Amy Paturel

Jeffery Battles, a 53-year-old with stage 4 lung cancer, says that he feels lucky to know that he has a rare genetic mutation.

The father of three from Connie Lake, Pennsylvania, wasn’t expecting lung cancer to become part of his life. Even when he started experiencing chest pains in February 2021, Battles originally dismissed the pains as lingering symptoms from an earlier case of COVID-19.

Jeff Battles said that knowing about his EGFR exon 20 insertion mutation has helped him be proactive in his lung cancer treatment. 

Photo courtesy of Ashley Stack Photography

Once he finally saw his doctor, he was diagnosed with non-small cell lung cancer, the most common type of lung cancer. He then immediately underwent genetic testing, which revealed that Battles had an EGFR exon 20 insertion mutation — information his doctors used to modify his cancer treatment. 

EGFR exon 20 insertion mutation is a mutation in the cells 

 of the epidermal growth factor receptor (EGFR), a protein on cells that helps cancer cells grow. Of note, cancers with an EGFR exon 20 insertion mutation doesn’t respond to tyrosine kinase inhibitors (TKIs), the typical treatment for EGFR-positive lung cancer.

In today’s episode of “Cancer Horizons,” Battles describes how he feels fortunate to know the status of his mutation, and how it helped him be proactive with his cancer treatment, finding support from his family and online communities.



 new treatments may stall lung cancer progression

 in patients with EGFR exon 20 insertion mutations in this feature from our 

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A man with lung cancer shares how learning about his EGFR exon 20 insertion mutation soon after being diagnosed has allowed him to be aggressive when pursuing a cancer treatment tailored to his rare mutation.  

Patient With Lung Cancer ‘Stays One Step Ahead’ of His Rare Mutation

In the fall of 2018, Teri Cettina began feeling a mysterious pain around her ribs. “I thought I had done too many ab exercises at the gym,” says the 55-year-old health writer from Portland, Oregon.

When Cettina visited her doctor, her blood and urine tests came back normal. But over the next several weeks, the pain worsened. Convinced her muscles were out of whack, she saw a physical therapist who did a 10-minute exam and told Cettina, “This is not musculoskeletal; it’s not a rib thing. It’s deeper — you need to see your doctor today.”

Later that day, Cettina had a CT scan and received a diagnosis: pancreatic adenocarcinoma. Cettina’s tumor was particularly troubling because it was entangled in her veins and branches of the aortic artery, making surgical removal virtually impossible. Such grim news would send even the most hopeful optimist into a tailspin.

Cancer and depression are biochemically linked, which complicates patients’ ability to stay positive. “Something about the development of the cancer leads to a chemical imbalance in the brain that manifests as depression,” says Dr. Allyson Ocean, associate professor of medicine at Weill Cornell Medical College in New York City. Left untreated, depression can interfere with patients’ ability to fight the disease.

“Depression is a deactivating condition, meaning you tend not to do things,” says Dr. William Dale, the Arthur M. Coppola Family Chair in Supportive Care at City of Hope Comprehensive Cancer Center in Duarte, California. “If you’re depressed, you’re more likely to skip an appointment or miss a medication and less likely to eat well, exercise and spend time with people who make you feel good.”

Despite tough odds and toxic treatments, people do survive pancreatic adenocarcinoma. “There may be a single digit survival rate for this diagnosis, but that means at least one person survived,” Cettina says. “I just keep saying to myself, ‘What one person can do, another person can do.’”

Studies about whether optimism such as Cettina’s improves cancer outcomes are largely inconclusive. It’s not clear whether a glass-half-full mentality can help patients with cancer live longer. What scientists do know is that there are plenty of perks to positive thinking — some of which have nothing to do with survival rates.

Ever notice how your mood changes when you see someone you love? Positive friends support you when you need it, stick around when you want to discuss the hard stuff and bring out the best in you just by showing up. Turns out those same qualities are key when putting together your health care team.

“I learned early on that you need doctors who are willing to fight for you, who believe you can beat the disease,” Cettina explains. “My first potential surgeon looked at me with sad eyes and told me I was going to get really sick very quickly and statistically had about 18 months to live.”

A week later, Cettina met with a different oncologist for the first time. He didn’t have great bedside manner. But he was logical, even hopeful, about Cettina’s odds. He told her, “There’s a 25% chance your cancer will respond to treatment to make surgical removal possible. That means 25 out of 100 people go through this treatment and come out of it. Why couldn’t one of those four people be you?” Cettina knew she had found the right oncologist.

No matter your type of cancer or its stage, the messages you receive are critical, says Ocean, who co-founded Let’s Win!, an innovative nonprofit dedicated to advancing pancreatic cancer research. “Our goal is to connect patients to the researchers, doctors and survivors who can give them reason to hope — not just because there is reason to hope, but because having a positive attitude enables patients to fight the disease in a stronger way.”

While there are no data to suggest that staying on the sunny side improves outcomes, there’s no doubt that if you have hope, you’re more motivated to try complementary treatments, ask questions and get second opinions. You’re also more likely to advocate for yourself. For Cettina, that meant telling her health care team that she didn’t want to hear about potential time frames or poor survival rates unless she specifically asked. She wanted to hear about pancreatic cancer survivors.

“I knew how bad the prognosis was because I’m a health writer,” Cettina says. “So, I skimmed over the scary statistics and focused on researching hopeful stories about survivors. That became my coping mechanism.” She found her first pancreatic cancer survivor on The University of Texas MD Anderson Cancer Center website, a middle-aged woman with stage 4 disease, just like Cettina. After the two connected via email and then phone, Cettina set out to find more survivors and learn everything she could about how they were beating the disease.

“Connecting with survivors is important,” Ocean says. “They can give you tips based on their experience, direct you to clinical trials and help you formulate questions for your physicians that you may not have thought to ask.”

In addition to assembling a team of experts who believe you can beat the disease and survivors who prove it can be done, it’s important to convene support closer to home. After receiving her diagnosis, Cettina knew she needed more people in her corner.

“I hadn’t been a big Facebook user, but I felt strongly that sharing this scary news with my network would somehow be helpful,” Cettina says. “The response was incredible. Just reading positive words from friends and loved ones made me feel better.” The outpouring of support — even from unexpected places — helped buoy her as she navigated rough waters.

In 1990, when Lonnie Reed was 40 years old, doctors gave her a breast cancer diagnosis. She elected to have a lumpectomy followed by radiation, and doctors followed her for several years before declaring her “cleared.”

But 17 years later, the broadcast journalist turned state representative from Branford, Connecticut, noticed hypersensitivity in the same breast when she was snorkeling through a school of blue tang in the Cayman Islands. The cancer was back.

“This second primary made me angry and depressed. I had worked so hard to live a healthy life. I felt betrayed,” Reed says. “The doctors said they had to do a mastectomy. I told them to take them both because my breasts were trying to kill me.”

Reed’s cancer was triple negative, which required a long course of chemotherapy. During treatment, she began re-evaluating her life. ”I discovered I didn’t have time or energy for people and activities that didn’t fill my cup,” Reed notes. She created a chart with two columns. In column A, she listed things that made her feel calm and happy. In column B, she listed the things that made her anxious or sad. Then she began the difficult work of pruning.

“Your time and energy have to be spent carefully when you have a serious illness (such as) cancer,” Dale says. “Patients and families can get stuck thinking about what happened six months ago or questioning how a doctor missed a mass on a mammogram. Unfortunately, we can’t change what happened a year ago, but we can do something right now that will make a difference. We can help people grab on to positive experiences and enjoy the life they have right now.”

Working with a therapist can help you not only cultivate gratitude but also challenge negative thought patterns. “I learned to ask myself: ‘Do you have proof that a certain bad thing is going to happen?’ If I don’t have proof, the next question is, ‘How do you feel when you believe this sad story?’” Cettina says. The idea is to recognize that these negative thought loops don’t serve you. Sometimes that requires getting out of your head and finding a purpose bigger than beating cancer.

Forge new relationships, join a cause that’s important to you or take a bucket-list trip that you’ve postponed. ”Just don’t stop having positive experiences because you’re sick,” Dale says. For Reed, that meant focusing her energy on environmental threats. Using her high-powered social connections in the media and political worlds, Reed not only fought to stop a dangerous gas plant project while undergoing chemotherapy treatment for her second bout of breast cancer, but she also ran for office.

“I had all of these people looking to me for leadership. That was really encouraging and made me feel present and empowered,” she says. “It gave me purpose and with the support of a team of amazing people, we killed the plant proposed for Long Island Sound. I thought, if I can defeat a giant floating gas plant, I can defeat cancer.”

After her last chemotherapy treatment, Reed traveled to Paris with her partner. When she returned from the trip, politicians from both sides of the aisle convinced her to run for a seat in the Connecticut House of Representatives — a seat she won in 2008.

The idea that you need to stay positive to effectively treat cancer can put a lot of pressure on an already overtaxed psyche. Amidst the barrage of “stay strong,” and “you’ve got this,” you may feel as though you need to hide your shock, pain, anger and grief from friends and family, and that takes a lot of energy.

“As a culture, we want to believe we can think ourselves out of cancer, that we can cause the cancer cells to go away,” says Dr. Jana Bolduan Lomax, a licensed clinical health psychologist in Denver who specializes in coping with cancer and survivorship. “The reality is, we don’t have that control, but we can create space for people to feel safe to be mad and angry, even if it’s inconsistent with their identities.”

People with late-stage disease often perform a delicate dance of trying to show people in their lives they’re strong while also trying to prepare themselves for their death.

The best way to address both the desire to live and the desire to let go: Get palliative care (also termed supportive care) involved.

“People think when you have palliative care on board that you’re giving up hope,” Lomax says. “That’s not the case at all. Instead, palliative care allows for better symptom management and enhanced quality of life.” Research also suggests it may help you live longer.

Results from a study published in Health Psychology in 2017 demonstrated that patients with advanced cancer who were depressed and who received palliative care interventions lived longer than those who did not get palliative care services. Researchers suspect that palliative care not only plays a role in managing symptoms but also helps patients focus on what’s most important to them: Finding joy despite a difficult diagnosis.

“Cancer takes up a huge slice of the pie. How can you reclaim some of the other slices of that pie?” Lomax says. For Reed, that meant laughter and music. She regularly indulged in all-out cancer laugh fests with her friends and created playlists of her favorite songs: Aretha Franklin’s version of “Bridge Over Troubled Water,” The Beatles’ “Here Comes the Sun” and Bette Midler’s “The Rose.” “‘The Rose’ always made cry tears of hope, and I would end these customized concerts with Helen Reddy’s ‘I am Woman,’” she says.

Cettina’s not-so-guilty pleasure is Netflix, especially shows such as “Outlander” and “Bridgerton.”

“Watching period pieces takes me out of my life for a while,” she says. She also regularly takes time out to tune into her body with qi gong classes, sound (and water) baths and journeys through the art of guided imagery, meditation and hypnosis. Although her goal with hypnosis was initially to alleviate the anticipatory nausea she experienced prior to chemotherapy, the therapist also harnessed the power of her mind to tackle big picture issues.

“He said things (such as) ‘Your body is a healing machine,’ ‘Your body wants to return to its healthy state,’ and ‘You’re going to surprise your doctors and cure this pancreatic cancer,’” Cettina says. “I didn’t believe his words in the beginning, but I listened to them over and over, borrowing his optimism.”

Six months after Cettina’s diagnosis, her tumor had shrunk significantly. However, the presence of liver lesions meant she was not eligible for potentially curative surgery. Long-term survival felt impossible. “I really felt smashed at that point. I curled up into a ball for a few days and felt really bad,” she says. But when Cettina emerged, she uncovered other treatment options she wouldn’t have pursued if she had been eligible for surgery.

“I think people’s mindset needs to be that they’re not dying of cancer. They’re living with cancer,” Ocean says. “To live a life of happiness and positivity is like medicine, and I do think it can help change the trajectory of the disease, even if it’s only a temporary change.”

With cancer, doors will close. When they do, the key is to look for a proverbial window. Cettina already has outlived her initial life expectancy. “I already feel (as though) I’ve won the cancer lottery,” she says. “I can’t say for certain whether my optimism has kept me going, but it has taught me that good things can come from a bad situation. I’ve been lucky before. I could be again.”

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Channeling optimism during your cancer journey isn’t just about living longer — it’s about living better.

Positive Thinking Is Powerful During and After Cancer Treatment

When Teresa Byrd stepped out of the shower in February 2012, she noticed an ominous black mole, about half the size of a pencil eraser, toward the back of her right shoulder. A former hairstylist in rural Missouri who was then 44, Byrd had grown up living on a farm and baking in the sun. She had never been to a dermatologist.

“The way I was raised, we didn’t go to the doctor unless we were in pain,” Byrd says. Still, she was concerned and made an appointment with a local dermatologist. “He took one look and said, ‘I’m almost certain it’s cancer,’” she recalls. Two weeks later, Byrd received the official diagnosis: melanoma.

An estimated 100,000 Americans receive melanoma diagnoses each year. Once incurable in advanced stages with dismal survival rates, the disease has emerged as one of the most responsive cancers to immunotherapy, a treatment that harnesses the power of the immune system to fight cancer.

“Despite the best application of surgery, radiation and chemotherapy, 600,000 Americans die of cancer each year. Immunotherapy has become a fourth arm that has been very effective at treating cancer, especially melanoma,” says Dr. Steven Rosenberg, a senior investigator at the National Cancer Institute (NCI) who has been instrumental in advancing immunotherapy research for nearly 40 years. This category of treatment includes approaches ranging from checkpoint inhibitors and vaccines to cell-based strategies, including techniques like tumor-infiltrating lymphocyte (TIL) therapy, which multiplies a patient’s own cancer-fighting immune cells so they can better attack the disease.

Because Byrd’s cancer had spread to her lymph nodes and adrenal glands, she began an aggressive course of early immunotherapy called interferon. “I took a shot every Sunday night for a year,” Byrd says. “I called it the devil drug because it made every part of my body ache for several days each week.”

Interferon held Byrd’s cancer at bay until 2013, when a knot she discovered under her arm seemed to double in size by the day. Doctors treated her with 25 rounds of radiation, followed by immunotherapy with the checkpoint inhibitor Yervoy (ipilimumab) in 2014, but the cancer continued to spread. “My oncologist leaned back in his chair, put his arms behind his head and said, ‘There’s nothing more we can do for you,’” Byrd says.

When the couple left the oncologist’s office on Oct. 7, 2015, Byrd’s husband, Wesley, called The University of Texas MD Anderson Cancer Center in Houston. A clinical trial preparing to start would be investigating a new therapy; if MD Anderson doctors could tide her over until January, she would be eligible to participate.

Enter TIL therapy, a form of adoptive cell treatment that relies on patients’ own fighter T cells, a type of white cells called lymphocytes, to obliterate solid tumors. Doctors remove a metastatic tumor, identify the fighter T cells that already recognize and attack the cancer, grow them by the billions in the lab, and then infuse them back into the patient to launch a sustained attack.

It sounds like science fiction, but scientists are increasingly discovering that TIL therapy is not only possible but also could offer the best chance of durable remission among a subset of patients with hard-to-treat disease. “What better place to find cells doing battle against cancer than within the cancer itself?” Rosenberg asks.

Dating back to 1988, Rosenberg’s team showed that extracting lymphocytes from newly removed melanomas, expanding them in the lab and using interleukin 2 (IL-2), a lymphocyte growth factor, to further boost T-cell activity could produce impressive response rates.

“That was the first direct demonstration that T cells were responsible for immunotherapy-mediated rejection of cancer,” Rosenberg says. His team went on to treat hundreds of individuals who had melanoma with TILs and discovered that nearly 40% of patients experience durable remissions and long-term survival. The latest research suggests that TIL therapy may produce results in other cancer types.

Unlike chimeric antigen receptor T-cell therapy, which is approved to treat some blood cancers and relies on genetically engineered immune cells to battle disease, TIL therapy recruits the patient’s unaltered T cells — but only the rare subset demonstrating a natural ability to zero in on the cancer. The rub: “Doctors have to deplete the patient’s immune system so that, when you infuse the TILs back into patients, they don’t have to compete against other immune cells for resources,” says Dr. Amod Sarnaik, a surgical oncologist at Moffitt Cancer Center in Tampa, Florida.

To temporarily annihilate any cancer cells circulating in the blood, patients go on lymphodepleting chemotherapy, which is essentially an amped-up regimen. Side effects include diarrhea, vomiting, mouth sores and debilitating fatigue. Patients may also experience anemia and reduced platelet and white cell counts.

The treatment is so grueling and the risk of opportunistic infection so great that patients are often hospitalized until after their TIL infusion takes place seven to 10 days later.

In November 2015, doctors at MD Anderson removed a piece of Byrd’s tumor from her lung, separated out the fighter T cells and began growing them in a facility lab. To complete the treatment, the Byrds moved to Houston in February 2016, leaving their youngest son at home during his senior year of high school with their oldest son, who was student teaching at a nearby school.

“I was gone for so much of Collin’s senior year,” Byrd says. “Colton, my oldest, recorded every event, every basketball game, every important moment. They would even FaceTime me and tell me what they were fixing for supper.”

While Byrd pushed through chemotherapy, scientists grew her T cells in the lab, expanding the count to 20.1 million. Then, on her husband’s 48th birthday, it was party time. “Everyone from the nurses to the doctors to the laboratory technicians came to my hospital room,” Byrd says. “It was like a big celebration. Our friends had planned to surprise Wesley with a birthday party in my room. They brought in pizza and beverages at the same time doctors came into my room with the infusion bag.”

Byrd wasn’t out of the woods yet. After TIL therapy, patients receive treatment with IL-2, a protein called a cytokine that helps the fighter T cells grow. It’s the same agent used in the lab to spur TILs to multiply. “IL-2 stimulates the T cells that have been infused back into the patient to grow and establish themselves as part of the patient’s immune system,” says Dr. Amir Jazaeri, director of the gynecologic cancer immunotherapy program at MD Anderson.

T cells sometimes cause fever and chills as they’re being infused, and the IL-2 administered afterward has potentially significant side effects, including changes in blood pressure and heart rate. Some patients even require treatment in the intensive care unit. “The chills and shakes were so violent that Wesley had to put a stocking hat on my head and a scarf around my neck.

I was layered in three heated blankets, and when the chills started up, he would sit on the bottom of my legs so I wouldn’t fall off the bed,” Byrd says.

Most of the side effects of treatment occur during the hospital stay and shortly thereafter. Because it’s a one-time treatment, the more time that passes after the T-cell infusion, the fewer the significant side effects. That’s a departure from immune checkpoint inhibitors, infused drugs that disable certain proteins to activate the immune system against cancer; patients need to stay on that treatment for months or even years at a time. As a result, “with checkpoint inhibitors, the onset of side effects could happen months after starting therapy,” Jazaeri says.

By the end of March 2016, Byrd was back home, preparing for her son’s high school graduation, and she hasn’t been on any therapy since. “It was one of the most emotional moments of my life,” Byrd says. “I didn’t realize how hard my illness was for my son until graduation, but I think the experience made us feel stronger and closer as a family.”

With the help of the single TIL treatment, Byrd’s body continued fighting the cancer for the next four years. As of February 2020, she has had no evidence of disease.

The success of TIL therapy rests largely on whether scientists can identify mutations inside the tumor. This allows them to test which T cells are able to recognize and attack the “drivers” of a cancer and then focus on multiplying that special population of immune cells in the lab.

Melanoma is the low-hanging fruit of immunotherapy targets because it’s usually induced by ultraviolet radiation and resulting DNA damage. “That’s why melanoma has a much higher rate of mutations compared to other types of cancers,” Sarnaik says. It also allows the immune system to distinguish a melanoma cancer cell from a normal cell, just as it would recognize bacteria or viruses.

Scientists are investigating whether cervical cancer would also be amenable to TIL therapy, because about 90% of these cancers are caused by HPV. “Cervical cancer doesn’t have the high mutational burden of melanoma, but it can still display targets on the surface of the tumor cells because it tends to be caused by a virus,” Sarnaik says. That makes it more detectable by the immune system.

Iovance Biotherapeutics in San Carlos, California, is already proving to be a leader in this space, with TIL technology in phase 3 clinical trials for advanced cervical cancer and metastatic melanoma. In May 2019, the company reported a 44% response rate among 27 women with advanced cervical cancer that had progressed on previous treatments, including three patients whose disease disappeared. Among 66 melanoma patients, 38% responded, including two who had no evidence of disease.

Rosenberg emphasizes that this kind of treatment is not cancer type-specific. The past decade brought an explosion of trials investigating whether TIL therapy may have a role in various cancers, including breast, colorectal and head and neck. “All cancers have mutations. The key is targeting them effectively,” he says.

That can be tricky, especially for common epithelial cancers. These types, which represent about 90% of new cancer diagnoses in the United States, begin in the cells that line organs such as the breasts, lungs and ovaries. Although Rosenberg’s team has developed highly selective techniques to identify the rare immune cells in these tumors that recognize the cancer, they amount to about 1 in every 10,000 to 1 in every 100,000 lymphocytes — like a needle in a haystack.

Even with these minuscule numbers, if doctors identify the right lymphocytes and expand them in the lab by the billions, some patients can achieve durable response rates. Judy Perkins, a nature lover and former engineer from Port St. Lucie, Florida, is just one example.

She received a diagnosis of stage 0 breast cancer in 2003, and her only treatment was surgery. A decade later, when her youngest child was graduating from eighth grade and her oldest was a high school sophomore, Perkins’ breast cancer returned. For two years she tried hormonal therapies and chemotherapies. She had even been in a clinical trial for a targeted drug called lucitanib. When those treatments failed and doctors told her she had only a few months to live, she started working on her bucket list.

“I spent as much time with my friends and family as I could. I intended to curl up with my cats and read books or watch TV until I died,” says Perkins, who was 50 at the time. A lobbyist and advocate for breast cancer research, Perkins decided to attend one last training conference: Project LEAD, sponsored by the National Breast Cancer Coalition. While there, she learned that an NCI-sponsored clinical trial was underway to investigate TIL therapy in metastatic cancers.

To be eligible, patients had to have at least two tumors, one to be removed to obtain the TIL and one for doctors to monitor to see if the treatment was working. Perkins was a good candidate because, unlike many other patients with breast cancer, she had tumors to work with. “Patients with (advanced) breast cancer often have bone-only disease. By the time they develop tumors that can be surgically removed, usually in the liver and lungs, patients are too sick to tolerate treatment,” Perkins says.

A few weeks after the training, scientists sequenced DNA and RNA from one of Perkins’ tumors, as well as normal tissue to determine which mutations were unique to her cancer. They identified 62 mutations in her tumor cells. The TILs recognized four of them. Researchers expanded those four TILs to 81 billion in the lab before reinfusing them back into Perkins.

Between her surgery in August 2015 and when the multiplied TILs were ready in December, Perkins had deteriorated dramatically. By the time she arrived at the National Institutes of Health, she was in a lot of pain and tumors had spread throughout her liver. She knew the odds of the TILs working were less than 15%, but she also knew it was her last chance for a viable treatment.

“Within days, I could tell the tumor was getting softer and smaller,” Perkins says. “By February, I had a 60% reduction in tumor size. By April, I was backpacking on the Appalachian Trail. And in May, I had my first clean scan.” The cancer was gone and has been ever since.

Perkins is still an outlier for her ability to receive TIL therapy and her dramatic response; her case was featured in a 2018 paper in 

. Researchers have seen similar results using TIL treatment for patients in the same trial with other cancers, including liver, lung and colorectal. “For those of us who were fortunate enough to have a complete response, none of us have ever relapsed,” Perkins says.

TIL therapy, though decades in the making, is still in its infancy, and the process is complex. “It’s important to understand that TIL is still a highly experimental treatment that’s only available at a few institutions,” Rosenberg says.

The ultimate in personalized immunotherapy, TIL therapy requires customizing a treatment for each patient. The time-consuming and expensive endeavor is expected to cost about half a million dollars, rising to over $1 million when hospital stays are added. Before receiving treatment, patients have to wait for scientists to identify the effective lymphocytes and grow them in a lab, a process that can take months. Many people with aggressive, metastatic disease don’t have that kind of time.

Plus, people with advanced disease may not be able to tolerate the high-dose chemo- therapy required to deplete the immune system or the IL-2 needed to boost T-cell production after infusion. Therapy requires two to three weeks of inpatient treatment, and even under ideal circumstances, there are no guarantees that it will work.

“A lot of research is going into exploring the responders versus the non-responders,”

Jazaeri says. Studies suggest that younger patients have higher odds that their TILs will successfully multiply in the lab than other groups — 94% for patients under 30 compared with 46% for those over 60. Women, too, produce a higher TIL generation rate than men at 71% versus 57%, respectively. Byrd and Perkins, both women, were well under 60 when they underwent TIL infusion.

Researchers are working hard to iron out these kinks. Iovance has already halved the time it takes to make TIL therapy, from 42 days to 22. And as a one-and-done treatment for metastatic cancers, TIL therapy could save health care dollars over the long run. “If a treatment works, it has been my experience that the genius of American industry will find a way around obstacles like production time and cost,” Rosenberg says.

Across cancer types, a unique immune-stimulating treatment called tumor-infiltrating lymphocyte therapy produces durable remissions that could last for decades.
 

Unleashing the Power Within Using Tumor-Infiltrating Lymphocyte Therapy

George Benson wasn’t concerned when he began experiencing lower abdominal pain in August 2009. Between a busy career and family life, with vacations planned and a son returning from the military, Benson, then 51, put off seeing a doctor.

“I thought it was a hernia,” says the truck driver from southeastern Michigan.

The pain persisted, then worsened, and Benson eventually saw his primary care doctor, who ordered blood tests and a CT scan. A landscape and abstract artist, Benson was shopping for a canvas when his doctor called with the news: Benson had a suspicious mass about the size of a softball over his left kidney.

“When I sat down with the urologist a week later, he showed me the mass and said he was 95% sure it was cancer,” Benson says. “To me, the mass looked like a fist wrapped around a fortune cookie.”

At the time, Benson didn’t realize his fortune would include becoming part of the changing face of advanced kidney cancer treatment. Within weeks, doctors cut off the tumor’s blood supply and he underwent surgery to remove the 10-pound mass. That was just the beginning of Benson’s decade-long treatment journey, which included participating in two clinical trials.

Over 70,000 Americans each year receive diagnoses of renal cell carcinoma or kidney cancer.

The five-year survival rate for patients with early-stage disease is more than 90% compared with less than 15% for those with advanced kidney cancer. Unfortunately, catching the disease early can be a challenge. Symptoms are vague and easily explained, and in the absence of certain predisposing genetic conditions, such as von Hippel-Lindau (VHL) syndrome and hereditary renal carcinoma, kidney tumors are frequently missed.

“We don’t have a good blood- or urine-based diagnostic test that might help us detect early stage kidney cancer,” says Dr. David McDermott, director of the biologic therapy and cutaneous oncology programs at Beth Israel Deaconess Medical Center in Boston. In fact, kidney cancer at any stage is often uncovered by a CT scan or ultrasound performed for another reason.

Unlike other solid tumors, such as breast, prostate and lung, kidney cancer is primarily driven by abnormally formed blood vessels. “The kidney cells and cancer cells sense a lack of oxygen (cellular hypoxia), even when there’s plenty of oxygen,” explains Dr. Ajjai Shivaram Alva, an associate professor at Michigan Medicine in Ann Arbor. The faulty mechanism causes the body to form new blood vessels that fuel the cancer.

With rare exceptions, kidney tumors do not shrink with chemotherapy or radiation.

Fortunately, Nobel Prize-winning research uncovered pathways that drive the growth and spread of kidney cancer, leading to the development of targeted treatments. Plus, scientists have long known that, like melanoma, kidney cancer is an immune-responsive tumor, opening the door to with the use of novel immunotherapies. Add it all up and doctors have more tools than ever before to combat kidney cancer.

Scientists are still working out which tumors respond to different treatments and why clear cell disease is often more sensitive to therapy. But according to McDermott, there’s reason to hope that immunotherapies known as checkpoint inhibitors, particularly in combination with other novel agents, can improve survival rates for patients with kidney cancer. The key, he says, will be targeting not only the microenvironment that supports the tumor (for instance, blood vessels) but also the tumor cells.

Historically, doctors treated kidney cancer with surgery, which is still a mainstay of treatment, especially for patients with disease in stages 1 to 3. But for one-third of patients, the cancer returns after surgery, possibly because cancerous cells have traveled to nearby lymph nodes or entered the blood supply. “Research is underway to understand whether preemptively attacking leftover cancer cells after surgery can help prevent recurrence,” Alva says.

Those options weren’t even a pipe dream when Benson received a diagnosis of stage 3b disease. After his surgery, he had follow-up CT scans done every three months for two years, then every six months for a few more years. In March 2016, a scan uncovered growth in a nodule on his right lung.

Benson’s best treatment option at the time was interleukin-2, a therapy that boosts the growth and activity of immune cells called lymphocytes. The problem: often intolerable side effects. “Your blood pressure drops so low (that) you can’t stand on your own,” Benson says. The drug also can cause fever, nausea, aches and pains, fast heartbeat and changes in liver function.

Between 2005 and 2010, a new wave of less toxic therapy options emerged, and survivorship after kidney cancer grew dramatically. Because all cells, even cancerous ones, need oxygen, Dr. William Kaelin Jr., a professor of medicine at Harvard Medical School and Dana-Farber Cancer Institute in Boston, set out to understand how the body senses and adapts to changes in oxygen levels.

“For years, scientists have known that mutations in the tumor-suppressor gene VHL led to von Hippel Lindau syndrome, a rare disorder that makes patients more vulnerable to kidney cancer,” says Dr. Toni Choueiri, director of genitourinary oncology at Dana-Farber. In 2019, Kaelin, a collaborator of McDermott and Choueiri, was a winner of the Nobel Prize in medicine for uncovering how cells adjust to changes in oxygen availability and how glitches in that process can lead to cancer. Kaelin, along with Dr. Gregg L. Semenza of Johns Hopkins Medicine in Baltimore and Dr. Peter J. Ratcliffe of the Francis Crick Institute in London, demonstrated that the protein made from a mutated VHL gene causes a cell to erroneously sense hypoxia, leading to expression of a protein called hypoxia-inducible factor-1 (HIF-1)-alpha and activation of genes involved in blood vessel formation, including VEGF.

Cancer cells with a mutated VHL gene use that chain of events to surround themselves with new blood vessels that feed their growth. So, Kaelin thought, what if that blood supply was cut off? This work led to clinical testing of drugs called VEGF receptor inhibitors, including Sutent (sunitinib), Votrient (pazopanib), Cabometyx (cabozantinib), Inlyta (axitinib) and Nexavar (sorafenib), and the creation of more than a dozen new therapy options.

In the fall of 2006, 51-year-old Shaun Tierney and his wife, Mary, were enjoying their newly empty nest when he felt a tug in his groin muscle while playing golf. Suspecting bursitis of the hip, Tierney’s doctor prescribed high doses of Aleve (naproxen).

The pain worsened over several months, ultimately radiating up Tierney’s right side. In February 2007, his doctor ordered an ultrasound. Tierney, an engineer from western Massachusetts, had stage 4 bilateral kidney cancer. The disease had already spread to his lungs, liver and bones.

“The oncologist told me the cancer was inoperable and resistant to chemotherapy and radiation — and that I should get my affairs in order,” Tierney says. Because he had received a diagnosis of multiple sclerosis at age 31, Tierney wasn’t eligible for immune-based therapies such as interleukin-2. Unwilling to give up, he went to Dana-Farber for a second opinion. “That’s when the tide started to shift from total desperation toward a vision for the future,” he says.

Shortly before Tierney’s cancer diagnosis, the Food and Drug Administration (FDA) had approved the VEGF inhibitor Sutent to treat kidney cancer, and doctors at Dana-Farber were already using the drug as a first-line defense against advanced cases.

After 12 sessions of targeted high-dose radiation therapy, Tierney started on Sutent, and within six months, many of the tumors had shrunk by 50%. “That proved to be a very successful strategy, with response rates in up to 40% of patients,” Choueiri says. “It didn’t cure cancer, but it allowed patients to live longer.”

Tierney took the drug for 13 years with scheduled 10- to 14-day breaks, but it was not an easy regimen. Because Sutent blocks blood vessel formation, it produces a host of side effects. Blood vessels become more rigid and blood pressure levels can skyrocket; patients may also experience nausea, vomiting, severe diarrhea, fatigue and low blood counts, and many have trouble tolerating long-term treatment.

Choueiri, Tierney’s oncologist, made many adjustments to his treatment doses and cycle times to minimize toxicities, but the side effects became increasingly severe. Toward the end of his Sutent odyssey, Tierney’s quality of life was severely affected. The good news is that there are many other options now: During the 13 years since Tierney received his diagnosis, the FDA approved 14 treatments to treat kidney cancer. These mainly include immunotherapies and targeted drugs, plus a couple of mTOR inhibitors designed for use after preferred medications stop working.

FIGHTING CANCER WITH IMMUNE-BASED COMBINATIONS

Dating back 30 years, scientists saw deep responses and even remission with immune-based interleukin-2 therapy among a subset of patients with kidney cancer. That told doctors that kidney cancer, like melanoma, responds to immunotherapy. In 2015, the FDA approved the first checkpoint inhibitor for the treatment of kidney cancer.

This unique class of drugs works by inhibiting proteins that keep the immune system in check, thus unleashing it to fight cancer.

Unlike the cytokines of the 1990s, such as interleukin-2, checkpoint inhibitors create a more targeted immune response. “With that, we’ve seen a tremendous uptick in the degree of clinical benefits patients are deriving from therapy,” says Dr. Sumanta (Monty) Kumar Pal, a medical oncologist at City of Hope, a comprehensive cancer center in Duarte, California. Pal calls this new class of drugs Immunotherapy 2.0.

Based on work done in other tumor types, scientists began combining checkpoint inhibitors that block the activity of the proteins PD-1 and/or PD-L1, including Opdivo (nivolumab), Keytruda (pembrolizumab) and Bavencio (avelumab), with checkpoint inhibitors that block the activity of the protein CTLA-4, such as Yervoy (ipilimumab). In April 2018, the FDA approved a combi- nation of Opdivo and Yervoy after a landmark study proved the immunotherapy regimen superior to Sutent. Not only did patients in the combination group gain a survival benefit, but about 10% of them also experienced a persistent and durable remission.

In early 2019, scientists began combining VEGF-targeted treatment and immunotherapy with jaw-dropping results. Response rates for the combined treatment reach up to 60% compared with 40% using a single agent, Choueiri says. Research suggests these novel therapies may even supersede surgical removal of the tumor in some cases.

“Those two regimens, PD-1 plus CTLA-4 and PD-1 plus a VEGF inhibitor, are new standards of care in the front lines,” McDermott says. “What we lack is head-to-head data, so we can’t determine which approach is superior or which combination should be used in which patient.” Some researchers suspect that creating a triplet therapy — VEGF inhibitor plus PD-1 plus CTLA-4 &mdash; could coax the response rate to climb even higher.

The big question is whether patients must remain on treatment indefinitely to continue experiencing benefit. According to McDermott, scientists need to do more studies to determine how safe it is to stop treatment in patients with deep responses. “It may be that if you get beyond 50% shrinkage or 80% shrinkage, you can take a break,” he says. “We don’t know what that cutoff is, but we know that the deeper your response, the more likely you are to be alive at five years.”

With so many treatment options for advanced kidney cancer, oncologists often aren’t sure which road to travel first. “One good way to figure that out is to calculate the patient’s risk score by evaluating certain variables,” Pal says. These include the patient’s white and red blood cell counts, overall function and lymph node involvement. “Using these parameters, we can tell if they fall into a favorable risk category, an intermediate-risk category or a poor-risk category,” he says.

For intermediate and poor-risk patients, doctors tend to side with a PD-1/CTLA-4 immunotherapy combination. For those with favorable risk, most oncologists start with traditional targeted agents, including VEGF inhibitors, or a combination therapy with a PD-1 inhibitor and a VEGF inhibitor. This way, the side effects and risks of the therapy are balanced against the aggressiveness of the tumor to create the most favorable risk/benefit ratio.

Still, oncologists and patients alike need to tread carefully.

“It’s important for people to understand that with immune-based therapies, side effects may not happen right away,” Pal says. “When you overstimulate the immune system, you can get serious side effects like diarrhea or liver function abnormalities, but those may come on weeks after initiating therapy.”

Patients like Tierney, who have an autoimmune condition, even a controlled one, are at greater risk of triggering a catastrophic immune reaction. Because Tierney’s multiple sclerosis has been dormant for 12 years, Choueiri prescribed a combination of the infused PD-1 drug Keytruda every three weeks and a daily oral VEGF inhibitor, Inlyta, in March. The regimen is the same as what would be prescribed for a patient without an autoimmune condition; Benson has been taking it since September 2019.

No matter which regimen they try first or last, many patients are alive because they participated in clinical trials. “Many of my long-term patients started therapies five to seven years before they were FDA approved because they were involved in a clinical trial,” Alva says.

The next round of trials may focus on HIF-1-alpha; the oxygen-sensitive protein can trigger or suppress the production of red blood cells and the formation of new blood vessels.“UnlikeVEGF,PD-1andCTLA-4blockade,HIF inhibitors more directly target one of the drivers of kidney cancers,” McDermott says. “They also have a very favorable toxicity profile, which makes them a potential candidate for combination therapies.” The first trial of a HIF-2a inhibitor (MK-6482), in patients who had prior treatment for renal cell cancer, recently reported responses, and now randomized trials are planned.

As researchers uncover more options for treating advanced kidney cancer, the beneficiaries of their hard work — patients like Tierney and Benson &mdash; are welcoming grandchildren, traveling the world and adopting new hobbies, living on time afforded them by the therapies available so far.

Since starting treatment at Dana-Farber in early 2007, Tierney has joined several grassroots, advocacy groups.

He is a patient representative for Dana-Farber/Harvard Cancer Center’s kidney cancer program, raising money for kidney cancer research through the Jimmy Fund. He also supports others with kidney cancer, both in person and through a global online community.

Benson continues working for the chair manufacturer that supported him during and after his diagnosis. He loves spending time with his three children and traveling with his wife, Brenda. In fact, she transitioned from an emergency room nurse to one specializing in oncology while Benson underwent treatment. The pair will celebrate their 35th wedding anniversary in July.

Both patients agree that receiving their diagnoses when they did allow them to benefit from advances in research and treatment that gave them a fighting chance. And now that scientists are on the cusp of uncovering even more treatment options for advanced kidney cancer, “there’s reason to be hopeful,” McDermott says.

A variety of novel treatments, including immunotherapies, extend life for patients with advanced kidney cancer.

Amy Paturel

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