3d illustration of a cross-section of a diseased skin with melanoma that enters the bloodstream and lymphatic tract
Credit: Christoph Burgstedt/Getty Images

A team from the Netherlands Cancer Institute in Amsterdam have shown for the first time in a randomized, controlled trial that cell therapy can delay disease progression in patients with advanced melanoma when compared with standard immunotherapy.

Speaking at the ESMO Congress 2022 in Paris, lead researcher professor John Haanen said: “This is the first time that a TIL [tumor infiltrating lymphocyte]-based approach has been compared directly to standard-of-care treatment, in this case ipilimumab. So, we are now able to position TIL treatment much better in the management landscape for patients with metastatic melanoma.”

In the last 10 years, the number of treatment options for patients with metastatic melanoma has increased greatly and now includes immune checkpoint inhibitors such as the PD-1 inhibitors nivolumab and pembrolizumab and the CTLA-4 inhibitor ipilimumab.

These drugs inhibit proteins that normally dampen the immune response, which in turn enhances the ability of the immune system to attack cancer cells. “They have a very good safety profile and quite high efficacy and are now often given as first-line therapy. But if patients fail first-line treatments, then the options become very scarce, particularly for patients failing anti-PD-1 drugs. So there is a real unmet need,” Haanen explained.

TIL therapy has previously shown promising response rates in Phase I and Phase II trials among patients with advanced melanoma, but the treatment has not been tested in the current immunotherapy landscape.

To address this, Haanen and team carried out the Phase III M14TIL trial. The study included 168 patients with unresectable stage IIIC–IV melanoma who were treated with TILs (n=84) or ipilimumab (3 mg/kg every 3 weeks for a maximum of four doses; n=84). The majority (86%) of patients were resistant to anti-PD-1 treatment.

Patients who were randomly assigned to receive TILs first underwent surgical removal of a melanoma lesion. T cells that were originally resident in the tumor tissue were grown in the laboratory. “The cells are not genetically modified. Just reactivated and expanded in numbers,” Haanen told to Inside Precision Medicine.

More than 50 billion of these personalized TILs were then infused back into the patient following chemotherapy.

Haanen noted that the chemotherapy was necessary because “infusion of billions of T cells requires physical space. They just do not fit.” Chemotherapy makes space by depleting bone marrow, which leads to much fewer white blood cells in circulation. The patients were also given interleukin-2 which helps the infused cells to survive.

After a median 33.0 months of follow up, the median progression-free survival time was 7.2 months in the patients who received TIL compared with 3.1 months in those given ipilimumab. The resulting difference between the two groups corresponded to a significant 50% reduction in the risk for disease progression or death with TIL.

Haanen described this finding as “absolutely practice changing.”

The overall response rate was also higher with TIL than with ipilimumab, at 49% versus 20%, which included complete responses in 20% and 7%, respectively.

Median overall survival was 25.8 months in the TIL arm and 18.9 months in the ipilimumab arm, but the difference between the two groups was not statistically significant for this outcome.

Toxicity rates were higher with TIL treatment than with ipilimumab—all patients who received the cell therapy experienced a grade 3 or worse adverse event compared with 57% of those who received standard care.

However, Haanen noted that “the adverse events in the TIL treated patients could all be attributed to the chemotherapy and IL-2,” and mostly consisted of bone marrow depletion (neutropenia, anemia, and low platelet counts) along with chills, fevers, shortness of breath, and fluid retention.

Discussing the possible mechanism by which TIL therapy is effective in patients who have failed anti-PD-1 treatment, 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.”

He 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.”

He also said that his team are now working to obtain EMA approval for their TIL therapy, which is expected to take 1 to 2 years, to try to ensure that it remains affordable, free from commercial pressures. The trial was run by academics in the Netherlands and Denmark, with no industry involvement.

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