Skin cancers

Tumour infiltrating lymphocyte therapy ’the new standard’ in advanced melanoma


Tumour infiltrating lymphocyte (TIL) therapy could soon become the standard of care for patients with advanced melanoma, according to clinicians from the Netherlands who have shown it is more effective than immunotherapy.

The first randomised controlled trial investigating T cell therapy in solid tumours has shown a significant benefit for tumour infiltrating lymphocyte (TIL) therapy compared with ipilimumab in patients with metastatic melanoma.

Presenting the results at ESMO 2022 in Paris, lead investigator Professor John Haanen of the Netherlands Cancer Institute (NCI) said the study had finally vindicated proof of concept work for TIL done twenty years ago, but which had since been neglected by the pharma industry following the emergence of checkpoint inhibitors.

He said the concept of TIL was similar to CAR T-cell therapy, with tumour infiltrating lymphocytes isolated and expanded from an individual patient’s melanoma lesion tissue before being reinfused.

A trial was conducted in 168 patients with unresectable stage IIIC-IV melanoma who had progression after systemic treatment and who had received anti-PD-1 therapy but not prior ipilimumab.

After a median follow up of 33 months, patients who received TIL had a 50% reduction in risk of disease progression (HR =0.50, p= 0.001) compared to those who received ipilimumab. The PFS was 7.2 months for patients treated with TIL and 3.1 months for patients treated with ipilimumab. The benefit in PFS was seen across all subgroups

The overall response rate (as per RECIST 1.1) in the 84 patients in the TIL group was 48.8%, with 20% having complete remission, compared to an overall response rate of 21.4% in the 84 patients in the ipilimumab group with 7.1% having a complete response. Clinician benefit was reported in 67.9% of the TIL group and 39.3% of the ipilimumab group.

The trial was not powered to show a difference in overall survival, and rates were not significantly different between the two groups. There was a median OS of 25.8 months for TIL patients and 8.9 months for the ipilimumab treated patients.

Adverse event rates were greater in the TIL group, mostly related to IL-2, such as fever, and were manageable, said Professor Haanen. This was reflected in higher quality of life scores in TIL treated patients compared to those treated with ipilimumab he said.

He said the results showed that TIL had the potential to become the standard of care in patients with metastatic melanoma, and notably in those who had previously been treated with anti-PD-1 therapies.

He added that the trial had been conducted by academic centres in the Netherlands and Denmark without pharma input, and the researchers hoped to make the TIL therapy available to patients in the Netherland as soon as possible at cost price.

The two main challenges are gaining regulatory approval and in building capacity and expertise within cancer centres for a procedure that was labour intensive, he added.

In an ESMO discussion session attended bv the limbic,  the results were welcomed by Professor Ignacio Melero, Co-head of Immunology and Immunotherapy at the University of Navarro, Spain, who congratulated the researchers on making a reality of the concept developed by Dr Steve Rosenberg and colleagues at the National Cancer Institute in Bethesda in the 1990s.

He said there were still many questions and refinements to be made regarding TILs, such as the development of predictive biomarkers and how it should be used in practice, such as in combination with immunotherapy or by intra-tumour administration.

Nevertheless, there was now a case for starting to use TIL therapy in the 15,000 cases of advanced melanoma in Europe per year, he concluded.

“I think there is sufficient efficacy and safety evidence to support standard practice of TIL therapy in incompletely respectable stage III and stage IV melanoma following anti-PD-1 failure,” he said.

Also commenting on the findings, Prof. George Coukos of the Ludwig Institute for Cancer Research at the University of Lausanne and University Hospital of Lausanne Centre Hospitalier Universitaire Vaudois, Switzerland noted that a combination of CTLA-4 and PD-1 blockade, and not ipilimumab, is now considered the standard of care in this setting.

But the results showed promise because experience showed that complete responses after TIL have been consistently associated with durable long responses and potential cure.

“Melanoma remains an area of unmet medical need,” he said. “In patients with BRAF mutations, responses to kinase inhibitors are often spectacular but are generally not durable, and for patients without BRAF mutations, checkpoint blockade is currently the only available effective therapy. The multiple kinase inhibitor lenvatinib in combination with checkpoint blockade is emerging as a therapeutic possibility. Now we have this study, indicating that a significant proportion of patients with melanoma could not only be helped but potentially cured with TILs.”

Finding the patients who are likely to achieve the most benefit is particularly important in view of the toxicity associated with the high-dose chemotherapy lymphodepleting regimen and the use of interleukin-2 regimen to support TILs therapy, which currently require hospitalisation, said Prof Coukos.

The future application of TILs in other solid tumour types also looks promising, he added.

“Preliminary data already exist from other groups that this approach can potentially be effective in patients with tumours induced by human papilloma virus, such as cervical cancer or head and neck tumours, as well as in non-small-cell lung cancer. The ideal would be to extend this application to all solid tumours,” said Prof Coukos.

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