Tumor Infiltrating Lymphocytes (TIL) as a first of kind FDA approved immunotherapy for cancer
Reporter: Stephen J. Williams, Ph.D.
Decades of pioneering research led to a first-of-its-kind FDA approval for a new type of immunotherapy—tumor-infiltrating lymphocyte (TIL) therapy.
Tumor infiltrating lymphocytes (TILs) have been thought for years to be a key immune regulator of the growth of tumor cells and these specialized T-cells have been found in many tumor microenvironments, especially in solid malignancies. It was felt, if one could purify these immune cells and genetically alter them to induce a killer T-cell response, these modified TILs would be a great therapeutic. However it has been a challenge to purify, modify, and induce these cells to be able to infiltrate the tumor microenvironment. These issues restricted their therapeutic utility towards solid tumors and posed this challenge for decades. However, just recently the FDA has approved a TIL therapy for metastatic melanoma, especially for those melanomas that failed PD-L1 immunotherapies or B-Raf inhibitors (if expressing the corresponding B-Raf mutation.
Jennifer Ficko has been cancer-free for more than seven years, thanks to a clinical trial and an innovative form of immunotherapy. Diagnosed with stage 4 melanoma in 2010, she enrolled in several clinical trials to little avail—the tumor either didn’t respond, or the treatment led to debilitating side effects. That was until 2017, when Jennifer enrolled in a clinical trial evaluating lifileucel, a novel type of immunotherapy called tumor-infiltrating lymphocyte (TIL) therapy. The treatment left her weak for months afterward—but it worked. Her tumors disappeared, and she has not had any recurrences since. The success of lifileucel for Jennifer and many other patients enrolled in the clinical trial led to its approval in 2024 (under the brand name Amtagvi), making it the first treatment of its kind to be greenlit by the U.S. Food and Drug Administration (FDA).
“Today I’m doing fabulously, and I am just thankful that I was given this opportunity,” said Jennifer, who was featured in the AACR Cancer Progress Report 2024.
The premise of TIL therapy was pioneered by Steven A. Rosenberg, MD, PhD, chief of surgery at the National Cancer Institute (NCI) and a Fellow of the AACR Academy, who long hypothesized that the patient’s immune system could be a powerful ally in the fight against cancer. “The accumulation of associative evidence led me to spend my entire career trying to find immunotherapies for the treatment of patients with cancer,” he said.Dr. Rosenberg remained committed to developing effective TIL therapy for more than three decades, leading the field in developing, testing, and enhancing this novel form of cancer treatment—research that was made possible by federal investments in the NCI.
What is TIL Therapy?
Lifileucel and other TIL therapies under investigation work through the same basic principle: collect the patient’s tumor tissue through biopsy or surgery, isolate from the tissue the T cells that have infiltrated the tumor (called TILs), promote proliferation of the isolated TILs to increase their number, and deliver the expanded TILs back into the patient along with an infusion of the protein IL-2 to stimulate TIL proliferation and activation within the patient’s body.
The 30-year Journey From Discovery to FDA Approval
The story of TIL therapy can be traced back to 1986, when Dr. Rosenberg and colleagues reported the discovery of TILs in human tumors and a method to expand them in the lab. When the human TILs were expanded and injected into mice, they led to regression of metastatic tumors in the liver and lungs. During the 1980s and ’90s, Dr. Rosenberg spearheaded clinical trials at the NCI testing TILs in patients. The trials illustrated the promise of TILs for cancer therapy, but they also revealed the shortcomings of this approach—namely the short-lived nature of treatment responses. Dr. Rosenberg and others continued to explore ways to overcome the challenges facing TIL therapy. In the early 2000s, they found that using chemotherapy to deplete the patient’s own immune cells prior to TIL infusion (called lymphodepleting conditioning) increased response rates and made responses more durable. Over the following decade, it became increasingly clear that TILs could be effective for patients whose melanomas did not respond to established treatments, and, in late 2023, researchers reported that almost 50% of patients who were treated with lifileucel after prior therapy were alive four years later—data that led to the historic FDA approval of lifileucel in January 2024.
The Importance of Cancer Research
“We have had a lot of progress in [treating] melanoma in the last 20 years,” said Harriet Kluger, MD, Jennifer’s oncologist and a professor of medicine at Yale University who was involved in the clinical testing of lifileucel. “We are able to control metastatic melanoma, and possibly even cure, in at least half of our patients now, but half isn’t enough. “That’s why these new therapies are important. Particularly, lifileucel is approved for patients in whom the other approved drugs don’t work,” she added. “Any time we can get results in that setting, we are getting closer and closer to our overall goal, which is curing 100% of our patients 100% of the time.”
Advances like these rely on investments to fund the basic, translational, and clinical research that pave the way for life-saving therapeutics for patients. “Cancer research is expensive, scientific research is expensive. And the more people we have that are smart, that have been educated appropriately, that are creative and innovative, the more of those people we can bring into research against deadly diseases such as cancer, the more rapidly progress will be made,” said Dr. Rosenberg.“The resources to do that, provided by the government as well as private institutions, I think [are] going to play a very important role. It has played an important role and will continue to play an important role.”
Other Articles of Note on Cancer Immunotherapy and Tumor Infiltrating Lymphocytes on this Open Access Online Scientific Journal Include:
Cancer-free after immunotherapy treatment: Treating advanced colon cancer – targeting KRAS gene mutation by tumor-infiltrating lymphocytes (TILs) and Killer T-cells (NK)
LIVE – 8/29 – CHI’s Oncolytic Virus Immunotherapy and ADOPTIVE CELL THERAPY, August 28-29, 2017 Sheraton Boston Hotel | Boston, MA
Another Promise for Immune Oncology
Issues Need to be Resolved With ImmunoModulatory Therapies: NK cells, mAbs, and adoptive T cells
Sleeping Threats: Immune System’s Watch on Dormant Cancer
Scanning electron micrograph of a human T lymphocyte (also called a T cell) from the immune system of a healthy donor. NIAID
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