The FDA has approved lifileucel (Amtagvi) as the first tumor-infiltrating lymphocyte (TIL) therapy for the treatment of advanced melanoma that has progressed following treatment with PD-1/PD-L1-targeted immune checkpoint inhibitors or BRAF inhibitors. This approval marks a significant milestone in cancer immunotherapy, offering a new personalized treatment option for patients with limited alternatives. The accelerated approval was granted based on clinical trial data demonstrating durable responses in a subset of patients with heavily pretreated metastatic melanoma.
How Lifileucel Works
Lifileucel is a form of personalized immunotherapy that leverages the patient's own immune cells to fight cancer. Unlike CAR T-cell therapy, TIL therapy uses T cells extracted directly from the patient's tumor. These TILs have already demonstrated the ability to recognize and infiltrate the tumor microenvironment. The process involves:
- Tumor Extraction: A sample of the patient's tumor is surgically removed.
- TIL Isolation: T cells that have infiltrated the tumor (TILs) are isolated from the tumor tissue.
- TIL Expansion: The isolated TILs are expanded in the laboratory to generate a large number of cancer-fighting immune cells.
- Lymphodepletion: Prior to infusion, patients undergo lymphodepleting chemotherapy to deplete existing immune cells and enhance the engraftment and efficacy of the infused TILs.
- TIL Infusion: The expanded TILs are infused back into the patient, along with doses of IL-2 to stimulate their anti-tumor activity.
Clinical Trial Results
The FDA's approval was based on data from a clinical trial of patients with advanced melanoma who had progressed on prior therapies. Key findings from the trial include:
- In a group of 73 patients, nearly one-third experienced a reduction in tumor size.
- Approximately 40% of responders had no disease progression one year after the one-time infusion.
- Longer-term data from a larger group of 153 patients showed similar results, with durable responses observed in a subset of patients.
- Responses were less likely in patients with brain or liver metastases or high tumor burden.
Martin Wermke, M.D., Ph.D., of the University of Dresden in Germany, reported at the ESMO meeting that some patients experienced ongoing responses lasting several years, with the longest lasting response approaching five years.
Side Effects and Considerations
All patients in the clinical trial experienced side effects, primarily related to the lymphodepleting chemotherapy and IL-2 administration. Common side effects included anemia, fever, and decreased platelet and white blood cell counts. Unlike CAR T-cell therapy, TIL therapy does not appear to cause cytokine release syndrome or severe neurologic effects.
William Sharfman, M.D., of Johns Hopkins Sidney Kimmel Cancer Center, noted that patients need to be relatively healthy with normal heart and lung function to be eligible for lifileucel treatment. Alexander Shoushtari, M.D., of Memorial Sloan Kettering Cancer Center, added that the high doses of chemotherapy and IL-2 limit the types of patients who can undergo the treatment.
The Future of TIL Therapy
Iovance Biotherapeutics, the manufacturer of lifileucel, has established over 30 treatment centers across the United States for TIL collection and administration, with plans to expand to 50 centers by the end of May. The company has priced lifileucel at $515,000 per treatment and has established a financial assistance program for patients.
Iovance is also investigating lifileucel in combination with pembrolizumab (Keytruda) as a first-line treatment for advanced melanoma. Furthermore, lifileucel is being evaluated in other solid tumors, including lung, ovarian, and head and neck cancers.
Researchers are also working on next-generation TIL therapies with enhanced potency and broader applicability. These efforts include genetic engineering of TILs to improve tumor recognition and eliminate the need for chemotherapy or IL-2.
Steven Rosenberg, M.D., of the National Cancer Institute (NCI), emphasized that decades of research on cellular therapies have paved the way for rapid advances in cancer immunotherapy. He stated, "We now have the knowledge of how to help the immune system target tumors," particularly solid tumors, which are responsible for the majority of cancer deaths.
