Pretreatment with chemo can improve the effect of immunotherapy
on aggressive breast cancer
It sounds complicated: giving cancer patients chemotherapy or
radiotherapy, not with the aim of killing cancer cells, but to put
the immune system to work so that it will respond better to
immunotherapy. Nonetheless, preclinical studies have shown that
this is a promising new way to increase the chance of success of
immunotherapy. It can strengthen the good immune cells and weaken
immune cells that aid cancer.
Researchers at the Netherlands Cancer Institute investigated
whether this is indeed the case in patients with metastasized
triple negative breast cancer, an aggressive form of breast cancer
that does not respond to a number of standard treatments.
The results of part 1 of the Netherlands Cancer
study, a phase 2 study with 67 patients with metastatic
triple-negative breast cancer, are promising. In particular,
pretreatment with cisplatin and doxorubicin appears to increase the
effect of immunotherapy.
The researchers, led by medical oncologist and researcher
Marleen Kok, published their results on Monday, May 13, 2019, in
the leading journal Nature Medicine.
Triple-negative breast cancer
breast cancer is an aggressive form of breast cancer that
often affects young people. This form of breast cancer is not
hormone sensitive - not to estrogen or progesterone - and therefore
does not respond to hormone therapy. It is also insensitive to
treatment with Herceptin. If the tumor spreads to other organs, the
cancer cells quickly become resistant to chemotherapy and patients
die from this condition.
However, a small number of recent studies (the TONIC study is
the fifth worldwide, but the first by a scientific institution
instead of a pharmaceutical company) have shown that immunotherapy
for triple negative breast cancer does have a chance of success.
Immunotherapy does not fight cancer itself but helps the immune
system to do so. It focuses primarily on T cells, white blood cells
that cancer cells can recognize and
With most forms of breast cancer, the chance of success of
immunotherapy is limited because there are few T cells in and
around the tumor. But with triple negative breast cancer, the
amount of T cells around the tumor cells is relatively high.
In March 2019, the American Food and Drug Administration
approvedimmunotherapy for a subgroup of patients with
metastatic triple-negative breast cancer. This made
CNN newsbecause it was the first time this has happened for
breast cancer. The treatment has not yet been approved in Europe.
Can we improve immunotherapy?
However, immunotherapy only works on a minority (on average 5%
and at most 23% in a specified subgroup) of patients with
metastatic triple-negative breast cancer. "Our question was: can we
improve that?" says internist-oncologist Marleen Kok, who is
leading the TONIC study.
Low dose chemotherapy or radiotherapy
The researchers have now been the first to investigate whether
they can increase the chances of success of immunotherapy by giving
patients a low dose of chemotherapy or radiotherapy for two weeks
prior to immunotherapy.
Research in the lab and in mouse models, including at the
Netherlands Cancer Institute, has shown that this can have a
stimulating effect on the immune system. "But then, the question is
whether it will also work like that for breast cancer patients,"
says researcher Maarten Slagter. "We have now investigated this in
patients with metastases from triple-negative breast
Patients were divided into five cohorts, or 'baskets' as they
are called in this type of clinical study. Cohort one
only received immunotherapy (drug nivolumab), cohort two was
pre-treated for two weeks with radiotherapy, and the remaining
three cohorts were pre-treated for two weeks with three different
forms of low-dose chemotherapy.
Positive effect with cisplatin and doxorubicin
Clinician-researcher Leonie Voorwerk, who conducted the research
together with Maarten Slagter: "We actually expected that all of
these pre-treatments would have a positive effect on the immune
system based on preclinical results, but to our surprise, we saw
this mainly with cisplatin and doxorubicin and less with the other
two pre-treatments: cyclophosphamide and radiation."
At the Netherlands Cancer Institute's immunology lab, the tumor
biopsies were thoroughly examined to see what happened at a
molecular-biological level. The researchers did indeed see T cells
entering the tumor after pre-treatment with chemotherapy (cisplatin
and doxorubicin) and subsequent immunotherapy. These T cells also
appear to do their cancer-killing work better in these patients
Part two: continuing with doxorubicin
Pre-treatment with doxorubicin appears to be the most successful
in the first small group of patients: after pretreatment with this
medicine, 35% of patients responded well to immunotherapy. In the
second part of the TONIC study, which is currently ongoing, the
researchers are, therefore, continuing with doxorubicin. The
patients are now divided into two groups. One group is pre-treated
with doxorubicin and then receives immunotherapy. The other group
immediately starts immunotherapy.
"We hope to validate the findings of the first part of the study
in more patients in the second part," says Leonie Voorwerk. "We
also already have a reasonable impression of which patients have a
chance of being helped by the immunotherapy and for which patients
the immunotherapy does not work as well. The next step is to
realize an actual test for selecting the right patients for
immunotherapy, with or without pre-treatment."
Type of study: phase 2
Open or closed: open
If you think you are eligible for this study, please discuss it
with your oncologist.