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PARIS -- More than twice as many patients with previously treated advanced melanoma remained progression-free at 6 months when they received their own tumor infiltrating lymphocytes (TILs) instead of immunotherapy, a randomized trial showed.

The primary data showed a 6-month progression-free survival (PFS) rate of 52.7% with TILs versus 21.4% with ipilimumab (Yervoy). A subgroup analysis showed that patients in almost all clinical and demographic categories benefited from TILs. A preliminary survival analysis showed a 2-year overall survival (OS) rate of 54.3% in the TIL group versus 44.1% in the control arm.

Despite potential production and funding issues, TILs could help address the substantial unmet need for effective treatment following progression on first-line immunotherapy, said John Haanen, MD, of the Netherlands Cancer Institute in Amsterdam, at the European Society for Medical Oncology (ESMO) annual congress.

"This is the first randomized trial investigating T-cell therapy in solid tumors, in this case, TILs as a second-line standard of care in patients with metastatic melanoma," he said in his concluding remarks. "TILs significantly improved progression-free survival compared to ipilimumab as first or second-line treatment, especially in patients with anti-PD-1-refractory disease."

"There were no new safety issues seen, as compared with what we know about lymphodepleting chemotherapy and interleukin-2. Health-related quality of life scores were higher in patients treated with TILs. Therefore, we think that TILs could become a possible new treatment option for patients with advanced melanoma," he added.

ESMO invited discussant Ignacio Melero, MD, PhD, of the University of Navarra in Spain, lauded Haanen and colleagues for their persistence to investigate a therapy that dates back more than 30 years but has gotten little traction in the oncology field, in large part because it is labor intensive and time consuming. He also alluded to other obstacles in the path to clinical practicality.

"I think there is sufficient information and evidence here to support the standard practice of TIL therapy in unresectable stage III patients or metastatic melanoma following anti-PD-1 failure," said Melero. "There is a clear unmet need for predictive biomarkers. ... Then we need logistical solutions for implementation in industry and academia. Pricing is clearly going to be an issue."

In his introductory remarks, Haanen noted that immune checkpoint inhibitors and targeted therapies have dramatically improved outcomes in advanced melanoma. Nonetheless, about half of patients with stage IV disease do not survive 5 years, creating a need for effective therapies to offer patients whose disease progresses on first-line immunotherapy.

As far back as the mid-1980s, investigators recognized that tumors contained components of the immune system, in addition to malignant cells. They hypothesized that enrichment of tumor tissue with tumor-recognizing T cells represented a novel strategy to treat cancer. Investigators at the National Cancer Institute, led by Steven A. Rosenberg, MD, PhD, provided , showing that mouse melanoma TIL cultures expanded in interleukin-2 could be used to treat the tumors.

More than 15 years later, Rosenberg and colleagues showed that TILs , too.

"In subsequent small and moderate-size phase I and II studies, performed mostly at academic institutions, these data were confirmed, and more recently by commercial entities," said Haanen. "They have shown that TILs, even in heavily treated patients, can have a clear effect."

Investigators in the Netherlands and Denmark collaborated to perform the first-ever randomized trial of T-cell therapy, using a production process similar to the one developed for early clinical studies. A resected tumor is either fragmented or enzymatically digested and cultured in an interleukin-2-enriched medium.

The cells are rapidly expanded in the presence of anti-CD3 antibodies and irradiated feeder cells to a total of two billion cells, which are infused in patients who have been pretreated with nonmyeloablative chemotherapy. The single infusion of TILs is followed by high-dose interleukin-2. Haanen said the entire process takes 4 to 5 weeks to complete.

Investigators enrolled patients with previously treated metastatic melanoma that had progressed on first-line immunotherapy. Patients were randomized to TILs or ipilimumab. The primary endpoint was PFS at 6 months, and the trial was powered to detect improvement from an estimated 20-25% with ipilimumab to 45% with TILs.

Data analysis included 168 patients. The primary analysis showed that TILs exceeded the predefined efficacy criteria, as the absolute difference between the treatment arms represented a 50% reduction in the PFS hazard (95% CI 0.35-0.72, P<0.001). With a median follow-up of 33 months, the median PFS was 7.2 months with TILs and 3.1 months with ipilimumab.

The TIL therapy led to more than twice as many objective responses (48.8% vs 21.4%), including almost three times as many complete responses (20.2% vs 7.1%). The clinical benefit rate (response plus stable disease) was 67.9% with TILs and 39.3% with ipilimumab.

Survival data remain immature, but a preliminary analysis showed a trend in favor of the TIL arm, which had a median overall survival of 25.8 months versus 18.9 months for the control group.

Grade ≥3 adverse events (AEs) were common with TIL therapy. The pre-infusion chemotherapy led to neutropenia in 100% of patients, thrombocytopenia in 89%, febrile neutropenia in 84%, and lymphopenia in 71%. Grade ≥3 AEs associated with TILs included febrile neutropenia in 73% of patients, hypophosphatemia in 60%, and fever in 45%.

Health-related quality of life favored the TIL arm, reaching a statistically significant difference at 6 months (P<0.01).

Despite the positive results, Haanen acknowledged challenges with moving forward with TILs. Beyond the lengthy and labor-intensive production process, the randomized trial was conducted without industry support. Some biopharma companies have begun to show interest, he said, but the bulk of the work continues to be conducted within academic settings.

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