Invading Cancer Cells With Immunotherapy Combinations

Mariena Browning of Pocatello, Idaho, was just 22 when she noticed a strange lump in her groin during the summer of 2018. Over the next few weeks, the lump grew and more lumps — swollen lymph nodes — appeared. She saw her primary care doctor, who referred her for an ultrasound and biopsy. The results indicated melanoma.

Browning then traveled to the University of Utah Huntsman Cancer Institute in Salt Lake City, where she was diagnosed with stage 3 metastatic melanoma with no primary source. “They did a full body exam, checked all my moles and removed any mole they saw,” Browning says. “None of them were positive for melanoma or any sort of cancer. It just happened, unfortunately.”

Her care team recommended that she join a clinical trial, but the trial was stopped just as Browning was set to join. In the meantime, new lumps developed on her stomach and neck. Biopsies of the new lumps showed melanoma, changing Browning’s diagnosis to stage 4. Tumor biomarker testing showed she had a mutation in the BRAF gene, causing the gene to make an abnormal version of the BRAF protein involved in a growth pathway that fueled melanoma’s growth.

Browning had surgery to remove all the lymph nodes in her left groin followed by an eight-month course of Braftovi (encorafenib) and Mektovi (binimetinib), targeted therapies to inhibit the BRAF protein. But she developed infections — specifically Clostridioides difficile (C. diff) and cellulitis — while taking the medications, so her care team decided to stop them.

Then the melanoma spread to her brain. That’s when Browning began immunotherapy treatment — specifically, a combination of Yervoy (ipilimumab) and Opdivo (nivolumab). Her doctors explained that the immunotherapy combination would put her immune system into “overdrive,” helping her system destroy the melanoma cells, she says.

WHAT IS IMMUNOTHERAPY?

Immunotherapy is different from other cancer therapies that work in a patient’s bloodstream (systemically). Instead of destroying both cancer cells and healthy cells, as chemotherapy does, immunotherapy drugs help the immune system recognize cancer cells as invaders and work to eliminate them.

“What we’ve learned is that the immune system has the ability to actually recognize and treat melanoma on its own, but it often needs a little bit of a boost to do that,” says Dr. Allison Betof Warner, a melanoma medical oncologist at Memorial Sloan Kettering Cancer Center in New York. Immunotherapy drugs help immune cells in the body — white blood cells known as T lymphocytes or T cells — recognize that cancer cells don’t belong there. “The second function of immune therapy is to help boost the strength of the T cells to actually kill the cancer,” she says.

The immune system uses immune checkpoints to make sure healthy cells aren’t destroyed during an immune response. The T cells recognize and bind to certain proteins, creating a stop sign (immune checkpoint) that tells the T cells to stop their disease-fighting work and protect healthy cells. But immune checkpoints keep the immune system from recognizing cancer cells, allowing tumors to grow.

Immunotherapy drugs called immune checkpoint inhibitors keep these proteins from binding and prevent the body from sending a stop signal to T cells. When they don’t receive this stop signal, T cells attack cancer cells, shrinking tumors or preventing them from growing.

“Immunotherapy basically retrains the immune system and turns it back on so that it then recognizes cancer as something that shouldn’t be there,” says Dr. Elizabeth I. Buchbinder, a medical oncologist at the Melanoma Disease Center at Dana-Farber Cancer Institute in Boston. “Unlike therapies that work on the cancer itself, it’s helping the immune system do something that it does already but isn’t doing well in this particular circumstance.”

Oncologists use different immunotherapy drugs to inhibit different checkpoint proteins from binding. The checkpoint proteins currently targeted by immune checkpoint inhibitors include interleukin-2 (IL-2), cytotoxic T-lymphocyte- associated antigen 4 (CTLA-4), lymphocyte activating gene 3 (LAG-3) and programmed death 1 (PD-1).

The first immunotherapy approved by the Food and Drug Administration (FDA) for melanoma was Proleukin (aldesleukin). The agency went on to approve Yervoy, Keytruda (pembrolizumab) and Opdivo for treating melanoma.

The FDA also approved a combination treatment of Opdivo and Yervoy for people with advanced melanoma. Today, new immunotherapy combinations are changing the potential course of treatment for people with this disease.

HOW IMMUNOTHERAPY COMBINATIONS HELP

One of the challenges with immunotherapies for people with advanced melanoma is that some people’s cancers don’t respond to them — or they stop responding to the drug after showing initial progress.

“I think the biggest issue is treating that percentage of patients that don’t respond,” Buchbinder says. “It’s figuring out what ... we need to do differently or what can we add.”

In some scenarios, it’s quite clear that combination immunotherapy is the best choice, according to Betof Warner, who added that data support improved outcomes with combination immunotherapy for people with liver metastases. “Similarly, patients who have brain metastases and, in general, patients who have bone metastases, I typically treat with combination immunotherapy as well,” she says.

New immunotherapy combinations to treat advanced melanoma with fewer side effects are an area of great interest among cancer researchers. Dr. Hussein A. Tawbi, professor of melanoma medical oncology at The University of Texas MD Anderson Cancer Center in Houston, released data earlier this year from the phase 2/3 RELATIVITY-047 clinical trial of combined treatment with the checkpoint inhibitors relatlimab and Opdivo. Treatment with the combination doubled progression-free survival (the time when a patient lives with cancer without disease progression) in study participants compared with Opdivo alone. And, Tawbi adds, toxicities in the combination treatment were manageable.

Tawbi expects a combination of relatlimab (which blocks the LAG-3 protein) and Opdivo (which blocks the PD-1 protein) to replace Opdivo as a single-agent first-line treatment for people with advanced melanoma. “If the FDA approves it, I don’t see any reason to ever use a single agent at this point because this is more effective and almost the same toxicity as (Opdivo) alone,” he says.

According to Tawbi, after one year the progression-free survival rate for the combination treatment was 47.7% (compared with 36% in patients treated with Opdivo alone). Moreover, he adds, side effects occurred in only 18% of participants treated with the combination therapy.

“I think one of the most impressive aspects of this is not just how much better it is than single-agent (Opdivo), but the fact that it comes at a very low cost of toxicity,” Tawbi says. “(Yervoy) and (Opdivo) gives you a one-year progression-free survival rate of 49%, but 55% have grade 3 (serious) or grade 4 (severe) toxicity.”

If approved, the relatlimab and Opdivo combination will be another tool doctors can use when melanoma continues to progress in patients, according to Tawbi. “It adds to our armamentarium of drugs against cancer and will help us think about better solutions for those patients,” he says.

For Betof Warner, the approval of relatlimab is something to look forward to. “For patients currently getting (Yervoy) plus (Opdivo), many or most of them will still get that combination,” she says. “But if a patient was going to be treated with single-agent PD-1, you expect that many of those patients will go on to get (Opdivo) plus relatlimab if and when that’s approved.”

ARE IMMUNOTHERAPY COMBINATIONS RIGHT FOR EVERYONE?

Potential toxicities are a critical consideration when weighing treatment with an immunotherapy combination versus a single immunotherapy agent, Buchbinder says. “The rate of toxicity is very, very high,” she notes. “Because they are activating the immune system — turning it on and making it recognize the tumor — they also can make it recognize normal things in the body as being abnormal or as something the immune system reacts against.”

When this happens, side effects can be challenging. People taking immunotherapy combinations can develop inflammation in the colon that causes diarrhea or inflammation in the lungs that creates respiratory problems. People may also have inflammation in the heart or liver.

“The good news is we’re getting better and better at treating these side effects,” Buchbinder says. “We’ll give steroids, such as prednisone or other drugs, that dampen down the immune system. Frequently, patients end up hospitalized because we want to make sure that inflammation decreases quickly and that they don’t get sick from something else while we try to fix the side effect from immunotherapy.”

The side effects of combination immunotherapy treatment were so severe for Browning that she had to discontinue after two infusions. Her eyes became yellow and enzymes in her liver became so elevated that she needed an immunosuppressant drug to control immune-related hepatitis. “I stopped treatment for about six months,” Browning says. “I was on prednisone during that time to get my liver healthy enough to be able to do treatment again.”

In June 2020, Browning began immunotherapy treat- ment again, but this time she was treated with Opdivo only. She finished her course in October 2021 and her scans continue to show no evidence of disease.

Of course, not all people treated with immunotherapy combinations experience severe side effects. Larry Webster, 68, of Haverhill, Massachusetts, was initially diagnosed with melanoma in 2017 after a shave biopsy (when a thin piece of skin is removed from the surface with a blade). He had two radical lymphadenectomies, surgery to remove a growing malignant mole on his left calf and cryoablation to destroy a small mass near his liver. He also participated in two immunotherapy combination clinical trials — one of a combined novel single agent PD-1 inhibitor, neoantigen vaccine and Opdivo and the other combining injectable CMP-001 with Keytruda.

“I generally felt fine while undergoing treatment,” Webster says. “The only side effects I experienced were some fatigue and flu-like symptoms toward the evening. I had chills, body aches and soreness at injection sites.”

Overall, side effects lasted about an hour or two and he managed them by going to bed. “I was always able to return to work the following morning,” he says.

In people who do experience side effects, one of the biggest fears is whether treating the side effects will dampen the effectiveness of immunotherapy, Betof Warner says. She compares the balance to a threshold — the drug needs to activate the immune system above a certain threshold to fight cancer. “Ideally, we’d be right at that threshold where it’s enough to treat your cancer and not enough to cause the side effect,” she says. “But unfortunately, we don’t have the ability yet to tune that as well as we would like. My goal with treating their side effect is to bring their immune system back down to the point where we are still above the threshold but they’re no longer (experiencing) a side effect.”

LOOKING TO THE FUTURE

It has been two years since Webster’s last treatment and he now sees his care team for regular scans and dermatology appointments. Although he acknowledges having initial concerns about participating in clinical trials, he says, “I realized immunotherapy was my best bet for treating the advanced melanoma. I believe the immunotherapy combination treatment I received has allowed me to live the good life I am currently living.”

Browning encourages others considering treatment with an immunotherapy combination to do their own research and trust their doctors. “Find a care team that listens to your opinions, worries and thoughts because that’s something that helped us for sure,” she says. “Find the care team you completely trust.”

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