Patient's own immune cells effective as living drug for melanoma
Results of the M14TIL trial have been presented: the world's first phase 3 trial looking into the effects of T cell therapy in solid tumors
A patient's own immune cells, expanded into an army of billions of immune cells in a specialized laboratory, can be used as a living drug against metastatic melanoma, an aggressive type of skin cancer, as the M14TIL (TIL) trial (TILs, or tumor-infiltrating lymphocytes) has shown. The TIL trial, the world's first comparative phase 3 trial in solid tumors in general, looks into the effect of T cell therapy in melanoma. Now that the results have been presented, TIL therapy could become a standard treatment.
The primary results of the TIL trial were presented at the ESMO 2022 congress in Paris on September 10, 2022.
The trial was carried out in collaboration between the National Center for Cancer Immune Therapy in Herlev, Denmark (CCIT-DK), and the Netherlands Cancer Institute (NKI) in Amsterdam, Netherlands.
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"Powerful immunotherapy for metastatic melanoma"
"Until around ten years ago, a diagnosis of metastatic melanoma was almost a death sentence. However, we can see patients today who are cured and can live a completely normal life", said Professor Inge Marie Svane, Principal Investigator of the TIL trial. "Several new immunotherapies were made available since 2012, with more and more patients cured yearly. But unfortunately, only half of our patients benefit from current immunotherapies. The TIL trial shows that cell therapy using the patient's own immune cells offers a high chance of benefit for the patient, even if prior immunotherapies have failed."
World's first phase 3 trial with T cell therapy for melanoma
Melanoma is an aggressive type of skin cancer. Ten years ago, most patients diagnosed with metastatic melanoma died within a year after diagnosis. In earlier clinical trials, cell therapy using the patient's own T cells as a 'living drug' showed promising results. However, a comparative phase 3 trial would be necessary to include TIL therapy in the arsenal of regular treatments. No such trial had ever been conducted. Therefore, Inge Marie Svane's team established a cell therapy program at CCIT-DK in 2009 and joined forces with the NKI in 2014, initiating an international trial: the TIL trial, which compared TIL therapy to standard immunotherapy with the checkpoint inhibitor ipilimumab. The results of the TIL trial have now been presented at the 2022 annual congress of the European Society for Medical Oncology (ESMO) in Paris.
Metastases smaller in half of the patient population
In almost half (49%) of the patients with metastatic melanoma who received TIL therapy, the metastases had decreased in size. In 20% of patients, the metastases had even disappeared completely. This also proved to be the case in patients who had already received prior treatment at the time of their participation in the trial. "These results show that TIL therapy is highly effective in patients who have failed standard immunotherapy, such as treatment with anti-PD-1 like Nivolumab or Pembrolizumab", stated Troels Holz Borch, investigator at CCIT-DK. These percentages were significantly higher than those in the patient group receiving standard immunotherapy (ipilimumab). In the ipilimumab group, metastases had decreased in size in 21% of patients, and in 7%, the metastases had disappeared completely.
Progression-free survival after six months is 53%
The progression-free survival, the percentage of patients who do not experience disease progression after a specified time period, was 53% after six months for patients receiving TIL therapy and 21% in the control group (ipilimumab). At a median follow-up time of 33 months for all patients, the median progression-free survival of patients who had received TIL therapy was significantly better (7 months) than that of patients treated with ipilimumab (3 months). "It means that there are fewer patients whose cancer continue to grow after TIL therapy, compared to other standard treatments," noted Professor Inge Marie Svane.
Better quality of life and cost-effectiveness
Next to assessing treatment efficacy, today's clinical trials also investigate a critical parameter: patient quality of life. Patients treated with TIL reported a better quality of life than those treated with ipilimumab. This concerned their general physical and emotional functioning and symptoms such as fatigue, pain, or insomnia. "Even though it is true that all patients experience significant side effects from TIL therapy, it is great to see that most patients can quickly resume their daily activities," says physician-scientist Marco Donia, investigator of the TIL trial. In addition, TIL therapy is more cost-effective than immunotherapy with ipilimumab. "Improved cost-effectiveness is a major benefit for healthcare systems, facing increasing financial costs and budget cuts at the same time", noted Marco Donia, who is also head of the Skin Cancer Committee at the Danish Medicines Council.
Read more about TIL therapy (in Danish)
Comparison with checkpoint inhibitors
The TIL trial compared TIL therapy to a different type of immunotherapy using the checkpoint inhibitor ipilimumab, a drug that reactivates T cells in patients' bodies to kill the tumor cells. In 2014, when the TIL trial started, this was the only registered immunotherapy for patients with metastatic melanoma. Inge Marie Svane added: "We have several new immunotherapies today. TIL therapy adds to the armamentarium of treatments available. However, it is a rather complex and relatively toxic treatment. Therefore, we believe it should be used when standard immunotherapies have failed, and only given to patients in good shape".
Read more about the different types of immunotherapy (in Danish)
How does TIL therapy work?
TIL stands for tumor-infiltrating lymphocytes: immune cells, T cells in this case, that have entered the tumor. The body trains these T cells to recognize and then kill foreign invaders, such as tumor cells. The presence of T cells in a tumor is a good sign because it means that the immune system has recognized the tumor as a foreign entity and wants to attack and destroy it. Many tumors, however, do not contain enough potent T cells. TIL therapy aims to multiply the patient's T cells, isolated from one of the tumor sites, into a vast army consisting of billions of T cells. The first step is to remove a patient's tumor tissue. The T cells in the tumor tissue are then multiplied in a specialized laboratory until they form a group of up to 100 billion T cells. This large number of cells is then returned to the patient through intravenous infusion. To make room for these quantities of cells, patients are treated with chemotherapy before the cell infusion. Once the T cells have been returned to the body, the patients receive the growth factor interleukin-2, which promotes the outgrowth of the T cells of the patient. The T cells and their offspring then continue to patrol the patient's body, looking for new and existing tumor cells to eliminate.
Not an easy treatment
TIL therapy is a one-time treatment that is not easy on the patient. All TIL patients experienced side effects to some degree, as did 96% of patients treated with ipilimumab. The side effects of the TIL therapy are usually not caused by the T cells themselves but rather by the chemotherapy pre-treatment, which is required to make room for the billions of T cells, and by the post-treatment with growth factor interleukin-2, which promotes rapid outgrowth of the T cells inside the body. This treatment can lead to high fevers and chills. This is why patients who receive TIL therapy are admitted to the hospital for about 2-3 weeks.
Read more about Thorbjørn's story (in Danish) What do these results mean for patients with metastatic melanoma?
Now that the phase 3 trial has been finalized with a positive outcome for TIL therapy, the researchers aim the treatment to be accessible as standard care for patients with melanoma. The Danish and Dutch authorities are already evaluating if early access can be granted to the treatment while waiting for regulatory approval.
Academic pharma
One thing that makes T cell therapy unique is that this 'living drug', the patient's own T cells, is produced at CCIT-DK itself and not at a pharmaceutical company, as is often the case. This is also known as 'academic pharma'. T cell therapies must be produced under stringent and hygienic conditions. To make TIL an available drug for the European market following the trial results, the European Medicines Agency (EMA) must first give its approval. The way in which production is to take place outside Denmark and the Netherlands will also be examined.
Future plans:
- Aim to reduce side effects by modifying the use of the growth factor interleukin-2
- Increasing efficacy of the treatment further, e.g. by genetically modifying the T-cells to increase potency.
- Refinement of treatment: For example, returning 1 billion instead of 100 billion T cells to the patient instead of 100 billion by using specific selection methods. Or applying other, even more precise forms of T cell therapy by genetically modifying the T cell receptors (the 'recognition structures on the surface of T cells' that recognize tumor cells)
- Using TIL therapy to treat cancer types other than melanoma
The TIL trial: an overview
- Who?
- Patients with late stage or metastatic melanoma
- After/during one first-line treatment at most or during treatment with anti-PD-1 checkpoint inhibitor after prior surgery
- Randomized phase 3 trial: TIL –therapy compared to checkpoint inhibitor ipilimumab
- Number of participating patients: 168
- Time: September 2014 (start inclusion) – June 2022 (data cut-off)
- Primary endpoint results: progression-free survival
- Also assessed: overall survival, quality of life, cost-effectiveness
The TIL trial was financially supported by Copenhagen University Hospital, Herlev, The Danish Cancer Society, The Capital Region of Denmark, Aase and Ejnar Danielsens Foundation and Dutch organizations. No commercial entities were involved in this study.