Peering into the future of CAR-T cell therapies

“I grew up in Colorado and in the mid ‘90s,” said Mindy Miller, lead research scientist and T cell immunologist at Terumo Blood and Cell Technologies. “There was an outbreak of this really wild and crazy new virus.”

At the time, Miller didn’t know what the virus was, but knew it was being spread by mice and killing otherwise healthy people.

One of her chores at the time was to go outside and clean out the chicken coop. But because of the virus, which turned out to be hantavirus, she didn’t have to do her chores anymore.

“I became obsessed with viruses and just learned everything I could.” She read every book she could find about viruses, which led her down a path that would define her career. She finished a PhD studying immune responses.

She has since devoted her career to the biopharmaceutical sector, focusing on topics such as autoimmunity, and more recently using cell therapies for different applications seeking to find ways to manufacture cells to make better cell products.

Her pursuit has involved understanding the biology of cells and knowing what resources they need and when they need them. The key is to apply that understanding to technology. Automated closed-system devices are helping to improve T cell expansion compared with traditional methods.  

“In our bodies, T cells can expand 10,000-fold and we never see that in a flask or in a culture,” Miller said. Conversely, flask and culture expansion tends to top out in the low hundreds. But by mimicking human physiology, scientists can push the limits of T cell capabilities. Her team has seen about 9,000-fold expansion, creeping closer to that which is capable in the human body. Her team balances the roles of biology and technology when working with cells: knowing what cells need and then figuring out how to meet those needs.

T cell expansion is limited by a lack of oxygen availability. “In a normal culture system, [cell expansion] is often limited by the rates of diffusion,” Miller said. In a traditional process there are “cells on the bottom of a culture dish and it’s filled with media. Oxygen has to diffuse through that media to get to the cell.” Terumo has addressed that problem with a device that perfuses oxygen into cells at a distance of less than 200 microns.

Novel uses for CAR-T cells

Chimeric antigen receptor (CAR) T cells are traditionally used to target B-cell cancers such as lymphoma. But their utility doesn’t stop there. “If you deplete the B cells, you can get fantastic remission of these autoimmune diseases,” Miller said. But using CAR-T cells to treat autoimmune diseases is complicated. “A traditional CAR-T cell will completely wipe out your entire B-cell compartment, and that’s really tough because humans don’t love to live without B cells. We are subject to disease, and we could get sick a lot.” She added, “CAR-T therapy is maybe too aggressive for a traditional autoimmune disease that’s not fatal.”

Scientists are working on finding solutions by engineering different CAR-T cells, one of which adds an extra “A” and is called chimeric autoantigen receptor (CAAR) T cells. “These are really cool because instead of making your T cell attack the antigen, you’re turning your T cell into the antigen.” She said instead of depleting a person’s entire supply of B cells, CAAR T therapies only target “the bad ones.”

“I don’t think CAR-T therapy for autoimmune diseases would be successful approaches like [CAAR T technologies], because we really need to protect our complete B-cell compartment.”

Stuart Gibb, head of scientific strategy at Terumo Blood and Cell Technologies, added that oncology indications have served as a trailblazer for CAR-T cell technology, “increasing the awareness of unique technologies that have to be developed for autoimmunity,” such as CAAR T cells and CAR-T Regulatory (CAR-Treg) cells.

CAR-Tregs can “quiet your immune system in a direct and targeted way,” Miller said. “In a lot of autoimmune diseases, like type-1 diabetes, there are a ton of different autoantigens,” even if one happens to be dominant. “The beauty of a Treg going into that space is its bystander effect, telling [other autoantigens to] be quiet. Instead of targeting diseases that only have one dominant autoantigen, by using CAR-Tregs, you can target diseases that have multiple autoantigens.”

Gibb said indications outside autoimmunity are also showing promise. Scientists are exploring CAR-T therapies for sensitized organ-transplant patients, who are people that have rejected one organ and then qualify for receiving a second transplant.

As CAR-T and other cell technologies advance, developers and manufacturers must be mindful of regulatory compliance. “Every single conference I go to,” Miller said, “the FDA and other regulatory bodies are there and up front. They are willing to take a proactive approach. They are listening and want to be part of the conversation very early, which is comforting because they want these therapies to move quickly.”

But Gibb pointed out that developers must also be concerned with the patient experience of receiving CAR-T therapies when they seek to improve technology. “We kind of pat ourselves on the back, thinking CAR-T is great, but the actual experience for people that receive CAR-T treatment is not pleasant.” Gibb asked, “Is the patient willing to accept the burden of the treatment in order to get to the other side of potential curative responses?” Such conversation has sparked a fierce debate among industry professionals.

Miller said such concerns drive new technologies, such using mRNA-based modifications to transiently express CAR-T cells. “If you can just deplete your body of auto-responding B cells, the B cells that come back are not going to be auto-responsive.” Moving toward such treatments could save patients from lifelong B-cell depletion.

Manufacturing considerations

Gibb said for non-oncological applications, the industry is still working to figure out the amount of cells needed for an effective dose, which will have ramifications on manufacturing as therapies are commercialized. He also said manufacturing and investment bottlenecks that affect oncological manufacturing could signal challenges for autoimmune production when associated therapies pass through trials and are commercialized.

But he said companies like Terumo can prepare for manufacturing by looking to the competition. “Push each other for technology. Push each other for increased awareness of the best phenotypes of cells you could choose.”

Gibb and Miller agreed that because the technology is in an early phase, it is difficult to anticipate manufacturing challenges that may arise, but the bottlenecks in oncological manufacturing warrant attention because the number of patients with autoimmune diseases is so high.

“If you think about the needs, it could be extreme,” Miller said, adding that although blood cancer affects about 200,000 patients per year in the US, “there are 25 to 50 million patients with autoimmune diseases.” She said it’s important that Terumo work to deploy its CAR-T platform devices quickly to CDMOs and train them on the technology, which Gibb specializes in doing.

Manufacturing efficiencies are also important for reducing the prices of cell therapies, which can cost hundreds of thousands of dollars and therefore be inaccessible to patients. “Automation is huge because it reduces manpower,” Miller said. “The most expensive part of making these [therapies] is paying the people to do it. These are highly skilled workers that have to go into highly controlled environments. By reducing the amount of time that people must be in a controlled environment, you can get higher throughput.”

“Shortening the manufacturing cycle is a hot topic for all device manufacturers,” Gibb said of decreasing costs. He emphasized the importance of producing each dose more quickly, but said, “manufacturing is one part of a more complex puzzle.”