CVI symposium 2013.
On the 11th and 12th October the CVI held its first International Symposium on Immunotherapy.
About 100 scientists and clinicians from around the world came to the Royal Society to discuss a
topic of increasing interest to the community of cancer immunotherapy researchers. The question
under discussion was “can standard cancer treatments improve patient responses to
immunotherapy”?
Background
To explain why this topic is important it is necessary to look at the current state of cancer
immunotherapy treatments. Over the past thirty years scientists working in the field of cancer
immunotherapy have made great strides forward in understanding how the immune system can be
harnessed to fight cancer. This led naturally to the development of a range of different treatments,
all with the aim of stimulating the immune system to recognise and kill tumours. Many hundreds of
clinical trials have been done with the plain result that cancer immunotherapy works and that some
patients respond very well. However, it is clear that there are limitations to these treatments and
not all patients respond to immunotherapy: While a limited number of patients have complete
remission of their cancer, and a greater number experience a temporary stabilization of their
disease, this doesn’t represent the majority of patients. The reasons for the lack of complete
response by some patients has taken several decades to discover. We now know that cancer and the
immune system affect one another. For example many cells of the immune system are suppressed
by cancer. The immune system is self-regulating because it is necessary to prevent the immune
system from running out of control. Cancer often highjacks this self-regulation with the result that
cancer patients are immunologically suppressed compared to healthy individuals. Moreover, as
tumours develop they often become resistant to immune attack. This can happen because the
immune system loses its ability to recognise them.
So what does this have to do with chemotherapy? Thirty years ago, at the outset of the modern age
of cancer immunotherapy, we believed that the immune system would be damaged by
chemotherapy or radiotherapy. For this reason standard treatments and experimental
immunotherapy treatments were always kept separate. It is slowly becoming evident that many
drugs that are used in standard cancer care have either positive effects on some cells of the immune
system while other drugs influence those cells that regulate the immune response. This means that
many drugs that are currently available to us have useful properties that might solve some of the
problems faced by immunotherapy. However, an understanding of which drugs affect the immune
response and how they do so remains sketchy.
What did the symposium aim to achieve?
The aim of the CVI symposium was to bring together experts in this relatively new scientific field.
Four separate questions were posed
1. Do some drugs make tumours more visible to the immune system?
2. Is the immune system stimulated by chemotherapy?
3. Can we counter-act the immune-regulatory response caused by cancer with chemotherapy?
4. What evidence is there that chemotherapy can be used in combination with immunotherapy?
The data presented at the symposium is a snapshot of the current state of cancer immunotherapy
and in answering these questions yet more questions will arise. However, it is possible to make some
broad statements on the basis of the work presented by these scientists.
Do some drugs make tumours more visible to the immune system?
In order to recognise tumours the immune system must encounter some signal that marks a tumour
as aberrant or foreign. Many tumours are studded with such markers but lose them during the
progression of the cancer resulting in a tumour that is immunologically invisible. This is a problem in
the context of immunotherapy because the very targets that the immune system should recognise
are not there. T cells, a type of white blood cell that is able to kill other cells including tumour cells,
recognise specific markers on tumours. Data was presented at the symposium demonstrating that it
is possible to increase or reinstate levels of these markers using drugs like gemcitabine or docetaxel
which are commonly used in cancer treatment. Other studies were presented which showed that
some proteins that are specific only to tumours can be enhanced by chemotherapy, and so
presumably act as more effective markers for recognition by T cells. Importantly one mechanism
that drives T cell recognition of tumours during treatment with chemotherapy was presented,
adding to our understanding of how chemotherapy alters tumour cells to be more susceptible to the
immune system. An interesting concept that is emerging from these and other published studies is
the idea that low (or lower) doses of drugs are needed to cause immunological effects than the
doses required to kill tumours. More research is required to understand this fully, but it means that
less toxic doses of these drugs might be used in the future in combination with immunotherapies.
Is the immune system stimulated by chemotherapy and can we counter-act the regulatory
response in cancer with chemotherapy?
Research was presented that indicates that chemotherapy induces activity in certain cells that are
central to the development of immune responses. Dendritic cells are important players in the
initiation of T cell responses (T cells rely on dendritic cells for their activation). Several speakers
showed how dendritic cells can be manipulated with drugs and how T cell responses can be
augmented using drugs like cisplatin and bortezomib. There were also talks which indicated that
other cells with anti-tumour properties can be activated. Natural Killer cells and gamma-delta T cells,
both of which are known to recognise and kill tumours, are stimulated by the drug zometa. This is
important because each of these immune cell types might be important in different cancers or at
different stages of the disease.
While some drugs stimulate the immune response it is becoming clear that other drugs like
cyclophosphamide and sunitinib can inhibit the cells that ordinarily dampen down immune
responses. The existence of these cells has been a key problem in the development of cancer
immunotherapy since these “regulatory” cells are often present in high numbers in cancer patients.
It is likely that the presence of regulatory cells impairs the response of patients to immunotherapy.
Thus the use of drugs to remove or inhibit the regulatory response is a step towards the
improvement of immunotherapy.
The symposium highlighted the importance of understanding the interplay between drugs and the
immune system. It is clear that some drugs stimulate bits of the immune system while depressing
others. The key to successful treatments in the future will be to understand how all of these
elements interact.
What evidence is there that chemotherapy can be used in combination with immunotherapy?
The first evidence that immunotherapy may be beneficial when used in combination with
chemotherapy probably arose through clinical observations of patients who returned to
chemotherapy after their experimental treatments. There are now many apocryphal examples of
how drugs and immunotherapy may be combined. However, with better understanding of how
drugs work comes more rational design for combined therapies. Examples of this were presented
during the symposium, indicating that drugs like decitabine, vemurafenib and cyclophosphamide
are good partners for immunotherapies (particularly vaccines).
What else did we discover at this symposium?
In future it is clear that targeting tumour cells or immune cells may not be sufficient. A new target
that is of growing interest for oncologists is the tumour stroma. That is to say those cells that are not
malignant but which are found in the tumour and which support tumour growth. Chemotherapy
alters these cells and may make them more sensitive to the immune system. Stromal cells may also
regulate how T cells get into tumours and their manipulation with drugs may therefore alter the
balance of immune cells in a tumour.
Several speakers talked about timing of chemotherapy with regards to immunotherapy. It is clear
that some chemotherapies may best be given after immunotherapy if the purpose of drugs is to
make available immunological targets on a tumour cell. Alternatively some chemotherapies work
through clearing or inhibiting regulatory cells which may be done prior to immunotherapy to allow
the immune system to be activated. Some data presented at the symposium indicated that the
immune system has a circadian-type rhythm and that immunotherapy and chemotherapy each have
different effects within this rhythm. More research is needed to understand these effects fully.
So what is the take home message?
Armed with knowledge about how tumours and the immune system behave when treated with
specific drugs we will be able to design combinations of treatments that work well together. For
example there is no point in making an immune response to a tumour when the markers that should
be recognised by T cells are absent. Specific types of chemotherapy might alter that. Likewise
chemotherapy seems to have an effect on some cells that otherwise repress the immune response.
That means that it might be possible to remove those cells using drugs prior to immunotherapy.
However, scientists must understand crucial questions of timing and dose. What is the best timing of
delivery for any particular combination of chemotherapy and immunotherapy? These are difficult
and costly questions to answer but are best arrived at through better understanding of how drugs
and immunotherapy actually work. An interesting concept that is emerging from these and other
published studies is the idea that low (or lower) doses of drugs are needed to cause immunological
effects than the doses required to kill tumours. More research is required to understand this fully,
but it means that less toxic doses of these drugs might be used in the future in combination with
immunotherapies.
At the end of the day the outcome of this symposium is clear. There is a lot of research out there
that demonstrates how chemotherapy drugs can be used in ways that differ from their original
purpose, particularly with regard to stimulating the immune system. While scientists express caution
about the use of combination therapies (chemo- and immuno- therapy) there is enough research in
existence for us to express optimism that some of these drugs will be useful in overcoming the
remaining barriers that prevent the delivery of effective cancer immunotherapies.