A novel treatment strategy with personalized cell therapy significantly improved progression-free survival compared to standard immunotherapy in patients with advanced melanoma, according to results from the phase III M14TIL trial reported by John Haanen, MD, PhD, and colleagues at the European Society for Medical Oncology (ESMO) Congress 2022 (Abstract LBA3).
John Haanen, MD, PhD
“This study shows for the first time in a randomized, controlled trial that cell therapy can be efficacious and beneficial for patients with solid cancers,” said lead author Dr. Haanen, of the Netherlands Cancer Institute. “For patients with melanoma, we see a 50% reduction in the chance of progression of the disease or dying from the disease, which is absolutely practice-changing. This is the first time that a tumor-infiltrating lymphocyte (TIL)-based approach has been compared directly to standard-of-care treatment—in this case, ipilimumab…. We are now able to position TIL treatment much better in the management landscape for patients with metastatic melanoma.”
“TIL therapy is an extraordinary therapy,” commented George Coukos, MD, PhD, of Lausanne University Hospital and the Ludwig Institute for Cancer Research, Lausanne, Switzerland, who was not involved in the study. “TIL is a new paradigm for treating cancers and, as these results clearly demonstrate, it’s efficacious and feasible at large scale. The findings raise hopes for the management and potential cure of metastatic solid tumors.”
George Coukos, MD, PhD
TIL Therapy
TIL therapy essentially involves taking a small sample from a patient’s resected tumor, growing immune T cells from the tumor in the laboratory, and then infusing the personalized TIL therapy back into the patient following chemotherapy. TILs recognize tumor cells as abnormal, penetrate them, and then work to kill them.
M14TIL Trial
The phase III M14TIL trial randomly assigned 168 patients with unresectable stage IIIC to IV melanoma to immunotherapy with the anti–CTLA-4 antibody ipilimumab or to TIL treatment; most patients had experienced disease progression on prior anti–PD-1 treatment. Results reported for the first time at the ESMO Congress 2022 showed that patients treated with TIL therapy had significantly longer median progression-free survival—7.2 months compared to 3.1 months in those receiving ipilimumab. The overall response rate to TIL therapy was 49% vs 21% for ipilimumab; median overall survival was 25.8 months vs 18.9 months. Patients are still being followed up for overall survival.
Treatment options for patients with metastatic melanoma have changed considerably over the last 10 years with the development of checkpoint inhibitors, including the PD-1 inhibitors nivolumab and pembrolizumab and the CTLA-4 inhibitor ipilimumab.
“[Checkpoint inhibitors] have a very good safety profile and quite high efficacy and are now often given as first-line therapy. But if patients [experience disease progression on] first-line treatments, then the options become very scarce, particularly for patients [whose disease progressed on] anti–PD-1 drugs, so there is a real unmet need,” explained Dr. Haanen. He added that in the current study, 89% of patients had experienced disease progression on anti–PD-1 treatment. The remaining patients joined the trial before anti–PD-1 therapies were licensed.
Exploring the possible mechanism by which TIL therapy is effective in patients whose disease progressed after anti-PD-1 treatment, Dr. Haanen suggested, “We think that the mechanism of resistance to anti–PD-1 treatment is mostly delivered by the tumor microenvironment. So when we take these cells out of their natural environment, reactivate them in the laboratory, grow them up to very large numbers, and give them back to the patients, we can overcome some of the escape mechanisms. And that’s what we are seeing—otherwise TILs wouldn’t work in this setting.”
Even though grade 3 or higher adverse events occurred in all patients treated with TIL therapy and 57% of those receiving ipilimumab, Dr. Haanen specified, “The side effects are well manageable, and most resolve by the time patients leave the hospital after their TIL therapy.”
He also added that most side effects were related to the other therapies, including chemotherapy and interleukin-2, which patients receive as part of the TIL regimen.
On the impact of TIL therapy, Dr. Haanen concluded, “TIL has the potential to benefit patients with a wide range of solid tumors, and trials are currently underway in many cancer types, including lung, cervical, and head and neck cancers.”
Dr. Haanen also explained that the trial was run by academics in the Netherlands and Denmark, with no industry involvement. The researchers are now working to obtain European Medicines Agency approval for their TIL therapy to try to ensure that it remains affordable, free from commercial pressures.
“The results from this phase III study could potentially lead to regulatory approval that would be practice-changing,” said Dr. Coukos. “It would enable countries that would consider this path to establish centers that can deliver TIL therapy for patients and establish this a potential second-line treatment in advanced melanoma.”
Disclosure: For full disclosures of the study authors, visit oncologypro.esmo.org.
