Colorectal cancer kills more than
49,000 Americans each year and is the second-leading cause of cancer deaths in
the US. Dr. Scott Waldman, Professor and Chair of Sidney Kimmel Medical
College’s Department of Pharmacology & Experimental Therapeutics at Thomas
Jefferson University, Dr. Adam Snook, and a team from Thomas Jefferson
University’s Departments of Microbiology and Immunology, Dermatology and Cutaneous
Biology, and Medical Oncology, have pioneered a vaccine to stop the spread of
cancers originating in the gastrointestinal tract, including cancers of the
colon, rectum, pancreas, stomach, and esophagus.
Targeted Diagnostics &
Therapeutics, Inc. (TDT), a biotechnology company headquartered in Exton, PA,
obtained the worldwide exclusive rights to this technology in 1994. After 15
years of research, and numerous preclinical lab and animal studies to evaluate
biological activity and safety, Dr. Waldman filed an Investigational New Drug Application
that was approved by the FDA in 2013. A successful Phase I clinical trial (completed
in 2015) tested stage I and II colon cancer patients to determine the vaccine’s
safety, tolerability, and immunological efficacy.
Viral Gene Inc. was established by
Chris Kim, President and General Counsel, to obtain funding for, and conduct, a
2017 Phase II trial. Viral Gene was granted worldwide exclusive license and
marketing rights for this vaccine technology from TDT. The trial will assess
the vaccine’s efficacy in blocking metastatic disease and improving patient survival.
Alpha Holdings, Inc., a Korean-based company has invested $8.7 million in Viral
Gene to fund the trial and commercialize the vaccine. Alpha Holdings is engaged
in the manufacturing of system semi-conductors and provides system-on-chip
(SoC) design for Samsung group. Alpha has a vast product portfolio and is Viral
Gene’s largest shareholder. Trial completion should take about 2 years, and
both companies also plan to conduct a Korean trial for the Asian market under
the direction of Dr. Waldman.
Harry A. Arena, MBA, President and CEO
of TDT, Chris Kim, and Dr. Scott Waldman recently spoke with Drug
Development & Delivery about the unique characteristics of the vaccine,
the patients who will benefit the most, and how a research team captured the
attention of investors.
Q: What is the TDT
Mr. Arena: TDT was formed in
1994 to commercialize technological discoveries made by Dr. Waldman in his laboratory
at Thomas Jefferson University. At that time, we signed a worldwide exclusive
license agreement with the university that included ongoing financial support
for Dr. Waldman’s research and a commitment to prosecute and pay for the
related patent work, while looking to sublicense the resulting applications
(including the vaccine technology) to large pharmaceutical companies. We are
sort of the middleman. That’s our model, and that’s always been our model: to
look at early stage university-based technology, support it, make sure the
patents are prosecuted properly, and then to look for the large pharmaceutical
companies to take it through the clinical trials and final product development
and marketing. TDT has been involved with this project from the beginning, and
we are excited about the prospects due to the funding infused from Viral Gene. Our
reward comes when we receive royalties on the sales of any resulting products.
Q: What is the
relationship with Viral Gene, and what made them the right fit for this
Mr. Arena: In this case, the
vaccine wasn’t picked up by a large company because of issues regarding how far
along the vaccine had been developed. We didn’t have other bids, and we wanted to
move forward. Viral Gene came along and was looking for something just like
this. They had the funding, were enthusiastic about the technology, and had a
game plan to build something in the biotech area. We then did a licensing deal
to piggyback what we had been doing to fund the project beyond the early research,
and fund the clinical trial work to get it to the point where we can get
approval. We brought it this far, and they will take it from here. They have a
sublicense from us to take the vaccine the rest of the distance from clinical
trials to marketing. Viral Gene plans to apply to the FDA for Orphan Drug
Status through its Office of Orphan Products Development because there is
little therapy available for the types of cancers the vaccine is targeting, and
the patient populations are fairly small.
Q: What is the market
potential for the vaccine domestically and globally?
Mr. Arena: There are approximately
150,000 colorectal cancer surgeries in the US each year with diagnoses
indicating various stages of the disease. Patients with other GI cancers
(gastric, esophageal, and pancreatic) total about 103,000. Those currently undergoing
chemotherapy, or who are immunologically compromised from other treatments, are
not candidates for the vaccine. The overall market size of the Viral Gene GI
cancer vaccine market in the US is approximately 165,000 cases annually. To
this, you could potentially add the population of surviving patients from years
prior to the vaccine’s approval.
Mr. Kim: Cancer vaccine
revenues in the US were reported at $14 billion in 2012, and are expected to
reach $20 billion by 2020.1 The current average and projected annual
growth rate to 2020 is 4.56% (CAGR). The US currently represents the largest market
for cancer vaccines and represented 60% of the global cancer vaccine market in
2016.2 The estimated insurance coverage of the vaccine is as much as
$80,000 per patient.
Q: Can you describe
how this vaccine was pioneered?
Dr. Waldman: Our team has been
focused on trying to understand the biology of the target of this vaccine,
which is Guanylyl Cyclase C (GCC), since the early 1980s. GCC regulates water
and salt secretion in the intestine, and is a protein shown to be highly accurate
in detecting the spread and recurrence of colorectal cancer whether in lymph
nodes or blood. In the 1990s, we recognized the unique utility for GCC in
managing patients with colorectal cancer as a marker and target of that
disease. The reason it’s a unique marker and target is because GCC is
selectively made in the intestines by the intestinal epithelial cells, which
are the single layer of cells that line the intestine. They are anatomically
compartmentalized and made in the intestine. GCC continues to be made and is overexpressed
by those cells once they transform from normal epithelial cells to colorectal
cancer cells. What's unique in this case is the target is normally compartmentalized
on the inside of the intestine. But when the disease metastasizes, the
metastasis carries the marker from the intestines to the inside of the body, making
it a unique target and marker. It gives us the ability to hunt, seek, and
destroy GCC-expressing metastatic tumors inside the body using a variety of
approaches without harming the intestine and without attacking the “normal” GCC
made by normal epithelial cells. This can be done because of the separation
between the inside of the intestine and the inside of the body. There is a
barrier – a compartmentalization – so we really leverage that to use GCC as a target.
It gives us the ability to attack metastatic colorectal cancer cells without
attacking the normal tissue. We can do that with antibody drug conjugates, but
we can also do that with our vaccine.
Q: How does the
vaccine work in the body?
Dr. Waldman: We leverage the
immune system to selectively go after metastatic colorectal cancer
cells. We are teaching the immune system to recognize GCC as a foreign
protein and attack it like it would attack a bacteria or virus. We
developed a vaccine for GCC that trains the immune system to go after
GCC on the inside of the body, not the inside of the intestine. We can
take advantage of that compartmentalization principle by using the immune
system. The vaccine takes advantage of adenovirus as a carrier of the
vaccine. The virus is non-replicating, so we take adenovirus and the
front half of GCC, and put it into the adenovirus genome. This package
becomes our vaccine, which we inject into muscle where it then makes virus
proteins and GCC from its genome. Remarkably, the GCC in the vaccine
gets presented to the immune system in the context of a viral infection.
The virus sends “danger” and “stranger” signals. It’s like a Trojan horse.
We trick the immune system into thinking it needs to react to GCC, and
what winds up getting attacked are the colorectal cancer cells; the
immune response kills those cells to improve survival.
Q: What makes this
vaccine unique, and is it supposed to replace the antibody drug conjugates?
Dr. Waldman: The vaccine has a
unique place in the armamentarium that we have to treat colorectal cancer. The vaccine
is designed to prevent secondary metastasis for the life of a patient. This is
for someone who has already been diagnosed with colorectal cancer and had their
definitive surgery to remove the primary tumors. They’ve had their primary
radio- or chemotherapy. They are now ostensibly free of cancer and on a surveillance
program. This vaccine will not have use against the primary cancer because it’s
sitting within the intestines, and the vaccine won’t attack that primary tumor.
About half of the patients with colorectal cancer will get recurrent disease,
and ultimately die of their disease because of hidden metastasis in their body.
We vaccinate them to attack and kill the cells that are there, but now they are
protected. We create a memory immune response that gives life-long protection
against the development of metastasis down the road. We have proven this in
mice that had cancer and were vaccinated, then given cancer again; they rejected
the cancer. We see the vaccine as being value-added in the continuum of care,
not only to prevent secondary metastasis acutely, but also to the remaining
life of the patient.
Q: Can you discuss
the type of dosing that will be required?
Dr. Waldman: We don’t yet know how
often the vaccine will need to be renewed. In the Phase I clinical trials, we
used a single dose. The next clinical trial will be segmented into two parts.
First, we will determine the right dosing regimen to give a patient. We gave an
average dose in the Phase I study. In the first part of the next trial, we want
to know how much we should give. We believe we can go up in dose considerably.
We want to find out if we can, and should, repeat those doses to boost the
response. Once we identify the right dosing regimen, we will address if the
vaccine dose makes patients with cancer live longer. The longer-term question
to ask is, will it be beneficial to give a booster every 1, 5, or 10 years? The
Phase II trial will commence next year.
Q: Does the vaccine
have applications for other types of cancers?
Dr. Waldman: The reason colorectal
cancer cells make GCC is because the cells from which they originated make GCC.
Most colorectal tumors retain the characteristics of the cell type from which
they originated. The characteristic pattern they retain is the making of GCC.
However, we learned some interesting things by looking at other tumors at other
sites in the GI tract. For instance, not all original cells in the GI tract
make GCC, but when they become tumor cells, they newly start to express GCC.
About 75% of lower esophageal cancer cells make GCC; 50% of gastric cancer
cells make GCC; and 25% of pancreatic tumors make GCC. Each of these tumors
become therapeutic candidates for the vaccine. We envision the next trials will
focus on tumors outside of colorectal cancer, such as pancreatic cancer and
esophageal cancer. We will focus on these high-need disease states in our next
phase to see if we can improve survival rates.
Q: What will this
vaccine mean to future cancer vaccination development?
Dr. Waldman: Immuno-oncology is
the flavor of the year, but most of the focus is on immune-modulating drugs.
There are other pieces to the immune-oncology continuum that can be exploited to
the benefit of patients, such as vaccines. Cancer vaccines really struggle to
identify the right target to go after. Our vaccine offers a unique target with unique
characteristics that target GI malignancies. The principles we learned about
GCC and the immune system can pertain to other cancer targets.
T: (973) 263-5289
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1. US Cancer Vaccine Market Outlook
2019 Research Report, February 2014.
2. US Cancer Vaccine Market Outlook 2022, RNCOS Industry
Research Solutions, July 2016.