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Dr Linda Stannard, UCT / Science Photo Library
Human papillomavirus has been implicated in cervical
cancer
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It has taken over 15 years to develop a vaccine against cervical cancer
and now, like buses, it seems that two will come along
at once. Last week, GlaxoSmithKline ann-ounced that it has submitted
an EU licence application for Cervarix, its vaccine against human papillomavirus
(HPV) 16 and 18, which together cause about 70 per cent of all cervical
cancers. This follows hot on the heels of that for Gardasil, the Merck
vaccine against HPV 16 and 18, plus two additional HPVs (6 and 11), which
account for an estimated 90 per cent of cases of genital warts. Assuming
all goes well, the Merck vaccine, recently fast tracked by the Food and
Drug Administration for a licence in the US, looks set to beat the GSK
product to market by a whisker. At that point, the comparative cost effectiveness
of the two vaccines will determine which company can reap the greatest
reward for the years of research and development.
Although Cancer Research UK this week predicted that one in 10 cases
of cancer could be prevented by anti-viral vaccines like Cervarix and
Gardasil (see p313), prophylactic vaccines against most common cancers
may never be developed because of the lack of any obvious microbial cause.
Instead, the venture capital is stacking up behind a growing range of
therapeutic vaccines, which are being administered to people who already
have cancer to stimulate their immune systems into destroying their tumour(s).
A variety of different technologies are being used, including whole cell,
dendritic cell, antibody, peptide and deoxyribonucleic acid vaccines.1
Some of the most promising results in placebo-controlled trials have
been achieved with autologous cell vaccines — injections of patients’ own
tumour cells rendered harmless by radiation or other techniques. No longer
capable of triggering cancer, these cells contain a range of tumour antigens
capable of eliciting an immune response. In a study of 558 renal cancer
patients, the five-year survival rate was 77 per cent in patients who
received six injections of autologous renal cell vaccine after nephrectomy,
compared with 68 per cent in those who had no adjuvant treatment.2 Similarly,
significantly greater recurrence free periods were reported in another
large study, where patients with colorectal cancer received injections
of an autologous tumour cell-BCG vaccine.3
More recently, US biotechnology company, Dendreon, reported superior
median survival rates in patients with asymptomatic metastatic, hormone-refractory
prostate cancer treated with autologous dendritic cells carrying prostate
cancer antigen, prostatic acid phosphatase (PAP). Dendritic cells are
particularly popular with vaccine designers because they are the body’s
own specialised antigen-presenting cells. They can be removed from the
cancer patient’s blood, combined with modified cancer cell antigens
and then re-injected in order to trigger an
immune response. However, as Angus Dalgleish, oncologist at St George’s
Hospital, London, explains, the drawback of all these autologous approaches
is that they are not practical for routine treatment: “Autologous
treatment is a service rather than a vaccine, and it is an expensive
service because it has to be re-designed for each patient. But the studies
which have been done using these methods have provided important proof
of principle,” he told The Journal.
At UK British biotechnology firm, Onyvax, where Professor Dalgleish is
also research director, the focus is on developing an allogeneic whole
cell vaccine against prostate cancer that does not have to be tailored
to each patient. Instead, the vaccine is formulated from three different
inactivated cancer cell lines from different stages of prostate cancer,
containing multiple antigen targets for the immune system. Phase 2 data
show that the vaccine may delay disease progression in hormone resistant
prostate cancer.
In the longer term, Professor Dalgleish predicts that DNA vaccines with
viral or bacterial vectors hold the greatest promise for
future cancer vaccines — once they can be shown to work. At Oxford
Biomedica, chief executive officer Alan Kingsman is optimistic that the
company’s DNA vaccine, Trovax, will do just that. Trovax uses the
tried and tested recombinant pox virus vector, modified vaccinia virus
Ankara (MVA) to deliver the gene for tumour associated antigen 5T4, a
protein present in high levels on 75 per cent of solid tumours, including
colorectal and renal cell cancers. “The MVA delivery system is
superb at inducing an immune response, especially in difficult situations,
such as cancer, where you are trying to get the body to react against
something which is seen as ‘self’”, Professor Kingsman
points out. Trovax has been tested in over 85 patients in open trials,
with promising effects on tumour response, time to progression and 12-month
survival. While looking to establish a partnership with a large pharmaceutical
company to take Trovax to market, Oxford Biomedica has recently raised
additional funding to enable it to embark on a pivotal phase 3 study
in renal cancer, scheduled to start this summer. Professor Kingsman predicts
that if the survival data already seen in open trials can be reproduced,
Trovax should have no difficulty getting to registration. “Our
aim is to get to market with renal cancer, and then to expand into other
cancers where there are high levels of 5T4,” he said.
The MVA delivery system is also being used by French company, Transgene,
as a vector for the gene for the mucin-1 (MUC-1) antigen commonly found
on breast, prostate, lung, pancreas and other cancers. Transgene’s
therapeutic cancer vaccine, TG 4010, also includes the DNA sequence coding
for the cytokine interleukin-2. Following promising open-label results
in advanced non small cell lung cancer (NSCLC), TG 4010 is being used
in combination with chemotherapy in a controlled phase 2 study in NSCLC.
Under way in the US is a phase 3 controlled trial of PANVAC-VF, a therapeutic
vaccine targeting MUC-1 and carcinoembryonic antigen (CEA), in 250 patients
with metastatic pancreatic cancer. The vaccine, developed by Therion
Biologics, has already yielded promising phase 2 results. If the overall
survival endpoint required in the phase 3 study is met, the vaccine will
be submitted for an FDA licence later this year. But, as with all the
cancer vaccines currently moving from the comfort of phase 2 studies
into the tough world of phase 3, this is a big “if”. The
cancer literature is filled with ageing reports of vaccines that conferred
unheard-of survival benefits in uncontrolled phase 2 trials, only to
disappoint when subjected to the harsher protocols of phase 3.
Those behind the new generation of vaccines believe that, by choosing
their tumour antigens more carefully and delivering them more attractively
to the immune cells they want to trigger, they can avoid earlier pitfalls.
However, judging from experiences of developing the cervical cancer vaccines,
there could still be years of frustration ahead.
References
1. Dalgleish AG, Whelan MA. Cancer vaccines as a therapeutic modality:
the long trek. Available at: www.ncbi.nlm.nih.gov (accessed 14 March
2006).
2. Jocham D, Richter A, Hoffmann L, Iwig K, Fahlenkamp D, Zakizewski
G, et al. Adjuvant autologous renal tumour cell vaccine and risk of tumour
progression in patients with renal-cell carcinoma after radical nephrectomy:
phase III, randomised controlled trial. Lancet 2004;363:594–9.
3. Vermorken JB, Claessen AM, van Tinteren H, Gall HE, Ezinga R, Meijer
S, et al. Active specific immunotherapy for stage II and stage III human
colon cancer: a randomised trial. Lancet 1999;353:345–50. |
The
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