At age 36, Misty Romine was in so much pain she begged her doctor for a hysterectomy. She had been diagnosed with HPV with cancerous cells the year before, but follow-up tests found no evidence of disease.

However, when she woke up from surgery, doctors confirmed what Romine already knew deep down: She had cervical cancer.

“It wasn’t that big of a surprise to me,” she said. “I just said, OK, what do we have to do now?”

Romine had both squamous cell carcinoma, the most common type of cervical cancer that develops from cells in the outer part of the cervix, and clear cell carcinoma, a very rare type of the disease that occurs in the lower genital tract. She underwent extensive chemotherapy and radiation treatment in Tallahassee, and while the squamous cell carcinoma went into remission, the clear cell carcinoma had spread to her abdomen and liver.

“They told me I had six months to a year left to live,” Romine said. “I told the doctor I know my body better than you, and I know that I am not going out that soon.”

Extensive research of comprehensive cancer centers across the country brought Romine to Moffitt Cancer Center and a first-of-its-kind trial involving tumor-infiltrating lymphocyte, or TIL, therapy. This approach harvests naturally occurring T cells that have already infiltrated a patient’s tumor, activates and expands them in a lab, then re-infuses those cells into the patient to seek out and destroy cancer.

In August 2018, when Romine was enrolled in the trial, TIL had shown success only in melanoma trials and was not approved by the U.S. Food and Drug Administration (FDA) to treat cancer.

“I thought, what do I have to lose?” Romine said. “If it works for me, great. If it doesn’t, at least it will help someone in the future. If you don’t have participants in trials, you won’t find a cure for cancer.”

FIRST SUCCESSES
When the National Cancer Institute began studying TIL in the 1980s, it focused on melanoma because that is one of the most heavily mutated cancers and has the most targets an immune system can attack.

Historically, there hadn’t been many advancements in treatments for patients with advanced melanoma, and in about half of patients the disease ultimately became resistant to traditional therapies. However, the National Cancer Institute trials showed TIL could be a viable option for patients who fail first-line treatments.

In 2009, researchers from Moffitt visited the National Cancer Institute to learn the TIL protocol, and Moffitt became the first cancer center outside of the institute to offer TIL to melanoma patients. Led by surgical oncologist Amod Sarnaik, MD, a phase 2 clinical trial for patients whose advanced melanoma had not responded to other treatments reported a 38% response rate to TIL. The data is currently under review and Sarnaik is optimistic the treatment will soon be FDA approved.

"I am very blessed to be in a position to actually see the genesis of a treatment at our center, carrying it all the way to regulatory approval. It’s a rare thing and hard to imagine at the time, but patients we treated 12 years ago are still in durable remission from their, at the time, incurable metastatic melanoma."

- Dr. Amod Sarnaik, surgical oncologist

“I am very blessed to be in a position to actually see the genesis of a treatment at our center, carrying it all the way to regulatory approval,” Sarnaik said. “It’s a rare thing and hard to imagine at the time, but patients we treated 12 years ago are still in durable remission from their, at the time, incurable metastatic melanoma.”

So far, Moffitt has treated about 80 melanoma patients on TIL trials, and once the treatment receives FDA approval, the cancer center estimates it will treat 50 to 60 patients annually to start. Sarnaik says the team is also continuing to investigate how to make TIL more successful for melanoma patients, including ways to speed up the cell manufacturing process, selecting more tumor-reactive TILs and combining TIL with other promising treatment options.

NOT ONE SIZE FITS ALL
As Moffitt clinicians and researchers began to see success with TIL in melanoma, they started to study the treatment in other solid tumor types. The biggest challenge with the therapy is that it’s not a one-size-fits-all treatment. Instead of recognizing a defined protein on a cancer cell, a TIL recognizes whatever that specific tumor is expressing. Even if patients have the same cancer type, their TIL product may not recognize the same thing.

“There are some really big outstanding questions, like what are the characteristics of a cell product that are the best? We still don’t know what we want our TIL product to look like,” said Shari Pilon-Thomas, PhD, an immunologist and co-director of Moffitt’s Center for Immunization and Infection Research in Cancer. “Another big question is how do we measure it? What tests do we do on a TIL product that are the most meaningful and that are going to correlate with a patient response?”

Moffitt researchers have received more than $26 million in grants to study TIL, and since 2015, they have launched 16 research projects focused on optimizing the cellular therapy.

One of those projects, partially supported by the SuzyQ Foundation and led by Pilon-Thomas and immunologist Daniel Abate-Daga, PhD, is focused on finding ways to stimulate TILs to grow more efficiently for lung cancer and melanoma patients. When a tumor is taken out of a patient, it contains the T cells that will be expanded in the lab for treatment, but also a mixture of other cells, including B cells, which specialize in producing antibodies.

“Our work started with the question of whether we can capitalize on the presence of those other immune cells in the tumor to make TILs even better or facilitate the expansion of those TILs,” Abate-Daga said. “Can we indirectly stimulate T cells by directly stimulating the B cell compartment?”

Other research projects are trying to solve the puzzle of timing: when to harvest a patient’s T cells and when to infuse a patient with the TILs so the treatment has the greatest chance of working. Many solid tumor patients have already undergone extensive chemotherapy or radiation prior to TIL, which could damage their immune system and reduce their chances of responding to cellular therapy. Studies are underway to investigate whether TILs can be made from a frozen tumor specimen if immune cells can be collected prior to any treatment and banked for later if needed.

To continue this important research, partnering with pharmaceutical and biotechnology companies is key. This summer, Moffitt announced a new strategic alliance with Turnstone Biologics Corp., a clinical-stage biotechnology company developing next-generation immunotherapies to treat solid tumors. Through this partnership, Moffitt will collaborate on the development of Turnstone’s pipeline of selected TILs for solid tumor indications, including melanoma, breast and colorectal cancers. The cancer center will also assist Turnstone with TIL manufacturing for upcoming clinical studies.

“It’s a win-win for both of us,” Pilon-Thomas said. “They get data and their trials up and running, and we get a lot of opportunity to do research that will benefit our patients.”

The new alliance’s first task is a Moffitt-sponsored phase 1 clinical trial evaluating a new TIL product in cutaneous and noncutaneous melanoma.

To help prioritize upcoming projects and other partnership opportunities, the TIL working group was established in early 2021. It comprises more than a dozen researchers and providers working in the field who share research ideas and decide which potential collaborations align closest with Moffitt’s goals.

“The industry has exploded — everyone wants to do cellular therapies right now,” Pilon-Thomas said. “We have resources that are limited and we can’t do everything, so the main focus of the group is to talk with the companies interested in partnering with Moffitt and determine where they fall on a list of who we want to move forward with.”

‘WINNING THE LOTTERY’
Since 2009, Moffitt has opened eight TIL clinical trials across multiple disease sites, with three more planned to open in the near future.

One of those trials is the cervical TIL trial that Misty Romine was part of. After receiving what she calls her “expiration date,” she was more than ready to give the experimental treatment a shot.

“I just knew that I wasn’t going to be gone in a year, I just knew it. I just know my body, and I knew I could keep fighting longer than that,” she said.

At Moffitt, Romine’s T cells were collected, expanded and, after a round of conditioning chemotherapy, reinfused back into her. The treatment came with some intense side effects, but three months later, Romine’s cancer had drastically decreased in size. Three months after that, her cancer was gone.

“It was like winning the lottery,” Romine said.

While Romine was the only patient out of five on the Moffitt trial to achieve a complete response to the treatment, there were others who achieved partial response.

"The fact that we had a patient, who was heavily pre-treated for years before her infusion, have a complete response makes us think, hey, this is something. We have more details to figure out, such as how and why it works in some and not others and make changes, but it’s pretty exciting."

- Dr. Robert Wenham, chair, Gynecological Oncology Program

“Cervical cancer is incurable once the patient has metastatic disease. The median life expectancy from the most recent data we have is at best two years,” gynecologic oncologist and trial co-principal investigator Robert Wenham, MD, said. “The fact that we had a patient, who was heavily pre-treated for years before her infusion, have a complete response makes us think, hey, this is something. We have more details to figure out, such as how and why it works in some and not others and make changes, but it’s pretty exciting.”

One arm of the trial is still open for patients who have never had any other systematic treatment for metastatic cervical cancer, and there are plans to reopen an arm for patients who have had prior treatment, particularly an immune checkpoint inhibitor.

The first-ever lung cancer TIL trial led by medical oncologist Ben Creelan, MD, has also seen success. Two of 16 advanced non-small cell lung cancer patients on the trial had a complete response after receiving the immunotherapy drug nivolumab prior to their TIL infusion.

Moffitt was also the first in the country to open a TIL trial in sarcoma for adolescent and young adult patients between ages 18 and 39 with metastatic sarcoma who have failed at least one other standard treatment therapy. While results are still pending, the team, led by surgical oncologist John Mullinax, MD, is also focusing on ways to optimize the treatment that patients receive on future trials.

Preclinical work is being done in multiple other solid tumor types, with the hopes of opening more novel trials in the future:

• PENILE CANCER: Only about 15% of patients with advanced disease will respond to chemotherapy, and almost half of patients will see disease progression. Early research shows TIL could be highly effective for patients who are HPV-positive or HPV-negative, and patients who have or have not received prior chemotherapy. The goal is to open a small pilot study combining TIL with immunotherapy for patients who are not good candidates for chemotherapy or who did not respond to chemotherapy.
• BLADDER CANCER: High-risk stage 1 bladder cancer tumors that fail first-line treatment have a less than 50% chance of responding to a secondline treatment or require surgical removal of the bladder. With funding from the Department of Defense, Moffitt has plans to open a clinical trial treating patients with intravesical TIL for Bacillus Calmette-Guerin-unresponsive bladder cancer. Instead of infusing the TILs back into a patient’s bloodstream, the TILs will be directed into the bladder via a catheter, which eliminates the need for preconditioning chemotherapy. This will also be the first time TIL is being used in an early stage cancer instead of metastatic disease.
• KIDNEY CANCER: Even though there has been progress with immune therapies, about 90% of advanced stage patients will still relapse. With no other good treatments, researchers are hoping TIL could be an option in the future. Preclinical work is underway to investigate how to optimize TIL for those patients.
• BREAST CANCER: Triple-negative breast cancer is considered aggressive because it grows quickly, has usually spread by the time it is diagnosed, and is more likely to come back after treatment. As part of the Turnstone Alliance, Moffitt is planning on using the company’s TIL technology in an upcoming trial to see if TIL can benefit these patients.

AHEAD OF THE GAME
There are a lot of pieces of the puzzle that need to be in place for a hospital to offer a cellular therapy like TIL to patients.

“You can’t just go anywhere and get put on a TIL trial,” PilonThomas said. “You have to have open trials, even better if it’s an investigator-initiated trial. You also have to be able to manufacture the cells or be able to get them. We are ahead of the game.”

Moffitt’s Cell Therapies Core is one of only five labs across the country selected by the National Institutes of Health to do diverse cell therapy research. The 10,000-square-foot facility produces more than 700 cellular therapies a year, which can be given to Moffitt patients or cryopreserved and shipped to outside hospitals.

In 2020, Moffitt opened the Immune Cell Therapy (ICE-T) unit to treat patients with cellular immunotherapies like chimeric antigen receptor T-cell therapy (CAR T). The unit has 12 inpatient beds and eight treatment bays for outpatient visits, and while it is usually filled with blood cancer patients, solid tumor patients enrolled in cellular immunotherapy trials are also treated on the floor.

“About a third of the cellular therapy trials we operate in ICE-T are for solid tumor patients,” said Frederick Locke, MD, chair of the Blood and Marrow Transplant and Cellular Immunotherapy Department and co-leader of the Immuno-Oncology Program. “The absolute number of patients we treat is lower, but as we get more trials and more FDA approvals we will be able to help more solid tumor patients.”

The ICE-T unit is also open to solid tumor physicians for rounding, where they can get experience treating both solid tumor and blood cancer patients and learn more about cellular therapies. This, combined with the infrastructure and protocols already in place, will make it easy to ramp up cellular therapy treatment for solid tumor patients when the time comes.

“I think once you get one FDA approval the field explodes, just like in CAR T. One approval and all of the sudden, you are able to test the treatment in multiple tumor types in clinical trials,” PilonThomas said.

Patient Misty Romine agrees: This is only the beginning.

“I don’t think a lot of patients even realize this is an option. I think TIL has a future in cancer treatments, and it’s so amazing to see them learning new things every day and making new discoveries every day.”

Romine is nearing the end of her five-year follow-up period and remains cancer free. She’s not sure why she responded so well to TIL but is hoping other patients can find the same cure in the future. “If there’s anything else I can do to help, I will,” she said. “I owe Moffitt my life.”

This article originally appeared in Moffitt’s Momentum magazine.