'Real life' research model for improvement of personalized
immunotherapy in cancer
Researchers from the Netherlands Cancer Institute and
others have shown that it is possible to obtain immune cells
(so-called killer T cells) from the bloodstream of a cancer patient
and expand them in a dish together with a living piece of tumor
from the same patient. Such a tumor piece is called a tumor
organoid. The immune cells develop the ability to kill the tumor
cells and to reduce organoid size, while leaving healthy control
tissue of the same patient untouched.
This gives research into immunotherapy an instrument with which,
for an individual patient -- but outside the body -- the complex
interaction between immune cells and cancer cells can be studied.
The researchers will also use this new research platform to enable
- in the long term - cellular immunotherapy: treatment of the
patient with his or her own immune cells as 'living drugs.'
Researchers Krijn Dijkstra, Chiara Cattaneo et al. published these results on Thursday August 9th
on the website of the scientific journal Cell. The research was led
by Emile Voest (contact person) and Ton
Tumors retain properties of tumor
Recently, tumor organoids have been shown to retain the
morphological and mutational properties of the original tumor. This
has opened the door to studying tumors outside the patient's body
and to testing the effects of various drugs. However, tumor
organoids had not yet been used to study immunotherapy. Now, that
has become possible.
Krijn Dijkstra, physician-researcher who is writing his doctoral
thesis on this study: 'to answer our questions about whether or not
immune therapy is successful, there is a great need for good "real
life" models. This is certainly going to help.'
We were anxiously waiting for such a research platform,' says
internist-oncologist Emile Voest, who has led the research. 'And
there are no laboratory animals involved.'
According to Ton Logtenberg, CEO of the Nasdaq-listed
immune-oncology company Merus, this kind of lab
research is of invaluable importance: 'The recent development of
new drugs that activate the patient's own immune system to kill
tumor cells, has revolutionized cancer treatment. The research that
has been done in the Voest group now provides unique opportunities
for developing improved and new combinations of these drugs in the
lab, before testing them in patients.
Live imaging of lung cancer organoids (first image) and healthy
lung organoids (second image) from the same patient, combined with
T cells that were 'trained' to recognize the tumor organoids. Tumor
organoids are attacked by T cells and are reduced in size. The
appearance of green cells indicates cells undergoing apoptosis
(programmed cell death). Healthy lung organoids, in contrast, are
completely unaffected by the presence of these T cells,
underscoring the specificity of the attack.
(Krijn Dijkstra and Chiara Cattaneo)
Why does one patient respond while another does
This new tumour model allows researchers to more easily study
the big questions and bottlenecks that now frustrate the wide
clinical application of immunotherapy. For example: why does one
patient respond well to immunotherapy and another not at all? How
do cancer cells bypass the immune system and how do immune cells
react to that? And finally: how can we intervene in all these
Colorectal cancer and lung cancer
The organoids were cultured from tumor tissue from 13 patients
with a specific form of colorectal cancer (mismatch repair
deficient colorectal cancer) and 6 patients with non-small cell
lung cancer. These subtypes of cancer are partly sensitive to
immunotherapy, because the amount of DNA damage is so substantial
that the immune system recognizes the cancer cells as 'foreign'.
However, only a minority of patients with metastatic cancer
responds well to immunotherapy. Using organoids, immune cells from
the blood of about one in three patients were successfully
'trained' to recognize tumor cells.
T cells recognize and kill tumor cells
The immune cells in question are T cells. T cells (for the
expert: type CD8+) are white blood cells with a dual function: they
recognize foreign elements and kill them as well, hence the
nickname killer T cells. From the bloodstream, they infiltrate and
attack the tumor. In the forms of immunotherapy that are now used -
as standard treatment or experimentally - these T cells take the
front stage. However, in the micro-environment of the tumor, all
kinds of mechanisms are at work that make it impossible, or no
longer possible, for T cells to recognize or kill the cancer cells.
These mechanisms can now be studied better.
'Fresh T cells'
Immunotherapy is aimed at strengthening and/or expanding T cells
in the tumor microenvironment. Immunotherapy was first applied to
cutaneous melanoma, an aggressive form of skin cancer, and only
afterwards to several other cancers. 'With melanoma, it is
relatively easy to grow T cells from the tumor itself,' says Voest.
'That has proved much more difficult with epithelial cancers such
as colorectal cancer and lung cancer.' That is why he is so happy
that his group has succeeded in obtaining T cells from the
bloodstream. 'T cells from the bloodstream are also likely to be
'fresher' than T cells that have already become exhausted during
their stay in the tumor microenvironment.'
The new discovery also opens the way to develop cellular therapy
in which T cells are 'trained' outside the body to recognize the
tumor and then returned to the patient. The organoids can likewise
be used to test combinations of immunotherapy and other
Krijn Dijkstra & Chiara Cattaneo et al.,
'Generation of tumor-reactive T cells by co-culture of peripheral
blood lymphocytes and tumor organoids'. Cell (2018), 9 August
Full article can be found here.