EXECUTIVE INTERVIEW - Viral Gene: Protein-Targeting Cancer Vaccine Could Boost Survival Rates

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 business model?

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 project.

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.

REFERENCE

1. US Cancer Vaccine Market Outlook 2019 Research Report, February 2014.
2. US Cancer Vaccine Market Outlook 2022, RNCOS Industry Research Solutions, July 2016.