A patient’s own immune cells, multiplied
into an army of billions of immune cells in a lab, can be used as a living
medicine against metastatic melanoma, an aggressive form of skin cancer, as the
TIL trial has shown. The TIL trial is the world’s first comparative phase 3
trial looking into the effect of T cell therapy in melanoma, and solid tumors
in general. Now that the results have come in , the Dutch National Health Care
Institute will assess whether TIL therapy () could become a standard treatment,
meaning that it will be covered by basic health insurance. The results are
published in The New Engeland Journal of Medicine (NEJM) on December 8. The trial
was headed by the Netherlands Cancer Institute in collaboration with the
National Center for Cancer Immune Therapy in Copenhagen.
Powerful immunotherapy for metastatic melanoma
Medical oncologist John Haanen from the
Netherlands Cancer Institute, who is leading the TIL trial, is very happy with
the results: “Remember: these are patients with metastatic melanoma. Ten years
ago, melanoma was so deadly that I would be seeing an entirely new patient
population every year. Now I’ve been seeing some patients for ten years. This
is largely due to the discovery of immunotherapy, which has revolutionized
treatment for melanomas. But we still find that about half of people diagnosed
with metastatic melanoma lose their lives within five years, so we’re still not
where we want to be — not by a long shot. 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 other immunotherapies fail.’
World’s first phase 3 study T cell therapy for
melanoma
A melanoma is an aggressive form of skin
cancer with a high rate of occurrence Ten years ago, a diagnosis with
metastatic melanoma would almost certainly lead to death within the same year.
In early 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,
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 will now be presented at the annual conference of the European
Society for Medical Oncology.
Metastases smaller in half of the patient group
In almost half (49%) of the patients
with metastatic melanoma who received TIL therapy, the metastases had shrunk.
In 20% of patients, the metastases had even disappeared completely. This also
proved to be the case in patients who had already received another treatment
prior to their trial participation. These percentages were significantly higher
than those among the patient group receiving standard immunotherapy
(ipilimumab). In the latter group, metastases had shrunk in 21% of patients,
while 7% saw a disappearance of the condition.
Progression-free survival after six months is 53%
The progression-free survival, which
refers to 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. 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).
Quality of life: return to professional life
While assessing a treatment’s efficacy,
more clinical trials nowadays also consider the patients’ quality of life.
Patients treated with TIL scored better in this area than those treated with
ipilimumab. This applied to their general physical and emotional functioning as
well as symptoms like fatigue, pain, or insomnia. “We also looked at whether
they could resume their careers and noticed that people were going back to
work,” 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 control group were still visible after 60 weeks. As an added
bonus, TIL therapy is much more cost-effective than immunotherapy with
ipilimumab.
Compared to checkpoint inhibitors
The trial compared TIL therapy to a
different type of immunotherapy using checkpoint inhibitor ipilimumab, which is
a drug that reactivates the body’s T cells that have been thwarted by the tumor
so they can continue to kill the tumor cells. In 2014, when the TIL trial
started, this was the only registered immunotherapy for patients with
metastatic melanomas. Research leader Haanen: “We have to remember that this
form of immunotherapy has also experienced a lot of development in recent
years, with more and more research looking to find more effective treatments
for metastatic melanoma, even for patients who have already received treatment
without 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
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 rapidly successive
post-treatments with growth factor interleukin-2, which ensures rapid growth of
the T cells. This 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 melanomas?
Now that the phase III trial has
concluded with positive results, the researchers want the treatment to be
covered by basic health insurance, making it accessible to patients in the
Netherlands. The Dutch National Health Care Institute (Zorginstituut Nederland)
is currently assessing whether TIL therapy meets the requirements (in terms of
science and clinical practice as well as cost-effectiveness) so it can be
included as a standard treatment in the basic health insurance package.
Patients in the Netherlands can
participate in the TIL trial until the end of 2022, through a referral by their
practicing physician. Treatment as part of this trial will be covered by basic
health insurance. Now that the TIL therapy is proven to be effective, patients
will no longer be randomized, meaning that all patients automatically receive
TIL therapy if they meet certain criteria.
EMA
One thing that makes T cell therapy
unique, is that this ‘living medicine’, the patient’s own T cells, is produced
at the Netherlands Cancer Institute itself, and not, as is often seen, at a
pharmaceutical company. This is also known as ‘academic pharma’. T cell
therapies must be produced under extremely strict, hygienic conditions. To
facilitate this, the Netherlands Cancer Institute has set up a special
Biotherapeutics Unit. In order to be able to produce TIL for the European
market following the results of the trial, the EMA, European Medicines Agency,
must first give its approval. The way in which production is to take place
outside the Netherlands will also be examined.
Future plans:
·
Reducing
side effects by modifying the use of 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, and after that
it stabilizes. But that initial drop is still bad news. The effects should
remain the same — or even get better.”
·
Refinement:
For example, returning 1 billion instead of 100 billion T cells to the patient.
Or applying other, even more precise forms of T cell therapy by genetically
modifying the receptors (the ‘feelers’ that recognize tumor cells) of T cells
·
Using
TIL therapy to treat cancer types other than melanoma
The TIL trial: an overview
·
Who?
Patients with late stage or metastatic melanomas after/during at most one first
line treatment or during treatment with anti-PD-1 checkpoint inhibitor after
prior surgery randomized phase III trial: TIL -therapy compared to checkpoint
inhibitor ipilimumab
·
Number of
participating patients: 168
·
Time:
September 2014 (start inclusion) — june 2022 (cut-off date)
·
Primary
end results: progression-free survival
·
Also
assessed: general survival, quality of life, cost-effectiveness
Journal article: https://www.nejm.org/doi/10.1056/NEJMoa2210233
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