Home' Australasian BioTechnology : Vol 26 No 2 Contents Australasian BioTechnology | Volume 26 | Number 2 39
'Immuno-oncology' is the current buzzword in
cancer treatment, with drugs like pembrolizumab
(KEYTRUDA®) and nivolumab (Opdivo®) providing
exciting new treatment options for an expanding
range of tumour types, including melanoma and
lung cancer. The ability to activate the immune
system to kill cancer cells has become a focus area
for oncology drug discovery and development.
Manipulation of the immune system to control cancer is not
a new concept; however, the idea can be traced back to at
least the 1890s, when William Coley began treating patients
with a preparation from streptococcal cultures (Coley's toxins)
to stimulate immune activity. The use of the BCG (Bacillus
Calmette-Guérin) vaccine for the treatment of bladder cancer
was an ultimate outcome from Coley's original concept.
Despite these early hints of efficacy, enthusiasm for immune
system involvement in (and control of) cancer has waxed and
waned over the subsequent years.
In the 1960s and the following decades, tumour immunology
again came to the fore as a result of studies into the rejection
of tumour transplants. It became clear that the immune
system had an ability to distinguish 'normal self' from 'tumour
self', and a number of tumour-associated antigens (TAAs)
were identified. This opened up the prospect of immunising
against cancer and, during the following years, development
of the first generation of cancer vaccines, which, at best,
yielded anecdotal evidence for patient benefit.
The modern era of cancer immunotherapy began with the
advent of recombinant DNA technology and the emergence
of the biopharmaceutical industry. Early initiatives included
the development of immune-stimulating cytokines, such as
the interferons (for example IFN-a, IFN-g) and interleukins (for
example IL-2). Although these drugs were approved for use
in niche cancer (and other) indications, their severe side effect
profiles and limited efficacy meant that the early expectations
for these drugs as the 'silver bullets' for the treatment of
cancer were never realised.
Over the same period, advances in DNA sequencing provided
new insights into cancer cell biology, and provided the
impetus for a new generation of therapeutic cancer vaccines.
Throughout the 1990s and into the 2000s, multiple variations
on the cancer vaccine theme (whole cells plus or minus
immune-stimulating cytokines, cell lysates, subunit vaccines,
DNA vaccines, et cetera) have
been taken into the clinic.
These products have
generally shown excellent
safety profiles, and
occasionally evidence for
the induction of relevant
immune responses, but
they have rarely shown
any meaningful efficacy.
The sole exception was
(Provenge®) for the treatment of
advanced prostate cancer, which
was successful in gaining market
approval in the United States and European Union, but was
a commercial disaster. The failure of multiple cancer vaccines
over the past 20 years has dampened enthusiasm for cancer
therapeutic vaccines (at least for the time being).
In contrast to the experience with cancer vaccines, the use
of antibodies as effector molecules, receptor antagonists
or drug-targeting agents has blossomed since the
1990s. Drugs such as rituximab (Rituxan®), trastuzumab
(Herceptin®), cetuximab (Erbitux®) and many others have
become established as standards of care across a range
of tumour types. While not necessarily acting strictly as
immunotherapies, these products have a demonstrated the
power of leveraging one arm of the immune system (the
humoral arm) for the treatment of cancer.
More recently, a greater understanding of the ways that
tumour cells evade and block the immune system has opened
up new treatment paradigms. Thanks to the pioneering work
of James Allison, chairman of Immunology at The University
of Texas MD Anderson Cancer Center in Houston, Texas, and
others, we now appreciate the complexity of the relationship
between cancer cells and the immune system. We now
know that cancer cells can deactivate killer T cells through
checkpoint pathways; that they can block T cell infiltration by
the expression of galectins and other inhibitory molecules;
and that they can downregulate the expression of MHC class
1 molecules, and thereby make themselves largely invisible
to the immune system. Clearly, cancer cells can manipulate
the immune system not to kill them, and understanding the
protection mechanisms has provided opportunities for drug
developers to out-manipulate the manipulators.
KEYTRUDA®, Opdivo® and YERVOY® are known as
checkpoint inhibitors (they block checkpoint pathways).
KEYTRUDA® and Opdivo® block PD1-PDL1 signalling
between tumours and immune cells, while YERVOY® blocks
a separate tumour cell/T cell engagement pathway (namely
CTLA4-CD28). In doing so, these antibodies release a cancer-
induced 'handbrake' on the immune system, resulting in
dramatic anti-tumour responses. In melanoma, previously
unheard-of response rates of around 30 per cent have
been achieved in late-stage patients. As impressive and
unprecedented as these response rates are, there is clearly
substantial room for improvement---a 30 per cent response
rate still means that the majority of patients are not deriving
benefit from the treatment.
High-priced therapies (often at a cost
of more than $100,000 per patient per
annum per drug) create challenges for the
Dr Ian Nisbet
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