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Welcome to our series on “Clinical Perspectives.” Read the introduction.

Dr. Daniel George

By D’Ann George, PhD, Medical Writer

In the old paradigm, based on chemotherapy, when a tumor grew while being treated with a drug, that meant the drug was no longer working to control the cancer and that was it. Time to move on to another approach — or to stop therapy — if no other treatments were available.

But with immunotherapy, which boosts the body’s own immune system so it can find and destroy cancer cells, oncologists like Dr. Daniel George are beginning to see evidence that some people can respond to treatment repeatedly.  

Reflecting on the cancer journey of one of his patients, George, a medical oncologist at Duke University and Chair of the Kidney Cancer Association’s Medical Steering Committee, asked himself a question: “what if immunotherapy works not once, not twice, but four times?”

The reason for the paradigm shift lies in the nature of the human immune system when activated by immunotherapy agents.

“With chemotherapy, when you have a treatment and it stops working, it’s because the cancer cells have become resistant to the drug,” George said. “But immunotherapy drugs aren’t fighting the cancer. These drugs are activating the immune system, which then fights the cancer.”

And it is possible for someone’s immune system to be reactivated many times.

“It’s a situation where clinical practice is forging ahead of clinical data,” George said. 

George recalled the person who first taught him that the immune system can be primed multiple times to tackle metastatic kidney cancer. He had been treating Allen Rogers, a metastatic renal cell carcinoma (RCC) patient, with various immunotherapy combinations for almost nine years. Starting with the single immunotherapy agent Opdivo (nivolumab) and continuing through four different immunotherapy combinations, Rogers’s cancer responded with a remission.

With each remission Rogers regained his strength and his quality of life. Each time surprised George, who didn’t know that re-starting immunotherapy would work since these combinations had not been studied in this setting.

Rogers’s experience, said George, “has been a lesson for me that there are some patients who aren’t resistant to immunotherapy. Their cancer might stop responding in a particular context of immunotherapy, but if we change that context by adding a second, different drug to the immunotherapy, then it’s not resistant to the immune system. The immune system can come back in and re-engage with the cancer over and over again.”

George compared re-challenges with immunotherapies to vaccines and treatments for coronavirus.

“We can think of what we do when we re-vaccinate for Covid, or when we use antivirals,” he said. “You knock the virus down, and maybe the patient can be re-infected again — maybe the infection comes back — but it doesn’t mean that just because it came back that the antibodies are not working, or that their immune system can’t fight it. It can. It just needs another boost. I see these immunotherapies as kind of like boosters, kind of like antivirals.”

The most common standard of care today for patients with metastatic clear cell RCC, the most common type of kidney cancer, is a combination of drugs that include an immunotherapy listed in the National Comprehensive Cancer Network (NCCN) kidney cancer guidelines (see table). All the immunotherapies listed have been proven in clinical trials to provide superior tumor response than targeted therapies (like tyrosine kinase inhibitors) alone.

While not everybody responds to immunotherapy, those that do can see dramatic decrease in the size of their tumor or prolonged control of their cancer, compared with older therapies. But response is not guaranteed to last, so what happens if the cancer eventually progresses on immunotherapy?

The re-challenge approach is not outside of the NCCN guidelines, George said, but it’s buried under the heading ‘alternative approaches’.

Taking advantage of the full range of treatment possibilities, George believes, is important for patients who progress past the preferred regimens but can do well by re-treating with other immunotherapy combinations, or even the same combination that they have tried before, like Rogers.

“I don’t think Rogers is going to be the only one,” George said. “I think there will be others for whom we can restart the immune system.”

Patient Perspective: Allen Rogers

On a recent Sunday afternoon, Allen Rogers was riding a Bobcat tractor around his 500 acre farm in South Carolina, a gathering place for his extended family. When he’s not working on the grounds of the farm or the “barndominium” there, he spends his time renovating his personal house on a lake in Pinehurst, North Carolina.

“Immunotherapies have let me live a normal life,” said Rogers, who was diagnosed with renal cell carcinoma (RCC) in 2007 at age 51. “I work on something every day.”

Rogers’s medical record reads like a mini history of how therapeutic approaches for kidney cancer have evolved over 15 years. A civil engineer living in Ohio with his wife and children, Rogers started his medical care at the James Cancer Center, part of Ohio State University. After his cancer recurred in 2009, Rogers received high-dose interleukin-2, an early and very toxic RCC treatment that is rarely used today.

Read Allen’s full story.

Insight: Dr. Tian Zhang, UT Southwestern Medical Center

Have you treated any patients similar to Mr. Rogers with a re-challenge? ​What were the results?

After a treatment free interval, I have rechallenged with PD-1 inhibition alone (nivolumab) – not as much with CTLA-4 inhibition (ipilimumab). Ipilimumab has been used in several trials without significant benefit, so re-using ipilimumab in patients who have disease refractory to immunotherapies should be an individualized decision for the patient. 

For nivolumab re-challenge after patients have had treatment free intervals, stable disease or partial responses have been the norm for my patients. 

*D’Ann George is married to Dr. Daniel George.

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