets exposed and all of the blood cells get exposed to the radiation.
However, we don’t often do this whole-body radiation. It is done probably less than half of a percent of the time. It is just not what we do as radiation oncologists. We radiate very, very small targets with high doses of energy. Whole-body radiation has nothing to do with what we do in radiation oncology.