Empowering the Immune System

Katie Ortman Doble was 31 years old when she was diagnosed with ocular melanoma, a rare type of cancer that originates in the eye, in May 2013. Since the cancer was contained to her eye, she underwent plaque therapy, a type of radiation therapy, and a biopsy to assess the disease further.

“I received a phone call a few weeks later letting me know that my cells were the best-case scenario,” Doble, now 43 and living in Denver, tells CURE. “They were classified as 1A, which meant there was a less than 2% chance that they would ever spread. So, I thought that was it.”

Her doctor advised Doble to undergo imaging every six months. Doble had clear images in April 2014. But in November 2014, imaging showed that there were at least 12 suspicious lesions on her liver. A biopsy needed to be done immediately.

The biopsy confirmed that she had stage 4 incurable cancer, and her oncologist told her she had 16 months to live. With limited options based on her disease’s genetic makeup, Doble’s father helped her find a clinical trial to participate in. This led Doble, her father and her fiancé across the United States to participate in multiple clinical trials and traditional therapies from January 2015 to mid 2018. She was eliminated from each trial due to side effects or tumor growth, but liver embolization, which is only Food and Drug Administration (FDA)-approved for metastatic colon cancer, stabilized her liver for several years.

After tumor growth in her liver was noticed in June 2020, she was connected with a doctor at the University of Pittsburgh Medical Center’s Hillman Cancer Center, who was conducting a trial in tumor-infiltrating lymphocyte (TIL) therapy.

“The way that the doctor described it was that he was essentially going to wipe out my immune system with chemotherapy, like you would wipe out a computer, then you reinstall the programs. He was then going

to reinstall this cancer that was taken out of my body and programmed like a robot to go back in and attack itself,” Doble says.

Doble underwent tumor banking in July 2020. The TILs were manufactured, and she underwent preparatory lymphodepleting chemotherapy, TIL infusion and high-dose interleukin-2 (IL-2) in September 2020.

“Every scan that I had, we were seeing really, really good results,” Doble says. “My doctor — he kept calling it a bumper crop of cells, like I had one of the largest batches of cells he’d ever grown before.”

Some tumors were disappearing, Doble adds, but one tumor on her liver kept growing. So, in September 2021, she and her husband flew back to Pittsburgh to have half of her liver removed.

“I woke up from that surgery, [my husband] Nick was sitting in the corner, and he was like, ‘He got it all. You have no evidence of disease,’” Doble recalls.

“It was a miracle day. I have had no evidence of disease for over three years now.”

TIL Therapy in Melanoma

Amtagvi (lifileucel) was the first TIL therapy approved by the FDA, in February 2024, for the treatment of patients with advanced melanoma whose disease progressed on or after anti-PD-1/PD-L1 therapy and targeted therapy.

“In the past, we only had immunotherapy and targeted therapy as standard options for these patients,” Dr. Sunandana Chandra, associate professor of medicine at Northwestern University Feinberg School of Medicine in Chicago, says in an interview with CURE. “Now we have not only another option, but an option that is very different from the existing approved regimens for metastatic melanoma.”

Chandra adds that this new treatment still has benefits and risks associated with it.

“The upside with TIL therapy is that it’s this novel, first-in-its-class approval [for] metastatic melanoma, where we’re using the patient’s own immune cells against the cancer,” she says. “The downside of TIL therapy is that it’s a rigorous regimen. It requires a huge commitment

from the patient. It is only able to be given in a very limited number of sites across the country.”

Another barrier to TIL therapy is the cost. According to a post on the National Cancer Institute’s website, the manufacturer of Amtagvi noted that a single treatment would cost $515,000, although the company said that financial assistance programs will be established for patients.

“[TIL therapy] is a therapy that, if it is effective, it’s a one-time treatment,” says Dr. Adam J. Schoenfeld, thoracic medical oncologist, and cellular therapist and early drug development specialist at Memorial Sloan Kettering Cancer Center in New York. “So, you don’t have to have repeated treatments down the road.”

Steps Involved in TIL Therapy

Patients who may be eligible for TIL therapy are those with advanced melanoma whose disease either progressed on or responded poorly by way of side effects to PD-1 antibody-based therapy, predominately Opdivo (nivolumab) or Keytruda (pembrolizumab). Given the rigor of TIL therapy, patients whose tumors have BRAF mutations are required to have disease progression after targeted inhibitor therapy prior to TIL therapy since targeted inhibitor therapy is less rigorous for patients.

Performance status is another assessment that is taken into consideration when determining whether a patient is a candidate for TIL therapy. This status factors in how functional a person is in their daily life, strength, time spent out of bed or a chair, and daily activities, among other factors. Care teams also assess each organ’s function — particularly the kidneys, heart and lungs.

Once a patient is considered eligible to undergo TIL therapy, the first step is surgery, during which a piece of the tumor is removed to obtain the material needed to make the T cells.

After tumor resection, the patient can return home, and the manufacturing period begins for the TIL product, which is done in an off-site facility. During this time, a patient may undergo bridging therapy or another treatment.

“In the lab, that tumor specimen that was obtained from the patient is then essentially chopped up, and the patient’s own T cells are extracted from it,” Chandra says. “Those T cells have been grown in the lab [and] — about three to four weeks later — are ready to be infused back into the patient.”

Before the TIL cells are infused, the patient undergoes lymphodepleting chemotherapy for five to seven days.

“Normally, we think about chemotherapy as a way to kill rapidly growing cancer cells,” Schoenfeld says. “But here, we’re actually using chemotherapy as a way to reset the clock on your immune system and create space for the TIL to grow when we infuse the TIL.”

After the lymphodepleting chemotherapy is completed, the patient receives the
TIL infusion in the hospital through a vein. During this time, experts say that patients receive up to a trillion T cells that were grown in the laboratory. A patient undergoing TIL is then closely monitored by their care team.

Following that, the patient is treated with high-dose IL-2, boosting the immune system in cancer therapy. This regimen is administered for up to six doses and may take a few days to complete.

“This [IL-2] is what is used to grow the TIL,” Dr. Amod Sarnaik, professor of cutaneous oncology and immunology at Moffitt Cancer Center and the University of South Florida in Tampa, Florida, tells CURE. “So, the thought is that if you just give the TIL without the [IL-2] ... that abrupt withdrawal may cause some problems for the TIL because they’re used to being grown in the high concentration of the [IL-2].”

This entire process, from tumor harvesting to completion of high-dose IL-2, experts say, can take between six and eight weeks. Toward the end of the process, usually after receiving high-dose IL-2, a patient can be discharged home if deemed appropriate. The patient then undergoes subsequent scans in an outpatient setting for care teams to determine whether the TIL therapy had an effect on the cancer.

Emotionally Investing in TIL Therapy

Jamie Troil Goldfarb, now a 47-year-old living in Takoma Park, Maryland, with her husband and 14-year-old son, was diagnosed with stage 2B melanoma in 2007. The 32-year-old, at that time, underwent surgery to remove it, and a sentinel lymph node biopsy showed clear results. After Goldfarb experienced several infections, her oncologist called the surgeon and urged him to investigate further to see whether a suture was left behind. During that surgery in December 2009, it was discovered that she had stage 3 melanoma, for which a wait-and-watch approach was suggested.

In January 2011, three months after Goldfarb gave birth to her son, Kai, her oncologist recommended she undergo a scan before she returned to work from maternity leave. That is when she learned that the cancer had metastasized to her liver and pancreas, marking her disease as stage 4, and her care team gave her a 15% chance of survival.

With her experience in patient recruitment for a company that conducted clinical trials, she knew immediately to look for options. She found a study assessing TIL therapy in melanoma, for which she was eligible.

Compared with the FDA-approved regimen with Amtagvi, Goldfarb received four full rounds of IL-2 before receiving the lymphodepleting chemotherapy and then the TIL infusion in September 2011. This TIL infusion was somewhat different from Amtagvi, as researchers took Goldfarb’s cancer cells and genetically engineered them to express IL-12 upon contact with the tumor.

Initially, months after the infusion, scans showed that her tumor was growing, which led the research team to consider other treatment options, although Goldfarb was not ready to do that. “I was very emotionally [invested in] this really intense clinical trial for TIL and then being cured,” she recalls.

In January 2012, her scans started to show that the tumors were shrinking.

“All of the tumors shrank over the next two years until I had no evidence of disease, and it’s been 12 years now, completely disease-free,” Goldfarb says. “My diagnosing physician told me that he would do everything in his power to buy me six months with the baby, and [Kai] just turned 14 last week.”

Side Effect Profile

Most of the side effects of this regimen may be associated with the lymphodepleting chemotherapy before the TIL infusion and the high-dose IL-2 after the infusion.

“I got a rash from the chemotherapy, and I couldn’t take steroids,” Doble recalls. “That was really uncomfortable. The TIL experience, it was a 22-minute infusion. It was totally uneventful. And then once the IL-2 hit, that’s when it kind of went downhill. ... [My doctor] was thrilled that I felt like s---. He’d come in and he’d be like, ‘This is good, Katie. This is so good because it means you’re responding.’”

Side effects associated with Amtagvi, according to the FDA, include fever, chills, tachycardia (abnormally fast heart rate), fatigue, febrile neutropenia (fever with a low level of certain white blood cells), diarrhea, rash, edema (swelling from fluid buildup in tissues), low blood pressure, infection, hair loss, shortness of breath and abnormally low oxygen levels.

“The TILs are designed to attack the tumor, but remember, the tumor came from our own cells, so the tumor and normal tissues sometimes share similar targets,” Sarnaik says.

Goldfarb mentions that she got vitiligo as a potential result of the TIL therapy, but other than that, she did not experience any other long-term side effects.

“I got [vitiligo] as an initial side effect around my neck,” she says. “And then five years ago, it [spread]. ... So now it’s everywhere, which is fine. ... I’d rather have vitiligo than cancer.”

With the high-dose IL-2, experts say that side effects can be “somewhat profound in the short term,” Schoenfeld says. This response, he adds, is because IL-2 stimulates the immune system, so it may cause shaking chills, fever, capillary leak syndrome (when fluid leaks outside of blood vessels and into legs and arms), and fluid around the lungs, causing shortness of breath.

Experts say that after a month or couple months after receiving TIL, patients typically regain their strength.

TIL Therapy in Other Cancer Types

Melanoma was one of the first cancers to be assessed in TIL therapy trials because of how heavily mutated it can present, experts say. Researchers are currently seeing whether TIL therapy can derive similar success in cancers that are also heavily mutated, such as lung cancer.

Studies are also focusing on the potential of TIL therapy in cancers caused by viruses, such as cervical cancer and head and neck cancer. Experts note that cancers with unstable DNA repair mechanisms, such as colorectal cancer, may also see success with TIL therapy. Research is also aimed at assessing TIL therapy in patients with aggressive cancers with minimal treatment options, such as gastrointestinal malignancies and sarcoma.

In addition to assessing the potential benefit of TIL therapy in other cancer types, researchers are aiming to see how TIL therapy itself
can be improved and expanded. For example, researchers are seeing whether there are more effective ways to manufacture TIL, such as identifying TILs that could be expanded or engineering TILs to make them more active. Additionally, researchers are investigating whether there is a way to manufacture TILs so they have other properties to potentially eliminate the need for chemotherapy before or high-dose IL-2 after the treatment.

Goldfarb says she “screams the praises of TIL every chance I get.”

“Every time [my son, Kai,] has a birthday, I think about how lucky I am that I get to see it,” she says.

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