POSTED: March 11, 2020

Combining Radiation + Immunotherapy

Dr. Ralph Weichselbaum is the Daniel K. Ludwig Distinguished Service Professor of Radiation and Cellular Oncology and Chair of the Department of Radiation and Cellular Oncology at the University of Chicago Medicine and Biological Sciences.
Dr. Weichselbaum is keenly interested in investigating how tumors spread and how we can use radiation therapy and immunotherapy to treat cancer.

Prostatepedia spoke with him about the potential for combining radiation therapy with immunotherapy.

Why did you become a doctor? What drew you to medicine in the first place?

Dr. Ralph Weichselbaum: I was interested in medicine and my father was a doctor, but at the time they were drafting people in Vietnam, and I think that was what pushed me over, to tell you the truth. But I’m very glad I did it.

What is oligometastatic disease?

Dr. Weichselbaum: Oligometastasis is not a very precise definition. Initially, Dr. Sam Hellman and I— he’s been a collaborator and teacher of mine for a long time—said one to five metastatic sites in our initial paper. The idea was that that one could use an ablative intervention and cure some patients who didn’t have widespread disease. I think the two trials that I’m familiar with in prostate cancer, the STOMP trial and the Oriole trial—which isn’t published— define oligometastatic prostate cancer as one to three metastases.

The idea is that oligometastatic is an intermediate stage between widespread metastases and local disease?

Dr. Weichselbaum: Yes. It’s like all processes; it’s a spectrum of things.

What are some of the advantages to treating these oligomets with radiation therapy versus surgery? Is the cancer control similar? What about side effects?

Dr. Weichselbaum: All good questions. I think there are no Phase III randomized trials published as yet, but some are underway. For prostate cancer, I infer that if patients have positive lymph nodes, they’re probably taken out. If they have bone metastases, they were irradiated. I think that’s the most appropriate thing to do under both sets of circumstances, however, I do not know for sure. I think in other oligomets, like colon to liver, if the patient is able to undergo an operation, I probably would recommend an operation because the results are quite good. For lung metastases, it’s a little more complex due to morbidities. I think it depends on the situation. Probably for solitary metastasis, I would recommend taking them out. There’s not a lot of data to suggest one is better than the other. For prostate cancer, it makes good sense to take out the lymph nodes and radiate the bone mets because I think there are some significant side effects to operating on bone. There are also some significant side effects to radiating the pelvis at very high ablative doses. But, I can’t say for sure that there is any data to support what I just said.

Some are exploring combining radiation therapy with immunotherapy. What is the thinking behind that?

Dr. Weichselbaum: Radiation was long thought to be immunosuppressive. That is it reduced white counts. In fact, wide-field radiation did depress immunity. Within the past 20 years, it’s been recognized that radiation is an inflammatory stimulus and it seems to help anti-tumor immunity. There is speculation as to why this occurs. Part of it is likely because after radiation the tumor activates “danger signals” which alert the body to the fact there is something foreign there. It’s a system that’s conserved by evolution to get rid of viral infections. By using what’s called the innate immune system, it recognizes these signals and then the innate immune system primes the adaptive immune system, the CD-8 cells.

Now, I think it’s a little bit overdone, and perhaps I’m responsible for  this in part. I think we need to add these immune-stimulatory drugs  to this to fully actualize the effects  of radiation and immunotherapy.  I know it’s still pretty primitive in terms of how these things are combined. Like anything, it’s probably been a little bit overdone, although I do think there are some interesting signals out there. Nonetheless, it requires a lot more study.

Which of these radiation-immunotherapy combinations and sequences look to be the most promising?

Dr. Weichselbaum: The most  promising study was in lung cancer of chemotherapy-radiation followed  by an anti-PDL-1. That was called  the Pacific trial. It shows us that immunotherapy, like radiotherapy or chemotherapy or surgery, is effective against small-volume disease. The laboratory data suggests that it’s the ratio of tumor cells to immune cells that really determines the outcome.
There are also combinations of the immune checkpoints anti-CTLA-4 and  anti-PD-1 with radiation. The idea has  been to shed tumor antigens, elicit  danger signals and then increase T cell priming and take the off peripheral T cells. I think this needs a lot more work in the context of radiation although there are groundbreaking papers with the checkpoint inhibitors. Regarding radiotherapy there are very  optimistic papers that I think are over- interpreted at the present time. There’s an interesting signal, but there is no data that really demonstrate a clear benefit. I might get some pushback from colleagues on that, but I think it’s probably the most conservative, realistic interpretation right now.

What are the side effects like with these combinations and sequences?

Dr. Weichselbaum: Right now these agents are given with focal radiation. The immunotherapy in this context probably has worse side effects than the radiation therapies. There are some side effects of the combined, but I don’t think they’re untoward more than immunotherapy alone or  radiotherapy alone although I do worry about combined lung and bowel toxicity.
So there’s not a synergistic effect in terms of side effects?

Dr. Weichselbaum: There may be in the long term. Most of the clinical trials with these combinations use limited  radiation fields. That limits the contribution of the side effects from radiation.

Is there anything else that you think patients should know, either about treating oligometastases with radiation or about  combining radiation with immunotherapy?

Dr. Weichselbaum: There is an interesting and rare effect called  the abscopal effect, in which  you irradiate one site and you get a response in another. This is very rare with radiation alone. When you add a checkpoint inhibitor, it seems to be more common. This converts, potentially, radiation from a local treatment to a systemic treatment, so that is very interesting. Again,  the abscopal effect is over-interpreted, but it suggests that combining radiation with other kinds of immunotherapies may be helpful.
The other thing is that by doing multi-site radiation, radiation can be converted to a systemic agent. I think that these are new uses for radiotherapy, unlike the debate over radiotherapy or surgery for primary prostate cancer. This is a bit different.
I also think that there may be,  in some men, a use for checkpoint inhibitors in radiation for local therapy. If we can combine radiotherapy with immunotherapies in local treatment, maybe we can reduce the dose  of radiotherapy, and in the long run,  get better cure rates with fewer  side effects. This is quite important.
I think people tend not to think about  that. Mostly people think about how are we going to cure metastatic disease, which of course is important. Nonetheless, I think we want  to make these primary treatments more effective and less invasive.

Do you think that’s because the clinical trial tends to focus on metastatic disease?

Dr. Weichselbaum: It’s also much easier to get a FDA-approval in metastatic disease. If you try to  do this in local prostate cancer,  you’d be doing this forever.

Do you think that’s just the way the clinical trial world and the approval process are structured?

Dr. Weichselbaum: Absolutely. That’s a little speculative. If something bad happens to someone who has only got a one-month life expectancy, it’s tragic but people can accept it. If something happens to somebody who’s going to live 15 or 20 years, the risk-benefit is much different.

They’ve been robbed of more years, I guess.

Dr. Weichselbaum: Well, you can’t  take a great risk if one has a potentially
 curable disease. There is much more at stake.

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