Editor's note: This article has been updated to properly credit the NCI and the Division of Cancer Treatment and Diagnosis.
A team from the Biopharmaceutical Development Program (BDP) is developing a new autologous cell therapy line that uses engineered chimeric antigen receptor (CAR) T cells to treat acute myeloid leukemia, a particularly aggressive form of pediatric blood cancer. This foray into cell immunotherapy represents a new avenue of research and development for the BDP, which has traditionally focused on biologics to fight cancer, HIV, and rare diseases.
With support from the National Cancer Institute’s Division of Cancer Treatment and Diagnosis, the BDP team is using an engineered virus developed by NCI and manufactured by Children’s Hospital of Philadelphia to genetically modify each patient’s T cells so they become toxic cancer-killers.
In special labs at the Advanced Technology and Research Facility (ATRF), the patient’s original T cells are infected with a virus that results in the T cell expressing an engineered CAR enabling the T cells to bind to a certain protein on the patient’s cancer cells. These weaponized T cells or (CAR T cells) then embark on a “search-and-destroy mission” to find cancer cells, attach to them and eventually kill them.
Collaborating with the NIH Department of Transfusion Medicine, Center for Cellular Engineering, the BDP developed the manufacturing capacity to support these types of autologous CAR T cell approaches in less than 12 months. The project started in the summer of 2018, and the U.S. Food and Drug Administration approved the Investigational New Drug application in July 2019. BDP is currently waiting for enrollment of the first patient.
Although a year might seem like an eternity for cancer patients (and their families) who are desperately hoping for remission, the program’s launch was nothing short of warp speed, given the complexity of the process.
No Time to Waste
About three years ago, Frederick National Laboratory’s Vinay Vyas, Ph.D., development scientist IV, ran into Anthony Welch, Ph.D., NCI project officer, in an ATRF hallway who shared some of the exciting research outcomes that NCI extramural and intramural scientists were achieving using cell therapy to target cancer.
“I thought it was something we should be pursuing, even though we knew it would require a lot of research and a steep learning curve,” Vyas said. “At first, it seemed like it might be impossible.”
When NCI leaders challenged the BDP to establish the capacity for producing autologous cell therapies, the BDP quickly responded. Although the team didn’t know a lot about cell therapy, they wasted no time initiating the program.
“We did a lot of research, learned a lot, and then began to put the pieces in place,” Vyas said.
Luckily for the BDP, their ATRF facility and quality systems were already compliant with the FDA’s current Good Manufacturing Practice (cGMP) regulations needed for CAR T manufacture, given that these systems are also required for other biologics. The regulations are designed to ensure consistent and standardized processes, including controls that support reproducibility and minimize or eliminate chances of contamination, mix-ups, and errors. Laboratory specifications for cGMP dictate everything from specialized air flow and filtration systems to seamless floor and wall coverings.
The BDP’s new cell therapy suites will allow scientists and technicians to monitor patient samples in real time. State-of-the-art sensors send signals immediately if there are any changes in prescribed lab and equipment temperatures, air pressure, etc. Specialized quality control areas enable scientists to run a battery of tests for each product manufactured, including safety testing and other quality attributes such as potency, identity, and content.
“You can’t just come in off the street and do this (cell therapy),” said Trevor Broadt, quality control manager for the BDP at FNL. In addition to ensuring cGMP compliance, he said it can take almost a year before staff receive all the necessary training to be cleared to work in the labs.
“Working with blood products was something completely new to us, so just learning the equipment and protocols was a challenge,” said Julie Blake, BDP production manager.
For many smaller organizations, the facilities, systems, and training that cGMP regulations now require for cell therapy products can be cost-prohibitive, which is why most CAR T cells have been made in research hospitals or university labs.
Addressing the Bottleneck
Bringing the cell therapy program online so quickly is certainly an accomplishment worth celebrating, but the BDP team is not resting on its laurels. They are also preparing to add the capability to produce the vectors necessary for engineering the CAR T cells.
“We need to develop platforms for lentivirus and retrovirus vector production,” Vyas said. “Many investigators have to wait three years before they can get these viruses.”
The BDP team has already completed the process development studies necessary to produce a cGMP lentivirus. Process development efforts are underway to develop the manufacturing processes for gamma-retrovirus production.
The BDP will ultimately have four additional cGMP suites at the ATRF for cell therapy or virus production. Broadt says the BDP will be able to triple its production capacity by the end of 2021, making its products available to many more intramural and extramural clinical trial investigators.
“This is an exciting process for us,” Blake said. “We can now be involved with patient care in a way that we have never been before.”
In fact, the BDP is actively developing the manufacturing process to support another autologous cell therapy, an anti-GD2 CAR T cell product for use in pediatric sarcoma and neuroblastoma. “This will be our second CAR product,” Broadt said. The manufacture of these cell products is also being supported by the NCI.
With this venture into cell therapy and virus production, FNL hopes to offer patients and their physicians additional treatment options. Currently, only Novartis and Gilead Sciences are marketing licensed CAR T cell therapy products that use the CD19 antigen to treat leukemia and lymphoma.
“What we are bringing to the cell therapy field right now is kind of unique,” Broadt said. “It is very exciting that we went from having no direct experience with cell therapies to clinical manufacturing in less than two years. That would be considered extremely rapid for our industry.