Radiation/Immunotherapy Combos Slow to Gain Traction, But Have Potential in Prostate Cancer

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.

OncLive: What makes radiation and immunotherapy an effective combination?

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.Finkelstein: 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.

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?

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.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.

Are there certain types of immunotherapies that may better pair with radiation than others?

What is on the horizon for the use of immunotherapies in combination with radiation in prostate cancer?

When I switched from working as an immunotherapist to radiation oncologist, I was told that radiation is immunosuppressive. That is only true in situations that require whole-body radiation, and that is not the method that we currently use. Professionally, the last 10 years for me have been spent trying to convince the field that radiation is not immunosuppressive. Now, I’ve spoken nationally on this and people are starting to understand that this makes sense.The only thing approved is sipuleucel-T in prostate cancer. It has an FDA approval to be commercially given. That is huge. Despite some of their business issues, which are now resolved, it is still the only thing that has that approval and is proven effective. The PD-1 therapies are very exciting but, in the prostate space, they have not been investigated as much.I currently am involved in a trial that combines radiation therapy and sipuleucel-T. It is looking at focal radiation in the metastatic castration-resistant setting coupled with sipuleucel-T.

We are in a sort of phase where everybody is starting to do these kinds of things their own way. The caveat of how we use these things is very much defined by what the patient selection is, what kind of therapies we are using, and how we are building that with the intricacies of both radiation and of the immunotherapies. Just because one immunotherapy specifically put together with radiation is not a good idea, does not mean that all immunotherapies and all radiation methods will not work.

Combination therapies are always challenging because you have to get something built that has clinical acumen with respect to one thing, and also clinical acumen with respect to a second thing. It takes years to prove that a drug works, much less a combination approach.

We need to be faster at being able to get these combinations going. The trial that I described with radiation and sipuleucel-T took 5 years in development before it was turned on, and that accrual is ongoing. We need to be faster. We need to make it easier for patients to get access to trials that build these combination therapies.

Champions, such as myself, are working hard to fight the good fight so that we can individualize and personalize cancer approaches. There is no more personalized approach than using one’s own immune system against cancer.