Regenerative medicine is
not all that new; tissue and organ transplants have been around for decades.
However, the Mayo Clinic has said, “But advances in developmental and cell
biology, immunology, and other fields have unlocked new opportunities to refine
existing regenerative therapies and develop novel ones.” It has also stated,
“Regenerative medicine is a game-changing area of medicine with the potential
to fully heal damaged tissues and organs, offering solutions and hope for
people who have conditions that today are beyond repair. Within regenerative
medicine, some of the most noteworthy developments are coming from the area of
tissue engineering. Combining cells with scaffolding materials to generate
functional tissue constructs describes tissue engineering at its most basic
The rejection of
transplanted tissue has been one of the major stumbling blocks in the treatment
of many chronic and age-related conditions. Immune suppressors are one avenue
for dealing with rejection, but tissue engineering by way of cellular
microencapsulation offers a different, and likely better, path.
MICROENCAPSULATION: THE NEW FRONTIER IN DRUG DELIVERY
Microencapsulation is a
process by which very tiny droplets or particles of liquid or solid material
are surrounded or coated with a continuous film of polymeric material. Most
microcapsules have diameters between a few micrometers and a few millimeters.
The idea was based on natural subcellular organelles, which contain proteins,
growth factors, or enzymes. The first suggestion was made in 1964 that
encapsulation could be used to replace cells or cell products lost due to
The polymeric material
essentially creates a wall that protects the encapsulated cells from rejection
by the body's immune system. This means that an organ could be grown in a bioreactor
to replace a diseased organ, and the risk of rejection would be virtually
eliminated. Harvard Apparatus has already grown and implanted an artificial
trachea grown from the patient’s own stem cells.
At the same time,
microencapsulation offers various significant advantages as a drug or treatment
delivery system, including: (i) an effective protection of the encapsulated
active agent or encapsulated live cells against degradation or destruction by
the immune system, (ii) the possibility to accurately control the release rate
of an incorporated drug over periods of hours to months, (iii) an easy
administration (compared to alternative parenteral controlled release dosage
forms, such as macro-sized implants), and (iv) the provision of desired,
pre-programmed drug-release profiles which match the therapeutic needs of the
NEUROLOGICAL DISORDERS: MICROENCAPSULATION OVERCOMES THE
One of the areas in which
this technology is most useful is in the treatment of neurological disorders.
Many drugs to treat maladies of the brain and central nervous system are
administered orally, but they cannot cross the blood-brain barrier readily. One
of the main advantages of cell microencapsulation is for the treatment of
neurological disorders in which some drugs have potential therapeutic possibilities,
such as growth factors or peptides, however, only at low and constant concentrations.
These microcapsules implants are able to secrete only the drug required by the
damaged tissue, because the implants with microencapsulated cell are formed by
Bringing this technology
out of the lab and into clinics is now underway. Living Cell Technologies
Limited (LCT) is an Austral-asian biotechnology company, and its lead product,
NTCELL®, is an alginate-coated capsule containing clusters of
neonatal porcine choroid plexus cells. Following transplantation, NTCELL
functions as a biological factory producing nerve growth factors to promote new
central nervous system growth and repair disease induced nerve degeneration.
NTCELL is in Phase I/IIa
clinical trial in New Zealand for the treatment of Parkinson’s disease. It has
the potential to be used in a number of other central nervous system
indications, such as Huntington’s, Alzheimer’s, and motor neuron diseases.
DIABETES: ENCAPSULATED CELLS MAY BE THE PATH TO A CURE
microencapsulation can address is type 1 diabetes. In type 1 diabetics, their
insulin-producing cells (beta islet cells of the pancreas) have been permanently
destroyed by an autoimmune disease.
According to Novo
Nordisk’s 2014 annual report, there are two things needed to cure this condition:
(i) a means to trigger stem cells to make unlimited quantities of insulin-producing
cells, and (ii) a means to encapsulate these cells so that the immune system doesn't
destroy them while at the same time allowing the encapsulated cells to respond
to glucose levels by producing insulin.
A research team at Harvard
has found a solution to the first issue, and Astra Zeneca has recently linked
up with that team to continue the work.
Living Cell Technologies
has formed a joint venture with Japan's Otsuka Pharmaceutical Factory to
develop LCT's DIABECELL. This product consists of encapsulated islet cells that
produce insulin and that are sourced from pathogen-free pigs.
Another entrant into the
type 1 diabetes cure sweepstakes is San Diego-based ViaCyte. In concert with
the Juvenile Diabetes Research Foundation (JDRF), the leading research and
advocacy organization funding type 1 diabetes research, ViaCyte filed an IND
application with the FDA in the summer of 2014. ViaCyte wants to initiate a
Phase I/II diabetes clinical trial to evaluate the safety and efficacy of its
VC-01TM product candidate, a stem cell-derived, encapsulated cell replacement
therapy. In a related development, ViaCyte submitted a Medical Device Master
File (called MAF) to the FDA in support of the Encaptra® drug delivery
system, the device component of the VC-01 product candidate.
A third contestant is the
Cell-in-a-Box® live cell encapsulation technology. The Cell-in-a-Box
technology is unique among all forms of cell encapsulation technologies. It
differs from the types of live cell encapsulation used by others because those
technologies use materials such as agarose (a derivative of seaweed) or
chitosan. Cell-in-a-Box capsules are made largely of cellulose, a bio-inert
material in the human body. Cellulose offers a number of advantages over other
encapsulation materials because it is derived from a naturally occurring
plant-sourced polymer that is relatively easy to obtain at reproducible quality
and is free from impurities. The Cell-in-a-Box capsules are much more robust
than capsules made from other materials and do not break down even after long
periods in the body. Indeed, Cell-in-a-Box capsules have been shown in clinical
trials to last for at least 2 years without being damaged or without causing
damage to tissues that are nearby. Also, Cell-in-a-Box capsules can be stored
frozen for years and when thawed, the cells inside the capsules are recovered with
about 95% viability – a hint as to their having a long shelf-life.
PharmaCyte has obtained an
exclusive worldwide license to use Melligen cells in developing a treatment for
insulin-dependent diabetes. This line of cells was developed by Professor Ann
Simpson and her colleagues at the University of Technology, Sydney (UTS) in
Australia. Melligen cells were shown to be effective in reversing the diabetic
condition in grossly diabetic mice whose immune systems were suppressed.
PharmaCyte intends to use Melligen cells encapsulated using the Cell-in-a-Box
technology in the pursuit of a treatment for insulin-dependent diabetes.
PANCREATIC CANCER: CELL-IN-A- BOX A NEW TREATMENT ALTERNATIVE
PharmaCyte is also looking
into the treatment of pancreatic cancer using Cell-in-a-Box-encapsulated
genetically engineered live cells designed to convert the well-known cancer
prodrug ifosfamide into its cancer-killing form using only one-third of the
“normal” dose of the chemotherapy drug. PharmaCyte Biotech’s pancreatic cancer
treatment was given the Orphan Drug designation by the FDA in December 2014. A
similar designation has been granted by the European Medicines Agency (EMA) in
In a Phase I/II clinical
trial, 14 elderly and very sick patients with advanced, inoperable pancreatic cancer
were treated at a single study site in Germany with the combination of
Cell-in-a-Box plus two courses of low dose ifosfamide. A single implantation
(near the pancreatic cancer) of 300 Cell-in-a-Box capsules containing ifosfamide-activating
cells was given to each patient.
The results from this
trial showed that the Cell-in-a-Box plus low-dose ifosfamide combination
increased the average lifespan of patients from about 5.7 months for gemcitabine
(the “gold standard” for the treatment of pancreatic cancer at the time) to about
11 months with the combination therapy, and doubled the percentage of 1-year survivors
from 18% to 36%, without any treatment-related side effects. The major conclusion
was that the combination of Cell-in-a-Box plus low-dose ifosfamide was a safe
and effective treatment for patients with advanced, inoperable pancreatic cancer.
A Phase II trial done with
the Cell-in-a- Box plus ifosfamide combination was also a single-arm study.
Here, 13 patients were treated at four study sites in Europe, but in this
trial, the dose of ifosfamide was doubled to two-thirds of normal to see if
there would be improved anti-tumor effects. Again, two courses of ifosfamide
were given. The main conclusion was that the combination of Cell-in-a-Box plus
one-third the normal dose of ifosfamide was the most appropriate combination to
use in all future clinical trials for a safe and effective treatment of advanced,
inoperable pancreatic cancer.
Now, a Phase IIb clinical
trial is being planned for the U.S., Europe and Australia. This trial will be a
multi-site, randomized study in which PharmaCyte Biotech’s pancreatic cancer
treatment will be compared head-to-head as a consolidation therapy with a
currently used chemotherapy plus radiation treatment in patients with
inoperable, non-metastatic disease whose tumors have ceased to respond to 4-6
months of treatment with the current “gold standard” for pancreatic cancer treatment,
the combination of the drugs gemcitabine plus Abraxane®. The two
consilidation therapies will be compared for effects on patient survival, tumor
size, whether they can change inoperable tumors into operable ones, on pain
associated with the cancer, and on the safety of the treatments and their
effects patients' quality of life.
A major problem associated
with the development of abdominal cancers is their production of malignant
ascites fluid that accumulates significantly in the abdominal cavity. This
fluid contains cancer cells which can "seed" and form new tumors.
Also, as ascites fluid accumulates, the abdomen becomes distended and painful
and this accumulation can be life-threatening.
As such, it must be
removed on a periodic basis - a painful and costly procedure. A series of
preclinical studies in mice bearing abdominal cancers is being done now in the
US for PharmaCyte Biotech by Translational Drug Development (TD2) to determine
the parameters under which PharmaCyte's pancreatic cancer treatment can slow
the production and accumulation of this ascites fluid. Once these parameters
are established, a Phase I/II clinical trial will be conducted by Translational
Drug Development (TD2).
Although type 1 diabetes
can begin at an early age, as our population ages, chronic and age-related
conditions, such as various cancers, are increasing in frequency. Until now,
managing them has been the only medical option. Drug or treatment delivery that
employs microencapsulation, one of many promising developments in the field of regenerative
medicine, offers not only treatments but also potential cures for a wide
variety of maladies, from diabetes to cancers to neurological problems.
this issue and all back issues online, please visit www.drug-dev.com.
Gerald W. Crabtree is PharmaCyte’s Biotech’s Chief Operating Officer. For much of his
45-year career, he has been active in cancer research and cancer drug
development. Since 1985, Dr. Crabtree has been involved with various biopharmaceutical
and biotech companies, where he has participated in or coordinated the
development of multiple drug candidates, assisted in the preparation of
clinical protocols and investigator brochures, participated in clinical trials,
prepared drug monographs, co-authored research and review articles, and served
as project manager for development of a major oncologic agent. He is a member
of the American Society of Clinical Oncology and the American Association for
Cancer Research and is also is a past member of research grant review committees
for the National Institute of Health and the American Cancer Society. Dr.
Crabtree established and directed, from inception, a department that monitored and
coordinated the development of oncologic and immunologic drugs from initial
discovery through regulatory approval in a major pharmaceutical company and
served as project manager for the development of the anticancer agent, Taxol®.
He earned his PhD in Biochemistry from the University of Alberta, Edmonton,
Alberta, Canada in 1970 and has published over 80 articles in peer-reviewed