A class of drug currently being used to treat leukaemia has the
unexpected side-effect of boosting immune responses against many
different cancers, reports a new study led by scientists at UCL and
the Babraham Institute, Cambridge.
The drugs, called p110? inhibitors, have shown such remarkable
efficacy against certain leukaemias in recent clinical trials that
patients on the placebo were switched to the real drug. Until now,
however, they have not been tested in other types of cancer.
The new study provides the first evidence that such drugs can
significantly restrict tumour growth and spread and reduce the
chances of relapse for a broad range of cancers. The researchers at
UCL, the Babraham Institute and Queen Mary University of London,
together with scientists from Genentech, South San Francisco,
showed that inhibition of the p110? enzyme helps to boost the
body's immune system to kill tumour cells.
"Our study shows that p110? inhibitors have the potential to
offer effective immunity to many types of cancer by unleashing the
body's own immune response," said Professor Bart Vanhaesebroeck of
the UCL Cancer Institute, who first discovered the p110? enzyme in
1997. "p110? is highly expressed and important in white blood
cells, called 'leukocytes'. Given that leukaemias are the result of
leukocytes becoming cancerous, they are a natural target for p110?
inhibitors. Now, we have shown that blocking p110? also has the
remarkable effect of boosting the body's immune response against
leukaemias as well as other cancers."
The team showed that inhibiting p110? in mice significantly
increased cancer survival rates across a broad range of tumour
types, both solid and haematological cancers. For example, mice in
which p110? was blocked survived breast cancer for almost twice as
long as mice with active p110?. Their cancers also spread
significantly less, with far fewer and smaller tumours developing.
Survival after surgical removal of primary breast cancer tumours
was also vastly improved, which has important clinical implications
for stopping breast cancer from returning following surgery. The
team's data further show that following p110? inhibition, the
immune system could develop an effective memory response to
completely fight off the cancer.
Lead author Dr Khaled Ali, who is now based at Amgen, San
Francisco, said: "When we first introduced tumours in
p110?-deficient mice, we expected them to grow faster because p110?
is important for the immune system. Instead, some tumours started
shrinking. When we investigated this unexpected effect, we found
that p110? is especially important in so-called regulatory T cells
which are suppressive immune cells that the tumours engage to
protect themselves against immune attack."
The p110? enzyme is a member of the PI3-kinase family, and is
sometimes called PI3K?. p110? and the other PI3Ks are hot drug
targets for the pharmaceutical industry as they are implicated in
many cancers and are readily druggable.
"Our work shows that p110? inhibitors can shift the balance from
the cancer becoming immune to our body's defences towards the body
becoming immune to the cancer, by disabling regulatory T cells,"
said Dr Klaus Okkenhaug of the Babraham Institute, which receives
strategic funding from the BBSRC. "This provides a rationale for
using these drugs against both solid and blood cancers, possibly
alongside cancer vaccines, cell therapies and other treatments that
further promote tumour-specific immune responses."
Professor Nic Jones, Cancer Research UK's chief scientist and
director of the Manchester Cancer Research Centre, said:
"Treatments that train the immune system to recognise and kill
cancer cells are showing huge promise in several types of cancer.
This new finding, although only at an early stage, offers the
potential to develop more treatments that can do this in many more
cancers, including ones that have real need for more effective
treatments such as pancreatic cancer.
"If the findings hold true in cancer patients this could make a
big difference to many of them. The good news is that because the
drugs used in this study are already being used in the clinic, we
could see rapid translation of this research into patient
benefit."
The paper, Inactivation of PI(3)K p110? breaks regulatory T-cell-mediated
immune tolerance to cancer, is published inNature.