Scientists have equipped a virus that kills carcinoma cells with
a protein so it can also target and kill adjacent cells that are
tricked into shielding the cancer from the immune system.
It is the first time that cancer-associated fibroblasts within
solid tumours – healthy cells that are tricked into protecting
the cancer from the immune system and supplying it with growth
factors and nutrients – have been specifically targeted in this
way.
The researchers, who were primarily funded by the Medical
Research Council (MRC) and Cancer Research UK, say that if
further safety testing is successful, the dual-action virus –
which they have tested in human cancer samples and in mice –
could be tested in humans with carcinomas as early as next
year.
Currently, any therapy that kills the ‘tricked’ fibroblast cells
may also kill fibroblasts throughout the body – for example in
the bone marrow and skin – causing toxicity.
In this study, published in the journal Cancer
Research, the researchers used a virus called
enadenotucirev, which is already in clinical trials for treating
carcinomas. It has been bred to infect only cancer cells, leaving
healthy cells alone.
They added genetic instructions into the virus that caused
infected cancer cells to produce a protein called a bispecific
T-cell engager.
The protein was designed to bind to two types of cells and stick
them together. In this case, one end was targeted to bind to
fibroblasts. The other end specifically stuck to T cells – a type
of immune cell that is responsible for killing defective cells.
This triggered the T cells to kill the attached fibroblasts.
Dr Joshua Freedman, from the Department of Oncology at the
University of Oxford, who was first author on the study said: “We
hijacked the virus’s machinery so the T-cell engager would be
made only in infected cancer cells and nowhere else in the body.
The T-cell engager molecule is so powerful that it can activate
immune cells inside the tumour, which are being supressed by the
cancer, to attack the fibroblasts.”
Dr Kerry Fisher, from the Department of Oncology at the
University of Oxford, who led the research said: “Even when most
of the cancer cells in a carcinoma are killed, fibroblasts can
protect the residual cancer cells and help them to recover and
flourish. Until now, there has not been any way to kill both
cancer cells and the fibroblasts protecting them at the same
time, without harming the rest of the body.
“Our new technique to simultaneously target the fibroblasts while
killing cancer cells with the virus could be an important step
towards reducing immune system suppression within carcinomas and
should kick-start the normal immune process.
“These viruses are already undergoing trials in people, so we
hope our modified virus will be moving towards clinical trials as
early as next year to find out if it is safe and effective in
people with cancer.”
The scientists successfully tested the therapy on fresh human
cancer samples collected from consenting patients, including
solid prostate cancer tumours which reflect the complex make-up
of real tumours. They also tested the virus on samples of healthy
human bone marrow and found it did not cause toxicity or
inappropriate T cell activation.
Dr Nathan Richardson, head of molecular and cellular medicine at
the MRC said: “Immunotherapy is emerging as an exciting new
approach to treating cancers. This innovative viral delivery
system, which targets both the cancer and surrounding protective
tissue, could improve outcomes for patients whose cancers are
resistant to current treatments. Further clinical studies will be
crucial to determine that the stimulation of the patient’s immune
system does not produce unintended consequences”.
Dr Michelle Lockley, Cancer Research UK’s expert on
immunotherapy, said: “Using the power of the body’s own immune
system to tackle cancer is a growing area of research. This work
in human tumour samples is encouraging, but can be complicated –
one of the biggest challenges of immunotherapies is predicting
how well they will work with the patient’s immune system, and
understanding what the side effects could be. The next stage will
be using clinical trials to test whether this is both a safe and
effective way to treat the disease in people.”
The virus targets carcinomas, which are the most common type of
cancer and start in cells in the skin or in tissues that line or
cover internal organs, such as the pancreas, colon, lungs,
breasts, ovaries and prostate.
