A Stronger Defense

STUART SHERROW of Wheatland, Missouri, knew in October 2017 that the palpable mass growing in his abdomen just above his belt line was a cancer recurrence. Just three months earlier, Sherrow, who was 55 at the time, had undergone surgery to remove a rare and aggressive soft tissue sarcoma called dedifferentiated liposarcoma (DDLPS) from the same part of his body.

Even though the surgery had removed all signs of cancer from his abdominal cavity, DDLPS often recurs. His doctors suggested chemotherapy to try to shrink the tumor followed by another surgery to remove the mass, but they told him the tumor would likely come back.

“He had this tumor, he had it removed, and then he recurred pretty quickly right after that, which was telling us that the tumor was just behaving very aggressively,” says Christina Roland, a surgical oncologist at the University of Texas MD Anderson Cancer Center in Houston, where Sherrow was treated.

Roland and her team suggested that Sherrow consider a newly launched clinical trial testing immunotherapy prior to surgery in people with DDLPS and another type of sarcoma called undifferentiated pleomorphic sarcoma (UPS). The phase II clinical trial at MD Anderson was looking at combining radiation with two variations of immunotherapy treatment: using Opdivo (nivolumab) with Yervoy (ipilimumab) or Opdivo alone. The hope was that administering immunotherapy and radiation would help shrink the tumor prior to surgery and that the immunotherapy would train his immune system to keep cancer from coming back. Given the prospect of the side effects of chemotherapy and his high chance of recurrence, Sherrow decided to join the trial.

“At the time, I didn’t have many options or choices,” he says. “This was a new type of way to treat this, and I felt that I’d at least maybe be helping someone else. It sounded like a better option for me.”

A Proactive Immune Response

Immune checkpoint inhibitors, which work by taking the brakes off the immune system so it can attack cancer, have transformed outcomes for many people with certain advanced cancers, including stage IV lung cancer and melanoma. While not effective for every cancer, immunotherapy has increased survival for many patients—sometimes shrinking metastases throughout the body.

Now, researchers are increasingly looking at immunotherapy before and after surgery for early-stage and locally advanced cancers. For example, some people with stage II and III non-small cell lung cancer and melanoma receive immunotherapy along with other treatments prior to surgery—called neoadjuvant treatment—and then go on to receive immunotherapy after surgery—known as adjuvant treatment—to help keep cancer at bay. The hope is that the use of immunotherapy before surgery will improve long-term cancer-fighting immunity, particularly in cancers that have a high chance of recurrence.

Triple-negative breast cancer (TNBC) is one such cancer. Although it often responds to chemotherapy, TNBC frequently comes back. In addition, TNBC lacks estrogen, progesterone and HER2 protein receptors, which are important targets for treatment in other breast cancer subtypes.

In 2021, the Food and Drug Administration approved the immunotherapy treatment Keytruda (pembrolizumab) together with chemotherapy before surgery, followed by Keytruda after surgery for stage II or III TNBC patients at high risk for recurrence. In updated results of KEYNOTE-522, the clinical trial that initially led to this approval, 64.8% of patients who received Keytruda with chemotherapy had a pathologic complete response, meaning they had no evidence of invasive disease in the surgically removed tissue at the time of surgery, compared with 51.2% in the placebo-chemotherapy group. After a median follow-up of 15.5 months, 7.4% of patients who had received immunotherapy both before and after surgery had disease progression or recurrence, compared with 11.8% of those who had not received immunotherapy.

The addition of the immune checkpoint inhibitor Keytruda before and after surgery has become the standard of care for people with stage II and III TNBC, given recent research that shows the approach increases overall survival, says Virginia Kaklamani, a medical oncologist at the Mays Cancer Center at UT Health in San Antonio. In a study published Nov. 28, 2024, in the New England Journal of Medicine, researchers analyzed 1,174 patients with stage II and III TNBC. In the group that received Keytruda and chemotherapy before surgery and Keytruda after, the estimated overall survival was 86.6% at 60 months, compared with 81.7% in the chemotherapy-placebo group. Keytruda can also be considered in some instances for people with high-risk stage I TNBC, Kaklamani adds.

Seeing Cancer Better

The idea of introducing immunotherapy before surgery builds on the thought that the presence of cancer could train the immune system to better see it—and that the cancer-fighting immune response could continue even after the cancer is removed, says Sapna Patel, a melanoma oncologist at the University of Colorado Cancer Center in Aurora. The question that researchers were interested in answering, she says, is, “What if you left the cancer in place, turned on the immune system, and said, ‘Go’? Would [the immune system] be more likely to see cancer that we can’t see?” The short answer across many tumor types—lung cancer, breast cancer, bladder cancer and melanoma—seems to be yes, she says. “Leave the tumor in place [for a short period of time], turn on the immune system, and the immune system can see the cancer better that way,” she says.

Patel led a phase II clinical trial that resulted in the adoption of neoadjuvant immunotherapy in people with stage III and IV melanoma who were eligible for surgery. At the time, immunotherapy was administered after surgery for patients with melanoma. Results from the trial, published March 1, 2023, in the New England Journal of Medicine, showed that patients who received immunotherapy before and after surgery had longer event-free survival than those who just had immunotherapy after surgery. In fact, 72% of people in the group that received immunotherapy before and after surgery were free of complications or return of the cancer at two years, compared with 49% in the group that received immunotherapy only after surgery. These results changed clinical practice to administer immunotherapy before surgery for many patients with stage III melanoma, Patel says.

Remaining Questions and Challenges

In many types of locally advanced cancer, neoadjuvant treatments with agents like chemotherapy are standard of care, but adding immunotherapy to these regimens has the potential to delay surgery. The delay could allow an aggressive tumor to spread if neoadjuvant treatments do not control the cancer. In addition, more treatment comes with additional risk of side effects, which can also set back surgery dates.

“We have to admit that [sometimes] this strategy does fail us—that the cancer starts to spread in the six weeks or nine weeks or 12 weeks that we’re waiting for surgery,” says Patel, who adds that this type of progression was rare in the melanoma patients who participated in her clinical trial. She also notes that cancers that progress on immunotherapy tend to be aggressive to begin with, making them difficult to treat in general. It’s unlikely that having surgery sooner would have improved the outcome in these cases, she says. “The medicine may not be controlling their cancer, but it speaks more about the biology of that cancer. It tells you that’s a very challenging cancer to deal with.”

Researchers are also looking into whether neoadjuvant immunotherapy might help patients with hepatocellular carcinoma (HCC), the most common form of liver cancer. Mark Yarchoan, a medical oncologist at the Johns Hopkins Kimmel Cancer Center in Baltimore, has published research that looks at patients with high-risk early-stage HCC who received neoadjuvant immunotherapy as part of their care at Johns Hopkins. Yarchoan notes neoadjuvant immunotherapy can help shrink tumors so patients can go on to have surgery. “We’ve taken patients who are outside of surgery criteria, prospectively given them immunotherapy and then taken them to surgery,” says Yarchoan. “We’ve found that some of these patients who traditionally would be considered incurable appear to be cured.”

Evidence is also growing for the use of immunotherapy before surgery for other high-risk cancers, including colon cancer that is characterized as mismatch repair deficient (dMMR) and HPV-positive head and neck cancer. A study published in the New England Journal of Medicine on June 5, 2024, found that neoadjuvant immunotherapy in locally advanced dMMR colon cancer led to responses in 98% of 115 patients, including complete responses in 68% of participants. And in some types of head and neck cancer, neoadjuvant immunotherapy combined with radiation has induced pathologic complete responses, says Ezra Cohen, a medical oncologist at UC San Diego Moores Cancer Center.

Results from the trial that Sherrow enrolled in were published Feb. 13, 2024, in Nature Cancer. In the study, pathologists analyzed tumor samples in the 17 patients with DDLPS and found a median of only 8.8% of the tumor tissue had been replaced by scar tissue. However, the pathology for the 10 people with UPS, the other type of sarcoma analyzed in the study, showed a median 89% of the tumor tissue was replaced with scar tissue. Most UPS patients had no trace of cancer in the tissue after their tumor was removed, Roland says.

While most study participants with DDLPS in the trial didn’t have a response to the immunotherapy, Sherrow’s case proved to be a remarkable exception. Now more than seven years after his second surgery, Sherrow still has no evidence of disease. Roland can’t say for sure why Sherrow’s cancer responded while others with DDLPS had progression, but her team continues to analyze tumor tissue from all patients in the study for clues.

Yarchoan says he is optimistic that neoadjuvant immunotherapy will continue to be used in several cancers, including liver cancer. “I personally believe we’re going to learn that the tumor that we see is not the biggest problem,” he says. “The biggest problem is the tumor that we don’t see, all those specks of tumor floating around that inevitably cause the cancer to come back.” With the addition of neoadjuvant immunotherapy, researchers are hoping a well-trained immune system stands a better chance of gobbling those up.

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