Patient’s own immune cells effective as living drug for melanoma

08-12-2022

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 TIL trial has shown. The TIL trial, the world's first comparative phase 3 trial in solid tumors in general, is looking into the effect of T cell therapy in melanoma. Now that the results have been published in The New England Journal of Medicine (NEJM), the Dutch National Health Care Institute will assess whether TIL therapy could become a standard treatment, meaning that it will be incorporated into the basic health insurance package.

“Powerful immunotherapy for metastatic melanoma”
Medical oncologist John Haanen from the Netherlands Cancer Institute, who is leading the TIL trial, is very pleased with the results: “Remember: these are metastatic melanoma patients. Ten years ago, melanoma had such a bad prognosis that I would be seeing an entirely new patient population every year – but now I've been seeing some patients for ten years. This is largely due to the discovery of immunotherapy, which has revolutionized treatment for melanoma. But we still see that about half of the people diagnosed with metastatic melanoma succumb within five years, so we're still not where we want to be – not at all. The TIL trial has shown that cell therapy using the patient's own immune cells is an extremely powerful immunotherapy for metastatic melanoma, and that this therapy still offers a high chance of improvement, 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, metastatic melanoma was almost certainly a death sentence within a year after diagnosis. In earlier clinical trials, cell therapy using the patients' 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, and no such trial had ever been conducted. Medical oncologist John Haanen from the Netherlands Cancer Institute decided to take on this task by initiating an international trial in 2014: 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 percentages were significantly higher compared to those seen 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).

Better quality of life and cost-effectiveness
Next to assessing treatment efficacy, today’s clinical trials also investigate the patients’ quality of life more often. Patients treated with TIL reported a better quality of life than those treated with ipilimumab. This concerned their general physical and emotional functioning as well as symptoms such as fatigue, pain, or insomnia. “Patients have to recover from their treatment, but after that most patients can quickly resume their daily lives,” says physician-scientist Maartje Rohaan, who coordinated the trial. “That's wonderful to see.” The differences in quality of life between the TIL patients and the ipilimumab group were still observed after 60 weeks. In addition, TIL therapy is more cost-effective than immunotherapy with ipilimumab.

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 the bodies of patients in order to kill the tumor cells. In 2014, when the TIL trial started, this was the only registered immunotherapy for patients with metastatic melanoma. Trial leader John Haanen: "We have to remember that this form of immunotherapy has also undergone great development in recent years, with research looking to find more effective treatments for metastatic melanoma, also in patients for whom prior treatment did not have the desired effects. The results of the TIL trial are a good addition to this. We have shown that treatment using the patient's own T cells that have been multiplied outside the body, can be very effective in patients with metastatic melanoma, even if previous systemic treatment failed.”
→ read more about the different types of immunotherapy

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, which are isolated from one of the tumor sites, into a huge 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 prior to the cell infusion. Once the T cells have been returned to the body, the patients receive the growth factor interleukin-2, which promotes 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
The TIL therapy itself, a one-time treatment, 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 growth of the T cells inside the body. This treatment can lead to high fevers and chills. Haanen: “In the future we would like to find a way to avoid the use of high dose interleukin-2 by developing a more precise form of the treatment by using a growth factor that causes fewer side effects.”

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 want the treatment to be included in the basic health insurance package, making it accessible as standard care for melanoma patients in the Netherlands. The Dutch National Health Care Institute (Zorginstituut Nederland) is currently assessing whether TIL therapy meets the requirements (in terms of scientific evidence and clinical practice as well as cost-effectiveness) in order for it to be included in basic health insurance as a standard treatment.

Patients in the Netherlands can participate in the TIL trial until the end of 2022, after referral by their oncologist. TIL therapy will still be covered by basic health insurance within the scope of the TIL trial. However, now that the TIL therapy is proven to be more effective than standard treatment with ipilimumab, patients will no longer be randomized in the trial, meaning that all patients automatically receive TIL therapy if they meet the necessary criteria.

Academic pharma
One thing that makes T cell therapy unique, is that this 'living drug’, the patients' own T cells, is produced at the Netherlands Cancer Institute 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 extremely strict and hygienic conditions. To facilitate this, the Netherlands Cancer Institute has set up a special BioTherapeutics Unit. In addition, the Laboratory for Cell Therapy of Sanquin Bloodbank is also equipped to generate TIL-products, to guarantee sufficient capacity for the production of TIL for patients treated at the Netherlands Cancer Institute, and Danish patients can visit CCIT for TIL Therapy. To be able to make TIL an available drug for the European market following the results of the trial, the European Medicines Agency (EMA), must first give its approval. The way in which production is to take place outside 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. John Haanen: "We are not satisfied yet. If you look at the graphs, you’ll notice an initial drop in survival rates, after which it stabilizes. But that initial drop is still bad news for patients. The effects should remain the same – or even get better over time.”
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 trial was led by the Netherlands Cancer Institute in collaboration with the National Center for Cancer Immune Therapy in Copenhagen.

The TIL trial was financially supported by the AVL Foundation, KWF Dutch Cancer Society, ZonMw, the Ministry of Health, Welfare and Sport, Stichting Avento, and Danish organizations.

Patient’s own immune cells effective as living drug for melanoma

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