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HowtoTreat
PULL-OUT SECTION
inside
www.australiandoctor.com.au
• From research to therapy • Stem cell clinical trials
The authors
• Stem cell treatments for specific conditions • Advising patients
DR KIRSTEN HERBERT,
consultant haematologist, Peter
MacCallum Cancer Centre, East
Melbourne, and Cabrini
Medical Centre, Malvern,
Victoria.
PROFESSOR ANDREW
ELEFANTY,
joint head, embryonic stem cell
differentiation laboratory,
Monash Immunology and Stem
Cell Laboratories, Monash
University, Clayton Campus,
Victoria.
REBECCA SKINNER,
senior manager,
communications, Australian
Stem Cell Centre, Clayton,
Victoria.
Stem cell therapies —
Part 2: the future
Background
ALMOST every week there is a newspaper article or television program featuring the latest breakthrough in stem
cell science. While these stories offer
hope to many suffering from incurable conditions such as spinal cord
injury, diabetes, multiple sclerosis and
cerebral palsy, they rarely present a
realistic picture of the time frame
required to take a preclinical discovery
through the clinical trial phase to
OUT NOW
become standard practice. For example, it has taken 12 years from the discovery of human embryonic stem cells
(ESCs) to the first safety phase clinical
trial of these cells for spinal cord
injury — a remarkably short time
frame considering the complexity and
challenges involved in the proposed
therapy. There exists a gap between
the public perception of how close we
are to clinical application of many of
the recent discoveries in stem cell science, and the reality. In most cases
many challenges still need to be
addressed to realise the full potential
of stem cell science.
In this second part of the two-part
series on stem cell medicine we will
discuss how stem cell research is
being taken from the laboratory to
clinical practice. We highlight clinical
trials that evaluate potential new
stem cell therapies. We also provide
practical advice for managing
enquiries from patients who are considering participation in a stem cell
clinical trial or bona fide medical
innovation, or who are contemplating travelling and paying for
unproven stem cell treatments being
actively promoted by clinics and
companies based overseas.
DR MEGAN MUNSIE (PhD),
director, education, ethics, law
and community awareness
unit, Stem Cells Australia,
Melbourne; formerly senior
manager, research and
government, Australian Stem
Cell Centre, Clayton, Victoria.
cont’d next page
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18 November 2011 | Australian Doctor |
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HOW TO TREAT Stem cell therapies — Part 2: the future
How does stem cell research become stem cell therapy?
IN the past decade there has been
an increase in the number of academic papers reporting the positive
results of animal studies investigating stem cell therapy for conditions
such as Parkinson’s disease and
spinal cord injury. Many people will
remember the images of a rat, crippled by a contusion injury to the
thoracic spinal cord, which recovered some mobility after receiving
treatment with oligodendrocytes
derived from embryonic stem cells
(ESCs).
The scientific community is entering the next phase of investigation
— to determine whether proposed
stem cell treatments are safe and
effective in human patients.
What are stem cell treatments?
Many types of stem cells can be used
for stem cell treatments (see Part 1 of
this series). The stem cells may be
obtained from the patient (autologous) or from a healthy donor (allogeneic). Most stem cell therapies use
cells that express HLA antigens, so
immunosuppressive therapy may be
required for allogeneic stem cell treatments, perhaps using similar regimens
to those used in bone marrow and
organ transplantation.
Stem cell-based treatments usually
aim to provide their curative effect
by the stem cells engrafting into the
affected tissue and regenerating or
replacing diseased or damaged cells.
However, some stem cell treatments,
most notably those using mesenchymal stem cells, may exert their benefit
through transient delivery of extracellular factors that encourage recruitment of endogenous cells or suppress
the host immune system (a paracrine
effect). Other proposed treatments
would use stem cells to deliver
chemotherapeutic drugs to destroy
inoperable tumours.
Stem cell treatments can be broadly
categorised into three types:
• Standard practice stem cell treatments — these are available,
widely accepted, clinically
proven, regulated, non-experimental treatments.
• Investigational treatments —
these are treatments in which the
benefit is not yet proven. These
include treatment as part of a
clinical trial, or one-off or limited-access treatments termed
‘medical innovations’ performed
under the supervision of a recognised institution, with institutional Ethics Committee approval
and with the awareness of the
regulatory authorities.
• Unproven treatments — these are
treatments in which the benefit
is not proven and the treatment is
not part of a clinical trial or
recognised medical innovation.
Figure 1 provides a summary of
the key features of each of these
categories.
Standard practice stem cell
treatments
A treatment is proven when it has
been approved by the appropriate
government regulatory body, which
in Australia is the Therapeutic
Goods Administration. This
approval is given only after extensive testing in clinical trials has
demonstrated that the treatment is
safe and effective and has an
acceptable risk–benefit ratio.
24
| Australian Doctor | 18 November 2011
Figure 1: Overview of stem cell treatments. (Source: Stem Cell Therapies Now and in the Future, 2011. Reproduced with permission.)
Stem cell treatments
Currently accepted,
widely used, proven
safe and effective
stem cell
treatments
• Peer reviewed
• Safety proven in
large-scale clinical
trials or through
years of experience
• Quality and safety
of cells regulated
by government
bodies
Investigation/experimental stem cell treatments
Clinical trials
• Scientific rationale is clearly
stated and explained
• Evidence of safety and
efficacy in preclinical
(animal) models is provided
• Scientific plan has been
peer reviewed
• Answers a scientific or
medical question
• Benefits medicine in
general, may benefit the
patient if successful
• Results are reported and
published
• Aims to prove safety
• Aims to prove the treatment
works
• Does not require payment
• Includes a recognised
Patient Informed Consent
form
• Patient is followed up long
term
• Practitioners and institution
take responsibility for
caring for the patient in the
event of complications
‘Medical innovations’
using stem cells
• Scientific rationale is
clear
• Evidence of safety and
efficacy in preclinical
(animal) models is
provided
• Treatment plan has been
peer reviewed
• Benefits the patient
possibly, if successful
• Offered to patients with
no viable alternative
• Carried out by experts in
the field
• Carried out at institutions
with good track record
and experience in the
technique
• Informed consent is
obtained
• Patient is followed up
long term
• Practitioners and
institution take
responsibility for caring
for the patient in the
event of complications
Phases of clinical trials
Of the four phases of clinical trials, the first three must be successful before the
product or treatment is eligible for regulatory approval.
Phase I
The first testing of a new drug, treatment or clinical device on a small group of
people (about 20-80) to evaluate safety. Phase I research studies can include
drugs or treatments that have been tested in animals but not previously in
humans.
Phase II
Phase II trials generally involve a larger group of patients to further evaluate
safety and explore the efficacy of the intervention. This usually involves one
group of patients receiving the experimental drug, while a second ‘control’
group will receive a standard treatment or placebo. Often these studies are
double blinded.
Phase III
Phase III trials continue to investigate the efficacy of the intervention in larger
groups of people (up to several thousand) by comparing it against other similar
interventions while monitoring for undesired effects. Once a phase III study is
successfully completed, regulatory approval can be sought for the drug or
therapy to be made available for use in clinical practice.
Phase IV
Once the intervention has obtained regulatory approval and it is available for
use, further studies are performed to monitor effectiveness and collect
information regarding undesired effects. Late Phase III/Phase IV studies often
compare an investigational drug or therapy with one already available.
Adapted with permission from Stem Cell Therapies Now and in the Future (see Online
resources, page 30).
The only area of medicine in
which stem cell therapy is standard
and accepted practice is in the area of
haematopoietic stem cell transplantation (HSCT), also known as bone
marrow transplantation (see Part 1
of this series). The first successful
allogeneic HSCT was reported in
www.australiandoctor.com.au
Unproven stem cell treatments
• Scientific rationale is not made
clear
• Evidence of safety and efficacy
in preclinical (animal) models is
not provided, or referenced
• Treatment plan has not been
peer reviewed by an ethics
committee
• Benefits the practitioner
(definitely) and the patient
(possibly)
• Offered to patients who feel they
have no other viable alternative
• Often offered by direct
marketing (eg, via the internet)
• May be carried out by
practitioners often not
recognised as reputable experts
in their field
• May be carried out at
institutions with no track record
for publications or research
• Informed consent is often not
obtained
• Legal recourse if something
goes wrong is often not clear
• Medical insurance is often not
clear
• Payment is required
1968, and it remains crucial to the
treatment of several disorders. The
collection of bone marrow under
general anaesthesia has largely been
replaced by the collection of
cytokine-mobilised HSCs from the
peripheral blood, which is a far less
invasive approach.
Investigational/experimental
stem cell treatments
Investigational stem cell treatments are always offered as part
of clinical trials or as a medical
innovation.
Clinical trials
Clinical trials of proposed stem cell
treatments are undertaken to determine their safety and efficacy, and
then to publish results in a peerreviewed journal so that the
broader medical, scientific and
patient communities can benefit
from this knowledge. By definition,
clinical trials must be evaluated and
approved from a scientific perspective by a Clinical Research Committee composed of scientific peers,
and from an ethics perspective by
an Ethics Committee made up of
individuals such as ethicists, scientific peers, the general public and
sometimes clergy. All clinical trials
must be listed on a recognised registry so that the international community is aware of trials being conducted at other sites.
Clinical trials begin as small,
proof of principle, safety and feasi-
bility studies (Phase I/II), and move
through to large, randomised studies testing efficacy (Phase III), onto
collecting detailed long-term data
on safety and clinical benefit (Phase
IV) (see box, left).
The importance of the clinical
trial process cannot be overstated.
While it may seem laborious and
detailed, this process ensures the
proper acquisition of knowledge of
safety and efficacy in human
patients, and these data support
regulatory approval.
The design of clinical trials that
evaluate stem cell therapy is similar
to that for any novel therapeutic
agent, procedure or device. Determining whether the proposed therapy is efficacious is complex, especially as many stem cell therapy
trials are in neurological diseases
such as spinal cord injury, cerebral
palsy, Parkinson’s disease and
stroke, where some degree of
recovery may occur spontaneously
as a result of limited neural regeneration or neuroplasticity, often in
the context of intensive physical
and occupational therapy. The
potential for a placebo effect in
these diseases is as real as in other
contexts, especially because these
diseases are often chronic and devastating to patients and carers.
A growing number of clinical
trials use cells derived from several
stem cell sources for a variety of
conditions. These will be discussed
in more detail.
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Medical innovations
Medical innovations using stem
cells are treatments that have the
following features:
• The treatments are offered as
one-off or special access treatments in a facility with extensive
experience in the relevant techniques and with the scientific
background of the treatment
being offered.
• Although the treatment is experimental, there is good scientific
rationale that the proposed treatment may benefit the patient.
Medical innovations are an
important way in which novel
treatments can be tried, but strict
requirements exist, including:
• Investigational use of any unapproved therapeutic agent must
receive authorisation from the
TGA via their Special Access
Scheme.
• There must be stringent peer
review by recognised experts in
the field who do not have a
vested interest in the treatment
(usually through the institutional
clinical research committee).
• The practitioner must have submitted a written plan to a peerreview committee, such as an
innovations committee, outlining
the scientific rationale and preclinical evidence that the proposed treatment will be safe and
effective.
• The practitioner must provide a
full description of the type of cells
used, how they will be collected,
processed and stored, and how
they will be administered to the
patient.
• There must be a description of
how the patient will be followed
up after their treatment, and
what contingencies are in place
if anything should go wrong.
• The research plan should include
a plan for publication of results
in a peer-reviewed journal.
• The patient or guardian must
provide full informed consent to
the satisfaction of the review
committee.
Unproven stem cell treatments
The emergence of stem cell science,
combined with the relatively slow
and careful pace of legitimate preclinical and clinical research, has
led to the emergence of practitioners who are willing to offer treatments claimed to be stem cell treatments, effectively circumventing the
clinical trial process.
Medical travel (also known as
medical tourism, health tourism or
global healthcare) — when patients
seek treatment in another country
— is not a new phenomenon but is
becoming increasingly commonplace. Most types of healthcare,
including
plastic
surgery,
orthopaedic surgery, reproductive
treatments, psychiatry, alternative
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Figure 2: Limbal biopsy from a human cornea resting on a contact lens, showing proliferation of corneal epithelial stem
cells which are located in the basal layer of the limbus.
Limbal biopsy
treatments, convalescent care and
dentistry, are available. Medical
travel may arise out of the desire to
access widely accepted treatment
at a cheaper price, or unproven
treatments generally not offered in
a patient’s home country. Many
patients opting for the latter treatments do so because they feel they
have no alternative treatments
available.
Increased media attention about
stem cells has resulted in increased
investment and interest in the area,
as well as hope that ‘a cure is just
around the corner’. As the profile
of stem cell science grows, so does
the proliferation of clinics offering
stem cell treatments globally.
Unlike many other forms of medical travel, the treatments offered
overseas using stem cells are generally not proven. Providers of stem
cell treatments vary in their assertions about the conditions that can
be treated, the degree of improvement to be expected and the cell
types and methodology used. Many
clinics offer the hope of cure or
major improvement of symptoms
for a range of illnesses.
Treatments offered include
intrathecal injections of autologous
bone marrow cells for diseases such
as motor neuron disease and spinal
cord injury, and brain parenchymal injections of fetal-derived stem
cells for diseases such as ataxiatelangiectasia, cerebral palsy and
stroke.
Some treatments are not even
human in origin, such as injections
of rabbit fetal stem cells for conditions ranging from Down syndrome to ageing and impotence.
Aggressive marketing tactics such
as direct-to-consumer advertising
via the internet often target vulnerable groups, such as parents who
may have the sense that there is
combination (Phase I/II). Only nine
trials are entering the more advanced
phases of evaluation.
A number of trials use tissue-specific stem cells derived from fetal stem
cells. The US Food and Drug Administration has approved several studies
using cells derived from human ESCs
to start early-phase clinical trials.
Keeping abreast of the clinical trials
involving stem cells is a daunting task.
The Australian New Zealand Clinical
Trials Registry and ClinicalTrials.gov
provide regularly updated information about clinical research, eligibility
criteria and location of trials. However, it can be difficult to gain a concise view on the progress made for
particular conditions. Drawing on
more than 600 enquiries made annu-
Stem cell treatments – the risks
A RECENT study of online advertising of unproven stem cell treatments
demonstrated that the portrayal of likely clinical benefit is overly optimistic,
overpromises results and underestimates potential risks. The Hopeful
Journeys study (described in box on page 30) identified that many patients
who participate in these unproven treatments identify the biggest risk to be
financial rather than medical.
As we have discussed, few stem cell treatments have been proven safe
and effective, including many of the advertised autologous stem cell
therapies. While documented evidence of adverse outcomes is scarce, there
have been high-profile cases that emphasise the need for caution:
• In 2009, it was reported that an Israeli boy with ataxia telangiectasia, who
had been taken to Russia three times at ages 9, 10 and 12 for intracranial
and intrathecal injections of fetal neural stem cells, had been diagnosed
with a multifocal brain tumour. Tests found that the tumours were of nonhost origin and had been derived from the cells of at least two of the donor
fetuses.
• In 2010, a patient treated in a private clinic in Thailand for serious kidney
disease by injection directly into her kidneys of autologous bone-marrow
derived stem cells developed masses in the kidneys. Doctors reporting the
case found that the patient had not benefited from the treatment, and
masses of blood vessels and bone marrow had formed at the injection site,
in a demonstration of the cells seeming to play out their natural biology.
• Recent animal studies have further demonstrated the possible dangers of
‘putting something where it does not belong’: mice treated for MS with
mesenchymal stem cells developed tumours composed of cartilage and
other connective tissue.
While these examples demonstrate the direct risks of cellular therapies,
other risks and considerations must be taken into account. For example, it is
critical that cells are cultured in xeno-free conditions (free from non-human
contamination) and that they are screened for viruses.
Some unproven stem cell therapies involve invasive medical procedures
including the direct injection of cells into the brain and spinal cord —
procedures that always carry an element of risk.
little choice but to pursue this
option.
Glossy websites often advertise
successes in terms of anecdotes and
lay media coverage. However, there
is a lack of clinical evidence of efficacy or safety, and often companies may fail to provide full disclosure to patients of risks involved,
appropriate follow-up, proper
indemnity for adverse events, true
characterisation of the exact nature
of the cells injected (stem cells
versus progenitors or fully differentiated cells), and may not inform
the patient about whether animal
products, particularly from bovine
sources, were used in the cell culture process.
Other concerns centre on the
risks associated with the treatment
(see box left).
Human cells for clinical treatment need to be stored and handled carefully to avoid contamination, and quality control is
necessary to ensure purity. For
example, patients receiving blood
transfusions in Australia are
assured that red cell preparations
have been screened for known
bloodborne diseases and stored in
the appropriate manner before the
transfusion. The same principles
may not apply to stem cell treatments overseas.
There is much that is unknown
about the behaviour of stem cells
once they are introduced into the
recipient. Do they engraft? Are they
rejected? Do they undergo rapid
senescence? Can they form
tumours in vivo (as has been seen
in animal models)? Do they actually repair tissues or exert paracrine
effects? Importantly, just because
they may come from the patient
does not mean that the stem cells
are free of risk.
In most cases of overseas clinics
offering unproven stem cell treatments, the host country has less
regulatory or legal oversight than
the patient’s home country. Without a formal system for medical
negligence claims in many of these
countries, few legal options would
be available for patients seeking
reimbursement or a legal hearing
if something goes wrong with their
treatment.
Of a less serious nature, there is
a growing trend towards marketing
products that providers claim will
stimulate a patient’s own stem cells.
One example is bovine colostrum;
others include a growing number
of anti-ageing and beauty products.
These products do not necessarily
contain any cells, but are still marketed as stem cell treatments. This
is misleading, and there is usually
no peer-reviewed scientific evidence
to support the claims of those who
report that applying, ingesting or
injecting these products will affect
the recipient’s stem cells.
Stem cell clinical trials
MANY clinical trials involving stem
cells are in progress. Most of these
involve haematopoietic stem cells
(HSCs) in treatments for malignancies of the blood and immune system
or as an adjunct to chemotherapy
treatments.
However, over recent years there
have been a growing number of trials
using mesenchymal stem cells (MSCs)
isolated from bone marrow, umbilical
cord blood and placental tissues. A
review of the public clinical trials
listed on the National Institutes of
Health’s clinical trials database, ClinicalTrials.gov, revealed that there were
more than 120 trials using MSCs for
a wide range of conditions, with most
being Phase I (safety) studies, Phase II
(proof of concept for efficacy) or
www.australiandoctor.com.au
ally to the Australian Stem Cell
Centre, we have summarised the current status of stem cell-based treatments for several commonly
requested conditions. We have tabulated current clinical trials for specific
conditions and provide a link to
where one can seek further information online (table 1, page 28).
cont’d next page
18 November 2011 | Australian Doctor |
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HOW TO TREAT Stem cell therapies — Part 2: the future
from previous page
Cardiac progenitor cells.
Cardiac repair
During the past 10 years, numerous clinical trials have been conducted to explore the effect of
autologous and allogeneic HSCs
and MSCs on congestive cardiac
failure, refractory angina and acute
MI. To date, the trials have demonstrated that these treatments are
generally safe. However, only
modest clinical benefit has been
observed.
The next step is to determine
which type of stem cell treatment is
best suited to the various pathologies in cardiovascular disease. Evidence suggests that bone marrowderived HSCs are best suited for
treatments aimed at limiting pathological remodelling of the
myocardium and relieving angina
via the paracrine effects of stem
cells, rather than through direct cell
replacement.
The regeneration of cardiac
muscle at the site of chronic scars
probably requires cells with true
cardiomyogenic potential, and
interest is in the recruitment of
endogenous cardiac stem cells
located in the epicardium. It has
been shown in mice that pre-treatment with proteins such as oral
thymosin beta(4) allows recruitment and differentiation of these
stem cells and institutes cardiac
repair after an ischaemic insult,
indicating that a protein-based
rather than cell-based therapeutic
approach may eventuate.
For acute MI, several clinical
trials involving bone marrow and
adipose tissue-derived stem cells
exist. In a small randomised double
blind trial of patients with ST-elevation acute MI, reinfused stem
cells isolated from adipose tissue
did not result in adverse cardiac or
coronary events after 18 months’
follow-up.
Spinal cord injury
After many years of campaigning
and preparation, clinical trials are
in progress for acute and chronic
spinal cord injury treatments using
stem cell-derived products.
Californian biotechnology company Geron have developed an
oligodendrocyte progenitor cell
product (GRNOPC1) derived from
differentiated human ESCs. The
trial aims to treat up to 10 patients
with acute spinal cord injury and it
is hoped the GRNOPC1 cells will
re-myelinate demyelinated axons in
the injured spinal cord. The primary objective of this Phase I study
is to assess the safety and tolerability of GRNOPC1 when administered by injection into the lesion
site in the thoracic spinal cord
between 7 and 14 days after injury.
The endpoints of the trial are safety
and neurological function, using
standardised testing at specific time
points to monitor sensory and
lower extremity motor function.
As this is the first trial involving
human ESC-derived cells, the
FDA has been understandably
cautious. In the interest of patient
safety, Geron’s final submission
to the FDA famously included no
less than 28,000 pages of details
of pre-clinical experiments in animals, processes and long-term
follow-up procedures. While
Geron has presented data on the
first two patients enrolled in the
trial, the final outcomes will not
26
| Australian Doctor | 18 November 2011
Bone marrow-derived
HSCs are best suited
for treatments aimed
at ... relieving angina
via the paracrine
effects of stem cells.
be known for some time.
In Switzerland, StemCells Inc is
recruiting patients for a Phase I/II
clinical trial using neural stem cells
derived from fetal tissue for chronic
spinal cord injury. Numerous other
studies using bone marrow stromal
cells exist, and while these have
been shown to be relatively safe,
the effect was limited.
While the long-term prospects
for stem cell transplantation for
spinal cord injury remain promising, there remain many challenges
to address in the development of
such therapies.
target dry age-related macular
degeneration (AMD) and the
other will treat younger patients
with Stargardt’s macular dystrophy. The program’s initial goal is
testing the safety and tolerability
of this therapy at different doses
and assessing whether progression
of the disorder can be slowed.
Similarly, a consortium in the
UK known as the London Project
to Cure Blindness is working with
human ESC-derived retinal pigment epithelial cells and expect to
begin a clinical trial within the
next 12 months to treat 12
patients with acute AMD.
Blindness
Corneal disease is a common form
of blindness. Limbal stem cells
present in the eye can produce differentiated cells to replace the
damaged or missing cornea. The
technique involves taking autologous, adult limbal stem cells from
the healthy part of the eye, culturing the cells, then transferring
them to the diseased cornea that
has had any damage removed (see
figure 2, page 25).
The largest published trial,
undertaken in Italy, tested the technique on 112 patients and reported
that the permanent restoration of a
transparent, renewing corneal
epithelium was attained in more
than three-quarters of the treated
eyes.
In Australia, a group at the University of NSW is trialling a similar treatment but they are using
contact lenses to culture and
deliver the cells. About 10 patients
have been treated, with the trial
ongoing and not due to report
until 2012.
In a new clinical application of
human ESCs, US-based company
Advanced Cell Technology has
enrolled the first of 24 patients in
separate Phase I/II trials. Using
human ESC-derived retinal pigment epithelial cells, one trial will
www.australiandoctor.com.au
Diabetes
Pancreatic islet cell transplantation
has been available for some years to
treat patients with type 1 diabetes.
However, while insulin independence
can be achieved in most recipients
of cadaveric islet cell grafts, difficulties such as sustained independence
from exogenous insulin, side effects
of immunosuppressants, access to
sufficient donor tissue given the need
for multiple donors and low success
rates of islet cell isolation have been
encountered. The ability to make
pancreatic beta cells from human
ESCs provides a possible alternative
source of insulin-producing human
cells. Californian company Viacyte
expects to launch clinical trials in
the next two years.
Given the autoimmune nature of
type 1 diabetes, another approach is
to use the immunosuppressive properties of MSCs. In a large Phase II
multicentre, randomised trial, USbased Osiris Therapeutics is evaluating the safety and efficacy of its
PROCHYMAL product on patients
with recently diagnosed type 1 diabetes. Results from this trial are yet
to be published.
Multiple sclerosis
As multiple sclerosis is now recognised as an immunological disease,
it has been suggested that stem cell
transplantation may ‘reset’ the
immune system and hopefully halt
disease progression. Globally, several ongoing or completed clinical
trials are extending the concept of
autologous HSC transplantation
to highly active forms of MS. The
rationale behind these trials is that
HSC transplantation may arrest
the progression of MS in patients
who have an especially aggressive
form of the disease that was diagnosed early and with a poor prognosis. By destroying the patient’s
immune
system
through
immunoablative chemotherapy
and reintroducing HSCs taken
from the patient’s own bone
marrow or peripheral blood, the
immune system can be theoretically reconstituted without the
immunological memory. In doing
so, the reappearance of autoimmunity is made unlikely.
The largest study is being carried out by Northwestern University in Chicago with an ongoing
Phase III trial of 110 patients,
based on their Phase I/II clinical
trial. In the initial published trial,
21 patients with a minimum fiveyear history of relapsing–remitting
MS that had not responded to at
least six months of treatment with
interferon beta were treated with
HSCT. The patients had MS for
an average of five years. After an
average follow-up of three years
after transplantation, 17 patients
(81%) improved by at least one
point on a disability scale, with the
disease stabilising in all patients.
While it is important to note that
the Phase I/II clinical trial was not
randomised and had no control
group, the group aims to confirm
the results with the randomised
Phase III trial.
Similar clinical trials are ongoing
or have been completed in other
US states, Canada, the UK and
Greece. In addition, MS Research
Australia has funded an Australian
Register of HSCT for MS. No clinical trials testing the procedure in
Australia exist. However, several
transplants have been performed
on Australian patients as medical
innovations (rather than clinical
trials). The registry aims to capture these experimental treatments
to track patient outcomes and
long-term prognosis.
Cerebral palsy
Speculation exists about the use of
umbilical cord blood for nonhaematopoietic-related treatments
for a variety of acute and chronic
conditions. One example is the
ongoing Phase II clinical trial at
Duke University, which is testing
whether the re-infusion of autologous cord blood will improve the
neurodevelopmental function of children between 12 months and six
years of age with cerebral palsy. The
study, which will treat 120 children,
is not due to report until 2013, but
has attracted significant media attention based on anecdotal reports.
Other trials using umbilical cord
blood for cerebral palsy and for
cerebral trauma at birth are underway. In Australia, private cord
blood bank Cell Care Australia in
collaboration with the Monash
Medical Centre is proposing a trial
to start soon.
cont’d page 30
(table 1 on page 28)
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HOW TO TREAT Stem cell therapies — Part 2: the future
Table 1: Summary of current clinical trials using stem cells
28
Disease
Organisation/
location
Stem cell type
Overview
Status
Clinical trials registry/
further information
Cerebral palsy
Duke University,
North Carolina, US
Autologous
umbilical cord
blood
The purpose of this Phase II study is to determine the efficacy of a single IV infusion of
autologous umbilical cord blood for the treatment of children with spastic cerebral palsy.
The randomised, blinded, placebo-controlled crossover study aims to enrol 120 children
between 12 months and six years of age from June 2010 to July 2013.
Ongoing,
currently
recruiting
participants
Registered on
www.clinicaltrials.gov,
identifier: NCT01147653
Georgia Health
Sciences University,
US
Autologous
umbilical cord
blood
This Phase I/II study will be a placebo-controlled, observer-blinded, crossover study to
evaluate the safety and effectiveness of a single, autologous, cord-blood stem cell infusion
for the treatment of cerebral palsy in children. The study aims to enrol 40 children between
the ages of one and 12 years with the trial due for completion in February 2013.
Ongoing,
currently
recruiting
participants
Registered on
www.clinicaltrials.gov,
identifier: NCT01072370
Neonatal hypoxic-ischaemic Duke University,
encephalopathy (brain injury) North Carolina, US
Autologous
umbilical cord
blood
This is a pilot study to test feasibility of collection, preparation and infusion of autologous
umbilical cord blood in the first 14 days after birth if the baby is born with signs of brain
injury. This Phase I study of feasibility and safety aims to enrol 25 children up to 14 days
of age.
Ongoing,
currently
recruiting
participants
Registered on
www.clinicaltrials.gov,
identifier: NCT00593242
Corneal blindness due to
limbal stem cell deficiency
University of NSW,
Australia
Autologous
In this Phase I study, a limbal tissue biopsy will be harvested from patients with unilateral or
limbal stem cells bilateral limbal stem cell deficiency diseases and placed in tissue culture on therapeutic
contact lenses. The cell loaded contact lens will then be placed over the defective eye to
allow cells to be transferred. The contact lenses will remain on the ocular surface for no
longer than 21 days. The ocular surface will be reviewed regularly for corneal epithelial
reconstruction. The trial is looking to enrol 30 patients with about 10 treated to date. The
trial is not due to report until 2012.
Ongoing,
currently
recruiting
participants
Registered on
www.anzctr.org.au,
identifier:
ACTRN12607000211460
Acute spinal cord injury
Geron Corporation,
US
GRNOPC1 —
human ESCderived
oligodendrocyte
precursor cells
The Geron trial is the world’s first clinical trial using human ESC derived cells. The primary
objective of this Phase I study is to assess the safety and tolerability of GRNOPC1 in
patients with complete American Spinal Injury Association (ASIA) Impairment Scale grade A
thoracic spinal cord injuries. Participants in the study must be newly injured and receive
GRNOPC1 within 14 days of the injury. The trial is looking to treat 10 patients, with the
primary endpoint of safety and a secondary outcome measure of neurological function.
Data on the first two patients were presented, with no serious adverse events reported.
Ongoing,
currently
recruiting
participants
Registered on
www.clinicaltrials.gov,
identifier: NCT01217008
Chronic thoracic spinal
cord injury
Stem Cells Inc,
Switzerland
Human neural
stem cells of
fetal origin
(termed HuCNSSC)
This Phase I/II trial is designed to assess both safety and preliminary efficacy in patients
with varying degrees of paralysis who are three to 12 months post-injury. The trial will enrol
12 patients in Europe with thoracic spinal cord injury, and will include both complete and
incomplete injuries as classified by the ASIA Impairment Scale. After transplantation, the
patients will be evaluated regularly over a 12-month period to monitor and evaluate the
safety and tolerability of the HuCNS-SC cells, the surgery and the immunosuppression,
and to measure any recovery of neurological function below the injury site.
Ongoing,
currently
recruiting
participants
Registered on
www.clinicaltrials.gov,
identifier: NCT01321333
Amyotrophic lateral
sclerosis (ALS, motor
neuron disease)
Neuralstem Inc, US
Human spinalderived stem
cells of fetal
origin
This is a Phase I trial of spinal-derived stem cells transplanted into the spinal cord of
patients with ALS. The goal of the study is to see if the cells and the procedure to transplant
them are safe. The study is looking to treat 18 patients by the completion date of April
2012. The company reported it had treated nine patients with no adverse safety events
Ongoing,
currently
recruiting
participants
Registered on
www.clinicaltrials.gov,
identifier: NCT01348451
Ischaemic stroke
ReNeuron, UK
Human neural
stem cells of
fetal origin
This Phase I trial is designed to test the safety of a manufactured neural stem cell line
delivered by injection into the damaged brains of male patients aged 60 years or over who
remain moderately to severely disabled six months to five years after an ischaemic stroke.
In addition, the trial will evaluate a range of potential efficacy measures for future trials.
Treatment will involve a single injection of one of four doses of the cells into the patient’s
brain in a carefully controlled neurosurgical operation performed under general anaesthetic.
The trial is designed to treat 12 patients and measure outcomes over 24 months. Three
patients have been treated to date, with no adverse events reported.
Ongoing,
currently
recruiting
participants
Registered on
www.clinicaltrials.gov,
identifier: NCT01151124
Osteoarthritis
Australian Catholic
University/Lakeside
Sports Medicine
Centre, Australia
Adipose-derived This Phase II/III randomised controlled trial aims to assess the changes in pain, cartilage
stem cells
and bone appearance, activity levels and lower extremity functional ability of patients with
knee osteoarthritis treated with faster intra-articular adipose-derived stem cell injection
compared with usual treatment of Hylan G-F 20. The trial aims to treat 60 patients.
Not yet
started
Registered on
www.anzctr.org.au,
identifier:
ACTRN12611000274976
Royal North Shore
Hospital/Regeneus
Pty Ltd, Australia
Adipose-derived This Phase II, randomised, double-blind, placebo-controlled trial will study the efficacy and
stem cells
safety of autologous non-expanded adipose-derived stem cells in the treatment of knee
osteoarthritis. The trial will evaluate the effects of the procedure on reduction of pain and
changes in other measures of quality of life in relation to knee osteoarthritis. The use of a
placebo control means that half of the patients will receive a dummy injection instead of the
cell mixture. The study will continue until the end of 2011.
Ongoing,
currently
recruiting
participants
Registered on
www.anzctr.org.au,
identifier:
ACTRN12611001046998
Multiple sclerosis
Northwestern
University, US
Autologous
haematopoietic
stem cells
This ongoing phase III trial of 110 patients is based on a completed Phase I/II clinical trial,
the results of which were published in 2009 (Lancet Neurology 2009; 8:244-53). Twenty-one
patients with relapsing–remitting MS who had not responded to at least six months of
treatment with interferon beta were treated with haematopoietic stem cell transplantation.
After an average follow-up of three years post transplantation, 17 patients (81%) improved
by at least one point on a disability scale, with the disease stabilising in all patients. The
Phase I/II clinical trial was not randomised and had no control arm. The research group
aims to confirm the results with this randomised phase III trial, which is due to be
completed by January 2013.
Ongoing,
currently
recruiting
participants
Registered on
www.clinicaltrials.gov,
identifier: NCT00273364
Dry age-related macular
degeneration (AMD)
Advanced Cell
Technology, US
Human ESCderived RPE
cells
The purpose of this Phase I/II study is to evaluate the safety and tolerability of subretinal
injection of human ESC derived retinal pigment epithelial (RPE) cells in patients with dry
AMD and to perform exploratory evaluation of potential efficacy endpoints. The study aims
to enrol 12 patients aged 55 years or over and aims to be completed by July 2013.
Currently
recruiting
participants
Registered on
www.clinicaltrials.gov,
identifier: NCT01344993
Stargardt’s macular
dystrophy
Advanced Cell
Technology, US
Human ESCderived RPE
cells
The purpose of this Phase I/II study is to evaluate the safety and tolerability of subretinal
injection of human ESC-derived RPE cells in patients with Stargardt’s macular dystrophy. The
study aims to enrol 12 patients, aged 18 years of age or over and aims to be completed by
September 2013.
Currently
recruiting
participants
Registered on
www.clinicaltrials.gov,
identifier: NCT01345006
Recent acute MI
Angioblast Systems,
US
Allogeneic
mesenchymal
precursor cells
The purpose of this Phase I/II study is to evaluate the safety and feasibility of transendocardial
Currently
injection of allogeneic, mesenchymal precursor cells in participants with acute MI. The
recruiting
secondary objectives are to collect late-term safety and efficacy data and to design subsequent participants
studies. The study aims to enrol 25 patients and aims to be completed by December 2013.
Registered on
www.clinicaltrials.gov,
identifier: NCT00555828
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HOW TO TREAT Stem cell therapies — Part 2: the future
from page 26
pany has begun a clinical trial
involving intracerebral injection
into patients with significant disability 6-24 months after stroke. In
this Phase I study they plan to
follow 12 patients for minimum of
two years. It is hoped that the
known anti-inflammatory, trophic
and pro-angiogenic properties of
the transplanted cells will aid
recovery.
Stroke
Although animal models of
ischaemic stroke have demonstrated
that stem cells can improve function, this is yet to be seen in human
patients. In a recent review of stem
cell treatments for stroke, the
authors noted that although no
adverse transplant-related events
were reported, there is ‘insufficient
evidence to support stem cell transplantation in treating ischaemic
stroke’.1
One company that is pursuing
stem cell treatment for ischaemic
stroke is UK-based ReNeuron.
Osteoarthritis
Using fetal neural stem cells that
have been genetically engineered
and expanded in culture, the com-
There is a growing body of research
regarding MSCs for the treatment of
osteoarthritis. It is thought that the
MSCs may have immune-modulat-
ing and anti-inflammatory properties and that they may contribute to
the regeneration of cartilage in the
damaged joint. Several groups are
planning to launch clinical trials
using autologous MSCs to treat
osteoarthritis of the knee, which is
the joint most commonly affected.
Within Australia, veterinary company Regeneus has attracted media
attention for its treatment of arthritic
dogs using autologous adiposederived cells. Based on its animal
results, Regeneus is now planning a
clinical trial using the same technology in humans with arthritic knees.
The initial trials aim to enrol 40
Advising patients on stem cell treatments
ONE of the greatest challenges in
advising patients about stem cell
treatments is contending with the
unrealistic expectations they or their
loved ones may have. Since many
people have heard about stem cells
and are familiar with the restorative
properties of bone marrow stem cells
in leukaemia, increasingly patients
are asking why stem cells can’t cure
their condition.
Further complicating matters is the
growing number of clinics and companies advertising unproven or
experimental stem cell treatments on
the internet. These clinics and companies operate outside the accepted
regulatory framework, often in countries such as India, China, and the
Dominican Republic. They have little
or no scientific support for their
approach and have not demonstrated
safety for their patients. They tend
to charge large sums of money, rely
heavily on patient testimonials to
endorse their treatment, and fail to
report their findings to the broader
medical community.
These groups generally employ
invasive delivery methods using the
patient’s own ‘stem cells’ isolated
from bone marrow, nasal epithelium
or adipose tissue, or stem cells
obtained from embryos, umbilical
cord blood or fetal tissue. The scientific community believes these groups
are exploiting the patient’s hope and
sense of desperation, as well as putting them at risk of complications (see
box right).
To help patients navigate this difficult pathway and decide whether a
proposed treatment should be pursued, the Australian Stem Cell Centre
has produced a handbook for
patients, Stem Cells Now and in the
Future (see Online resources), to provide background information about
stem cells, including what steps should
be involved in the development of a
new stem cell therapy, as well as specific points to consider before deciding
whether to travel overseas. The handbook was developed in conjunction
with Australia’s leading patient advocacy groups and seeks to empower
the patient to request specific information from the clinic that they are
intending to visit (figure 3).
Importantly, once the information
is obtained, patients are then encouraged to speak to their doctor about
the therapy. It is important that such
Reference
Figure 3: Checklist for patients and carers — questions to ask the provider of the experimental treatment.
The cells
❏ What type of cells are you using (my own, someone else’s, cells from umbilical cord blood, fetal tissue or embryos)?
❏ Do you use animal products (particularly bovine, or cow-derived*) to grow the cells?
❏ Do you test the cells for viruses (HIV, hepatitis B, hepatitis C, HTLV-I and HTLV-II)?
❏ Could the cells harm me? Could they form tumours or could they cause autoimmune problems?
❏ Will my immune system reject the cells?
The procedure
❏ How are the cells delivered? Are they injected**?
❏ How many visits are required?
❏ What are the potential complications of injection?
❏ Do I need to take any medications afterwards?
❏ If so, what are their side effects?
❏ What chance is there of the treatment working? What evidence are you basing this on?
Transparency and accountability
❏ Did this treatment undergo ethics committee review?
❏ Are you collecting data to publish?
❏ Have you published data already?
Personnel
❏ Who is the doctor performing the treatment?
❏ Is he/she a specialist in treating my condition?
Medical care and practicalities
❏ Will my travel insurance cover my treatment?
❏ Who covers the cost of any medical complications?
❏ Who looks after me if I become unwell overseas?
❏ What happens if I become unwell back at home?
❏ Cost: what is included in the price (travel, accommodation, meals, insurance, medications, hospital bed costs,
consumables used during treatment, cell processing costs)?
* Many cell culture techniques use products derived from cows or calves. This carries a theoretical risk of variant Creutzfeldt–Jacob
disease (mad cow disease).
** Injections into brain, spinal cord or pancreas carry risks of damage to these structures.
Source: Stem Cell Therapies Now and in the Future. Reproduced with permission.
Hopeful journeys: experiences of Australians seeking stem cell treatments overseas
MORE Australians are seeking the unproven or experimental stem cell treatments offered by overseas clinics and companies.
A study (Hopeful Journeys) was undertaken in 2010 by the Australian Stem Cell Centre in partnership with sociologists
from Monash University to capture the experience of 16 Australians who have had such treatments. This included carers
of children treated overseas. All procedures were invasive, ranging from IV and IM delivery of cells, to intracranial and
intrathecal injections. Stem cells were stated to have been sourced from the patient’s bone marrow or from donated
umbilical cord blood or from human embryos. Conditions treated included cerebral palsy, vision impairment, MS and
spinal injuries.
It was clear that all of those interviewed believed they were well informed. They sought information from the internet,
from other patients who had undertaken similar journeys, and from the doctors at the clinic they wished to visit. They did
not usually discuss their decision with their Australian doctors.
They were frustrated that a suitable stem cell treatment was not available in Australia and some believed they had only
a limited window of opportunity to pursue the treatment if it was to be effective. They believed they were realistic in terms
of their expectations and did not expect miracles, but classified risk in terms of losing their money. Risk to their health did
not appear to be a significant consideration. They discussed the high financial cost of their treatment ($10,000-$40,000 a
treatment) and their reliance on fundraising. Interestingly, they all stated that ‘it worked’ although they agreed that the
changes were not strictly clinical improvements (some did see improvements if only transitory) but benefits of another
kind. Specifically, many stated that it gave them hope.
The challenge is how to maintain hope for these patients while raising legitimate concerns about the risks associated
with the stem cell tourism phenomenon.
a conversation is encouraged, not
only to assist the patient in making
an informed choice, but to ensure
that their medical practitioner is fully
aware of the proposed treatment and
can monitor the patient’s health on
their return.
Stem cell treatments offer enor-
patients and will be conducted at the
Royal North Shore Hospital in
Sydney.
A similar study is due to start soon
in Melbourne. The Australian
Catholic University in conjunction
with the Lakeside Sports Medicine
Centre are preparing to enrol 60
patients with osteoarthritis of the
knee to test the safety and efficacy
of the injection of autologous adipose tissue into the affected joint.
Australian biotechnology company
Mesoblast has a strong interest in
osteoarthritis with its allogeneic MSC
product RepliCart but does not have
any active clinical trials.
1. Boncoraglio G, et al. Stem cell
transplantation for ischemic
stroke. Cochrane Database of
Systematic Reviews 2010;
Issue 9.
Further reading
Available on request from
[email protected]
Online resources
• The Australian Stem Cell Centre.
Patient Information Handbook:
Stem Cell Therapies Now and in
the Future:
www.stemcellcentre.edu.au/
For_the_Public/Patient/Handbook
.aspx [updated April 2011]
• International Society for Stem
Cell Research. Closer Look at
Stem Cell Treatments and Patient
Handbook:
www.closerlookatstemcells.org
• AusCord — Australian National
Network of Umbilical Cord Blood
Banks:
www.abmdr.org.au/dynamic_
menus.php?id=4&menuid=86&m
ainid=4
• Royal Australian and New
Zealand College of Obstetricians
and Gynaecologists. Statement on
Umbilical Cord Blood Banking:
www.ranzcog.edu.au/womenshealth/statements-aguidelines/college-statements/451umbilical-cord-blood-banking-cobs-18.html
• Australian New Zealand Clinical
Trials Registry: www.anzctr.org.au
• US National Institutes of Health
Clinical Trials Database:
www.clinicaltrials.gov
mous promise. While we are closer to
developing safe and effective treatments for some conditions, we are
not there yet.
There is no How to Treat quiz this week.
NEXT WEEK GPs need to be well versed in how to approach the common, the esoteric and the sometimes dangerous problems that occur in the female
lower ano-genital tract. The next HTT examines vulvar disease. The authors are Associate Professor Richard Reid, school of rural medicine, University of
New England, Armidale, and University of Newcastle; and Dr Michael Campion, senior staff specialist, pre-invasive unit, gynaecological cancer service,
Royal Hospital for Women, Randwick, NSW.
30
| Australian Doctor | 18 November 2011
www.australiandoctor.com.au
HOW TO TREAT Editor: Dr Giovanna Zingarelli
Co-ordinator: Julian McAllan
Quiz: Dr Giovanna Zingarelli