Not sure if most can get through to the membership link, so I also copied and pasted the article.... Below....

http://static.fiercemarkets.com/public/ads2/catalent/2012/fiercebiotechreport4.pdf

Preventative vaccines have
changed the face of infectious
disease, even leading to the
near eradication of polio.
Now therapeutic vaccines are
looking to change the treatment of cancer and
other diseases, with the potential of minimal side
effects, shorter courses of treatment and reduction
of recurrences. The science is exciting and the
results are positive. But there’s no such thing as
a free lunch, and the challenges of manufacturing
cancer vaccines, particularly those that are tailored
to a single individual, could mean that the increased
costs and complex logistics could risk making this an
impractical solution to an already complex problem.
Why vaccines?
The body’s immune system normally searches and destroys
foreign invaders, such as bacteria, but one of the
reasons that cancer is so successful is that the tumors have
the ability to “hide” from the immune system, protecting
them from mankind’s natural defenses. The rationale behind
cancer vaccines is to expose the cancers to the immune system,
prompting the body to attack them. This has the promise of a
less toxic form of therapy than chemotherapy, as well as the possibility
of a treatment that seeks and destroys even the smallest
Can c e r I m m u n ot h e r ap y P r o d u c t i o n :
F i e r c e B i o t e c h S p e c i a l R e p o r t
toProfitability
FierceBiotech
THE BIOTECH INDUSTRY’S DAILY MONITOR
content brought to you by:
By Suzanne Elvidge
OvercomingObstacles
Page 2 FierceBiotech Special Report
tumors, or those where the surgeon’s knife cannot
go, potentially cutting the chance of cancer
recurrences or metastases.
“The field of vaccines is very exciting,” says
Lloyd Johnston, senior vice president of pharmaceutical
research, development
and operations
at Selecta Biosciences.
“Cancer vaccines allow us
to harness the immune
system to get to diseased
tissue that would be hard
to access otherwise.”
Cancer is a complex
disease, with distinct differences
between different forms of the disease,
and even differences within the same type--a
single tumor can host a range of different malignant
cells. This makes treatment thorny in
most cases, and it’s highly unlikely that any
one vaccine could perish all tumors. To get
around this problem, companies are looking
at different approaches, from personalized
vaccines like Dendreon’s Provenge (sipuleucel-
T), which is the first cancer vaccine to be
approved by the FDA and is created from a
treatment recipient’s own cancer cells, down
to small peptides made from a handful of
amino acids and designed to trigger a response
to a tumor antigen, such as KAEL-GemVax’s
GV1001.
“The model will be different for each vaccine,
as cancer is not a homogenous disease,”
says Carlos Santos, senior vice president of
product development and regulatory affairs
at Biovest International, a developer of cancer
vaccines.
The vaccine approach and
its challenges
There are two key approaches to developing
therapeutic cancer vaccines--patient-tailored or
personalized vaccines that are created for each
individual, targeting the specific antigens on
his or her own cancer cells, and “off-the-shelf”
vaccines that will be effective for wider groups
of patients, and target cancer antigens that are
common to the majority of the cancer cells in
each cancer type.
“Personalized vaccines are a very exciting
area in cancer treatment--because each individual’s
tumors have some individual characteristics,
this would give an exact match,” says
Johnston.
Each type of
vaccine has its
own challenges--
because personalized
vaccines are
made individually,
they have the issue
of cost and scalability;
whereas
the challenge of
off-the-shelf vaccines
is finding
the right target and the right immunogen. The
ingredients for cancer vaccines range from simple
peptides, through viral-based vaccines and
DNA vaccines, to whole proteins and whole
cells, and the latter two categories include both
personalized and off-the-shelf examples. Each
of these types face their own manufacturing
challenges, depending on their source material
and the endpoint, as Samuel Duffey, CEO,
president and general counsel at Biovest, says.
Manufacturing personalized
vaccines: the challenge
Personalized whole cell vaccines use modified
versions of the patient’s own (autologous)
cells (1). Patient-tailored cell-based vaccines
are inherently complex.
As mentioned before, there is only one cancer
vaccine on the market so far, Dendreon’s
Provenge. The vaccine is based on the patient’s
own immune cells, and Dendreon describes
Provenge as autologous cellular immunotherapy.
It was approved by the FDA in April 2010,
and is recommended for use by the National
Comprehensive Cancer Network. However, its
manufacturing is not straightforward.
Provenge treatment involves physicians taking
a sample of the patient’s white blood cells,
including antigen-presenting cells (APCs; also
known as dendritic cells). The cells are then
sent away to be processed with a fusion protein
that combines the antigen prostatic acid phosphatase
(PAP), found on around 95% of prostate
cancer cells, and granulocyte-macrophage
colony stimulating factor (GM-CSF), which
helps the immune response. The resulting vaccine
is couriered back to the hospital and given
to the patient, and this process is repeated
twice for a total of three doses over about a
month (2).
Cancer Immunotherapy Production: Overcoming Obstacles to Profitability
Cancer is a complex
disease, with distinct
differences between
different forms of
the disease, and even
differences within the
same type--a single
tumor can host a range
of different malignant
cells.
Lloyd johnston
Page 3 FierceBiotech Special Report
“For no disease other than cancer would
physicians and patients put up with such a
complex process--taking blood and tissue
samples, sending them off for processing, waiting
and getting back the two shots,” says Dana
Leach, founding partner of BioCinD, a biopharma
and biotech consultancy.
Stephen Dunn, president and senior managing
director of research at LifeTech Capital,
adds: “Dendreon’s vaccine does have complex
logistics--the vaccine has a very short shelf life
as it needs to be administered within 18 hours
of preparation, and this is compounded by
having to be given three times over a month,
but needs to be made afresh for each dose.”
Manufacturers of prophylactic vaccines for
preventing infectious disease can sell the vaccines
at lower costs and still make a profit, because
the manufacturing costs are low and the
markets are huge. If necessary, they can also
work from smaller margins.
Individualized vaccines are always going to
be more expensive. This is for a number of reasons.
Firstly, it’s a costly and complex manufacturing
process. Secondly, there’s a lot of money
invested in the R&D, especially for a first-inclass.
And thirdly, it’s a restricted market size--
while the cancer market as a whole is huge, the
size of the market for individual cancers can be
quite small. So, to remain viable, the margins
for these vaccines need to remain good.
Discussing this in an interview with The Life
Sciences Report, Dunn estimated that there are
around 250,000 patients with prostate cancer
who can be treated with Provenge at any one
time. This means that to make an income from
the vaccine, uptake needs to be good and the
margins need to be large. However, to date, the
uptake of Provenge has not been good, and the
margins have remained low (3)--according to
Dunn, Provenge’s sales in the first quarter of
2012 were $82 million, with a gross margin of
27%, which has changed little from the fourthquarter
2011 sales of $77 million (26% gross
margin).
“Dendreon believes that it has ways to
improve the efficiency of Provenge’s manufacture,”
says Dunn, which has potential to
improve the margins. “But as it stands, this
vaccine is always going to have a small gross
margin,” he adds.
All of this has cast doubt on the ability of
Dendreon to make a profit from its sales of
Provenge. According to EvaluatePharma, Dendreon,
already battered, has seen a 20% fall
in share price between May 11 and 18, based
on positive data from the combination of two
drugs, Zytiga and Lupron, as well as a formal
investigation from the SEC (4).
“I’m not convinced that Dendreon’s vaccine
model can succeed economically or practically,
as the process is complicated and the price is
high,” says Leach.
However, is the story
just about the ability of
this individual vaccine
to make a profit, or is it
a wider story about the
impact of Dendreon on
the future of personalized
cancer vaccines?
Provenge and
the future of
therapeutic cancer vaccines
As a pioneer in the field with a first-in-class
drug, Dendreon has had to tackle a lot of technical
challenges, as well as educate physicians
and patients about a new approach to cancer
treatment.
“Whatever the manufacturing issues, we
have to remember that [Provenge] was the first
successful cancer vaccine,” says Leach.”[All
involved at Dendreon] do have to be congratulated
in their work--they have created something
entirely new and gained GMP approval
for a very complex process where it’s not easy
to show consistency, and have met and overcome
technical challenges.”
Cancer Immunotherapy Production: Overcoming Obstacles to Profitability
“I’m not convinced
that Dendreon’s
vaccine model
can succeed
economically or
practically, as
the process is
complicated and the
price is high.”
Page 4 FierceBiotech Special Report
However positive the scientific outcomes,
though, there has been an impact on the therapeutic
cancer vaccines field, particularly where
investment is concerned.
“The lesson learned--immunotherapeutic
vaccines can work, but patient-specific versions
that have to be manufactured one dose at
a time will be really expensive, and biotechnology
investors will not justify the investment.
This has had a knock-on effect across the
industry, and you hear vaccine companies presenting,
and stating that their approach is ‘not
the same as Dendreon’s’--the red flag for investors
is the phrase ‘patient-specific,’” says Dunn.
Vaccine developers, both those focusing on
personalized and on off-the-shelf vaccines,
can learn from Dendreon’s manufacturing
struggles.
“We don’t want to risk throwing out the
baby with the bathwater where Dendreon is
concerned--the company is the pioneer in this
field, and everyone has learned a lot from the
company and its research. Will the company
survive--yes. Will Provenge be profitable--not
as it stands. Dendreon won’t sit still, and [its]
science and technology will look to create second-
generation vaccines and improved manufacturing
techniques,” says Dunn.
The future of personalized
cancer vaccines: cutting
the manufacturing costs
Perhaps one route to successful and profitable
personalized cancer vaccines is taking a
much simpler approach. Biovest’s BiovaxID
platform starts with a lymphoma tumor
sample. The cancerous B cells in this sample
have receptors on their surface that are crucial
for the tumor cell’s survival. Rather than using
a whole cell, Biovest creates copies of the cell
receptors on the patient’s tumor cells, which
are then given as a vaccine with GM-CSF and
KLH, a foreign protein that kicks off an immune
response, resulting in destruction of the
cells.
“Even though it’s individualized, the manufacturing
process is not that complex, as it’s
based on antibodies, which can be made and
purified using standard and well-established
techniques, and we are taking steps to automate
each step as much as possible,” says Santos.
“As there is a wait of up to 18 months or
so between chemotherapy and vaccination, the
process isn’t as urgent.”
One of the advantages of Biovest’s approach
is that all the patient-specific doses can be
made at the same time and stored, immediately
cutting the costs. ImmunoCellular Therapeutics
is also taking this approach, manufacturing
around 20 doses of its personalized cancer
vaccine, ICT-107, at a
time (3).
Developing techniques
to process more
vaccines for more patients
at a larger scale
will reduce the costs of
producing personalized
vaccines, according to
Johnston: “There are at
least two parts to the
final cost of any drug-
-the cost to make the
drug and the cost to
develop the drug. For
individual personalized
vaccines, this includes
the costs and logistics
of tissue harvesting and
processing, as well as
the R&D, which will
push the costs up,” says
Johnston.
Another approach to cutting the cost per
dose is to reduce the amount of vaccine needed
per administration. According to Leach:
“Delivery systems, formulations and adjuvants
could reduce the amount of vaccine needed.”
However, the issue with using adjuvants is
that they are often proprietary, and they need
Cancer Immunotherapy Production: Overcoming Obstacles to Profitability
One of the
advantages of
Biovest’s approach is
that all the patientspecific
doses can
be made at the
same time and
stored, immediately
cutting the costs.
ImmunoCellular
Therapeutics is also
taking this approach,
manufacturing
around 20 doses
of its personalized
cancer vaccine, ICT-
107, at a time (3).
Page 5 FierceBiotech Special Report
to be licensed-in, which adds to the costs
and the complexity of the development
process.
“It’s frustrating for researchers when
they believe that their vaccine could
work better with a specific adjuvant
but they need to license it in--I truly
believe that this has impeded the
growth of vaccine technology,” says
Leach.
Alternatives to personalized
vaccines
While the patient-specific approach
is always going to be the
best way scientifically and therapeutically,
according to Dunn, it
is challenging how to make the approach
a commercial success. As an alternative,
the off-the-shelf approach to therapeutic
vaccine development and manufacturing
will have larger markets and lower development
and manufacturing costs, and so should
be the route to better margins and increased
profitability. Peptide vaccines use the off-theshelf
approach, and are the simplest to manufacture,
ranging from around 9 amino acids to
about 30 amino acids, depending on the target
and the type of immune response needed. As
an example, KAEL-GemVax’s GV1001 is 16
amino acids long and includes two epitopes
(parts of an antigen), triggering off an immune
response against hTert, which is found on the
surface of many cancer cells.
Whole protein vaccines used as an off-theshelf
approach can be complex to develop,
because the research team has to select the
protein target, work out a manufacturing process,
make sure that it is expressed and folded
in exactly the right way, and then negotiate the
regulatory processes.
“However, once a protein manufacturing
process is sorted, with yields up and costs
down, then the cost of goods falls dramatically,
even for complex proteins like monoclonal
antibodies--the costs of these have fallen
around tenfold,” says Leach.
Algae can be engineered to produce complex
folded proteins without glycosylation (3).
Other alternatives for manufacturing proteins
include Medicago’s virus-like particles and
monoclonal antibodies produced in genetically
modified plants, which promises a faster
turnaround and lower costs than other protein
technologies.
Viral-vector-based vaccine technologies,
once developed, have
an economy of scale,
as once the technology
is developed for one
vaccine, it can be used
for other indications,
which keeps the costs
down. Even whole cell
vaccines can be off-theshelf,
using cell lines
(allogeneic cells) that
are grown from tumors
of the same type (1).
Examples of allogeneic
cancer vaccines include
BioSante Pharmaceuticals’
GVAX vaccines
(originally developed
by Cell Genesys), in
Phase I and II trials for
melanoma, myeloma,
leukemia, and colorectal,
prostate, breast and
pancreatic cancers. The
cells are cancer cells that have been genetically
modified to express GM-CSF, and are off-theshelf--
all patients with the same type of cancer
receive the same type of vaccine.
Selecta Biosciences is using a synthetic approach,
creating synthetic nanoparticles. As
Johnston explains: “The attraction of this tech-
Cancer Immunotherapy Production: Overcoming Obstacles to Profitability
Viral-vectorbased
vaccine
technologies, once
developed, have an
economy of scale, as
once the technology
is developed for
one vaccine, it can
be used for other
indications, which
keeps the costs
down. Even whole
cell vaccines can be
off-the-shelf, using
cell lines (allogeneic
cells) that are grown
from tumors of the
same type (1).
Page 6 FierceBiotech Special Report
nology is that it’s a lower-cost
and more compact route to
manufacturing using standard
pharmaceutical unit operations
as it is a completely synthetic
manufacturing process that
doesn’t require biological processes
that are often capital
intensive and costly.”
The expanding field of biomarkers,
and the growth of
genetic profiling, is opening up
the field for vaccines that are
not individualized but that are
targeted at small (or even large)
groups of people. While not
saving money for individual
vaccines, these allow the vaccines
just to be used in those
people most likely to respond, saving money for
the healthcare providers overall, and freeing up
the non-responders to try other forms of treatment.
These would be used in conjunction with
companion diagnostics to identify the appropriate
patient groups.
Therapeutic vaccines: the
cost vs. the price
The cost of therapeutic vaccines isn’t as simple
as just the price that is paid--as Robert McNally,
president and CEO of GeoVax, explained, because
vaccines aren’t given over long periods,
even if they are more expensive per dose, they
still could be lower cost than long-term therapies.
One of the cost issues that isn’t always calculated
is that of the cost of
cancer to society, particularly
that of the treatment
of side effects of chemotherapy,
and the time lost
from work or caregiving.
Biovest’s Duffey expanded
on this: “When we look
at the commercial aspects
of a product, we need to
think about the benefit to the patient as well,
and cancer vaccines are generally near benign
where side effects are concerned. Vaccine prices
are not abstract, they are related to patient benefit,
and societal and patient costs will become
increasingly important--it’s more than just efficacy
and cost.”
In conclusion
When President Richard Nixon signed the National
Cancer Act of 1971 (6), this was regarded
as the beginning of the war on cancer. However,
despite huge investments (the National Cancer
Institute in the U.S. spends $5 billion a year on
research), and a few exciting breakthroughs in
cancer therapeutics over the last 40 years, the
outlook for patients with metastatic disease is
not much better than it was a few decades ago
(7).
“I believe that we have got as far as we can go
with chemotherapy--we
have to accept that there
will never be a single
magic bullet--and the
future of cancer treatment
is through combinations
of chemotherapy,
radiotherapy and targeted
therapies, with an aim to
manage the disease rather
than cure it,” says Leach.
Cancer vaccines are an
exciting step toward effective cancer treatment
with fewer side effects. They are still very much
in their infancy, but there is a lot of hope for
their future, whether it’s a personalized vaccine
using Dendreon’s model, or a simpler (and potentially
lower cost) approach based on protein
or smaller fragments.
“The vaccine field is likely to be a mixture of
individualized vaccines and ‘one size fits all,’
and the individual vaccines are always going to
Cancer Immunotherapy Production: Overcoming Obstacles to Profitability
One of the cost issues
that isn’t always
calculated is that of
the cost of cancer to
society, particularly that
of the treatment of side
effects of chemotherapy,
and the time lost from
work or caregiving.
robert McNALLY
Page 7 FierceBiotech Special Report
be the more expensive option, but it will depend
on what is being treated -- in some cases the
higher-cost vaccine could still be cost-effective,”
says McNally. “In 10 years, there are likely to be
a plethora of cancer vaccines in development,
and in 20 years, they could be standard therapy,”
predicts McNally.
The issues with Dendreon may have had a
short-term impact on the market, but the abundance
of research under way should revive the
excitement in the field, and even Dendreon,
especially if it does manage to streamline the
process, could be able to keep a toehold as the
first-in-class. So watch this space.
“Dendreon’s vaccine is the first to have become
available on a commercial basis--it’s showing the
way, and less expensive approaches are likely
to come along,” says McNally. “Someone has to
start.”
References
1. CancerQuest. “An Introduction to Tumor
Vaccines.” CancerQuest. [Online] [Cited:
21 May 2012.] http://www.cancerquest.
org/tumor-vaccines-introduction.html.
2. “Sipuleucel-T immunotherapy for castration
resistant prostate cancer.” Kantoff, P
W, et al. Jul 2010, N Engl J Med, Vol. 363,
pp. 411-422.
3. Mack, George S. “Vaccine Therapies Hold
Promise for Investors”: Stephen Dunn.
The Life Sciences Report. [Online] 12
April 2012. [Cited: 25 May 2012.] http://
www.thelifesciencesreport.com/pub/
na/13072.
4. EvaluatePharma. Weekly Market Movers
(to 18 May 2012). EP Vantage. [Online]
18 May 2012. [Cited: 25 May 2012.]
http://www.epvantage.com/Universal/
View.aspx?type=Story&id=297244§i
onID=&isEPVantage=yes.
5. “Algae-Produced Pfs25 Elicits Antibodies
That Inhibit Malaria Transmission.”
Gregory, James A, et al. 5, 2012, PLoS
One, Vol. 7, p. e37179.
6. NCI. The National Cancer Act of 1971.
National Cancer Institute: Office of Government
and Congressional Relations.
[Online] 23 December 1971. [Cited: 25
May 2012.] http:// legislative.cancer.gov/
history/phsa/1971.
7. Davies, Paul. “The final frontier in the war
on cancer.” Daily Telegraph. [Online] 17
February 2012. [Cited: 25 May 2012.]
http://www.telegraph.co.uk/science/
science-news/9065707/The-final-frontierin-
the-war-on-cancer.html.
Cancer Immunotherapy Production: Overcoming Obstacles to Profitability