Gus’s work

Our Achievements

This page lists some of the achievements of our Principal, Professor Angus
Dalgleish and his team, both before and during the existence of the Cancer
Vaccine Institute.
Tumour cell vaccines (vaccines made from a patient’s tumour OR tumour cells
grown in culture).
Gus was involved in some of the very early work (circa 1996) on tumour cell
vaccines, and specifically how vaccines could be made from cells that were not
from the patient’s own tumour (these are referred to as “allo” vaccines). This
interest has been key to much of Gus’s work and continues almost to the present
day. In addition to pre-clinical work, Gus has been involved in clinical studies,
specifically the Onyvax prostate cancer vaccine and earlier the Canvaxin studies
for melanoma. These early trials were very encouraging. At first, however, these
were not born out in later studies, an event that ultimately hampered the
development of those vaccines. It is clear now that poor results in late stage trials
were down to a variety of problems. However, an understanding is now emerging
from these trials which indicates that the vaccines are still useful.
Dendritic cell vaccines (cells which are involved in the body’s immune system
to fight and protect from infections and disease)
Dendritic cell (DC) vaccines are among the best therapeutic vaccines that have
been developed. Gus has been interested in these vaccines and has been
influential in bringing them into mainstream vaccine research. Despite this DC
vaccines remain expensive (they are made bespoke for each patient) and there
are arguments about the best formulation of vaccine. For this reason more
research has been required to develop them further. We are now looking at ways
of manipulating patients’ immune systems so that a much cheaper non-bespoke
vaccine can be administered.
The CVI funded the development of two laboratories which allowed Gus to do DC
vaccine trials; a clean-room which was used for some of the early trials and more
recently the Helen Feather Laboratory which allowed him to do a DC trial in
melanoma patients. This phase I trial took several years and treated about 30
patients. Results from the trial (yet to be published) have supported a possible
link between inflammation and vaccination (see below).Aldara.
Aldara was originally licensed for use as a wart cream, however, it was
discovered that it can be effective in treating melanoma. Gus has maintained an
interest in this and other drugs that stimulate the immune system through
receptors called TLRs. These receptors are important in boosting immune
responses and particularly in stimulating dendritic cells
The CVI part-funded a clinical trial of the drug Aldara in patients with metastatic
melanoma, which resulted in two scientific papers that have had an impact on
melanoma treatment. The first paper demonstrates how skin lesions respond to
treatment with topically applied Aldara and cell stimulator injection. The second
paper shows how treatment with Aldara alters systemic immune responses. This
is one example of how it may be possible to induce the immune system to kill
tumours without making complicated, expensive vaccines.
The use of Aldara alongside a cell stimulating injection is now routinely
prescribed by oncologists across the UK.
Mycobacterial vaccines (vaccines which are prepared from a strain of bacteria)
Bacterial infections have been associated with remission in some cancers. Gus
has been involved in quite a few studies of vaccines based on the use of bacteria,
particularly strains of mycobacteria (BCG, vaccae and more recently obuense).
Gus’s team did some of the original work demonstrating proof of principal that
mycobacterium vaccae could be used to treat prostate cancer. A series of clinical
trials in prostate cancer, melanoma, renal and lung cancer followed. Some of
these trials demonstrated improved survival benefit. Late stage trials showed that
patients receiving 4 or more injections of vaccine did better than those with less
than 4.
More recently a new mycobacterial strain has been developed by Immodulon
Therapeutics. Gus has been involved clinically in recruiting and treating patients
with this new vaccine. A phase I study in melanoma demonstrated the safety of
the product and showed some positive clinical results. A multi-centre, phase II
study for pancreatic cancer is underway. It is hoped that the vaccine will be
available for future CVI funded projects.
Inflammation and Cancer
Gus has been publishing reviews on the links between inflammation and cancer
for at least a decade. The early reviews were more specifically about the link
between chronic inflammation as a causative factor in cancer. However, he has
been a strong protagonist for the concept that some kinds of inflammation are
bad in a cancer vaccine setting. He has suggested that anti-inflammatory drugs
(such as aspirin) might enhance responses to therapeutic vaccines. This concept
now has some support in the literature and has been reported widely in the
media.
Combination therapies (where different drugs are used in combination)

There are a range of drugs that Gus is interested in which may alter the immune
response or which sensitise tumour cells to killing.
A. IMiDs (variants on the drug thalidomide)
Gus has worked extensively with Celgene Corporation, which manufactures
IMiDs, to understand how these drugs work. He has 14 primary papers
demonstrating that these drugs alter tumour vascularisation, boost some
elements of the immune response and inhibit some cells which suppress immune
responses. Gus’s work in this area has been very important on the road to
licensing for the drug Lenalidomide which is now used in myeloma and is being
trialled in other haematological malignancies. There is strong interest in
combining lenalidomide with vaccines.
B. Artemesinins (drugs currently used to treat malaria)
A recent interest has been in this family of drugs. Currently one particular drug,
artesunate is used in a clinical trial of colorectal cancer. Collaboration with our
surgical colleagues led to a short project which aimed at determining the
mechanism of action of artesunate and some of the other artemesinins. This
work was funded by the CVI and was published recently.
C. Gemcitabine (a chemotherapy drug)
The CVI recently funded Gus in a project which showed how Gemcitabine alters
tumour cells in a way that makes them more recognisable to the immune
response. This work is ongoing and further valuable observations are being
generated. In addition chemotherapy seems to induce tumours to secrete
substances that would prevent further blood supply being delivered to tumours
and which activate elements of the immune response. This work supports the
idea that chemotherapy may be used to stimulate and maintain immune
responses alongside therapeutic vaccines.
D. Low Dose Naltrexone (LDN) (a drug which has been used to treat narcotic
addiction)
This is another drug for which new uses are becoming apparent. In particular
there is some new evidence that Naltrexone targets some receptors seen
predominantly on immune cells. This work is ongoing and will take the form of a
PhD project funded by the CVI.
In addition Gus is very interested in using LDN in patients with ovarian cancer.
Several reports exist, including preclinical studies and case studies, to suggest
that LDN may be useful in this application. The work that the CVI is currently
funding is likely to provide an explanation, in part, for how this drug works in
cancer.
E. Zometa (a drug which is used for patients with bone cancer).
Gus has been using Zometa with some patients who have solid tumours. There
is evidence that Zometa can stimulate elements of the immune response and in
particular may work well in combination with mycobacterial vaccines (see above).

Source: http://www.cancervaccine.org.uk/CVI%20Achievements.pdf