Unleashing the Power Within Using Tumor-Infiltrating Lymphocyte Therapy

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.

GRUELING PREPARATION

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.

TIL THERAPY IN TRIALS

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 Nature Medicine. 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.

CAVEATS WITH CUSTOMIZATION

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.