Disruptive Technologies and Mature Regulatory Environment Vital for Cell Therapy Maturation


Immuno-oncology and CAR T cells energized the field of regenerative medicine, but for cell and gene to deliver on their promises, new, disruptive technologies and new modes of operation are needed. Specifically, that entails improving manufacturing to control variables and thus ensure product consistency, and maturing the regulatory environment to improve predictability.

“Manufacturing cells is not like manufacturing small molecules,” Brian Culley, CEO of Lineage Cell Therapeutics, told BioSpace. “For cell therapy products to mature into ‘real’ products that deliver on the promises of 10 years ago, they must be scalable – which drives affordability – and they must solve their purity issues.”

On the clinical side, cell and gene therapies must find places where small molecules, antibodies or other traditional approaches may not be the best option.

For example, “The era of transplant medicine is unfolding before us,” Culley said. “Because of the transplant component, cell therapy may enable changes the body never could do alone.”

Lineage is addressing dry AMD and spinal cord injuries with two of its therapeutics.

“Our approach is fundamentally different from traditional approaches. We replace the entire cell rather than modulate a pathway. There is a rational hypothesis where cell therapy can win, but first we need to fix the operational hurdles,” Culley said.

To address the manufacturing challenges, Culley said, “We work only with allogeneic approaches. For us, not being patient-specific is a huge advantage.”

Not long ago, the industry was focused on 3D manufacturing in bioreactors.

“We’re beyond that,” Culley said. “For our dry AMD product, we can manufacture 5 billion retinal cells in a three liter bioreactor. The advantage is that the cells exist in a very homogenous space and are 99% pure.”

As a result, they are more affordable and can be harvested with little manipulation.

“Manual manipulation affects gene expression,” he pointed out, so minimizing that, as well as the vast quantities of plastics typically required, results in a more controlled process and a more consistent product.

Additionally, Lineage introduced a ‘thaw and inject’ formulation, so the cell therapy can be thawed in a water bath, loaded into a chamber and injected, all within a few minutes. Traditional dose administration requires washing, plating and reconstituting the cells the before they are administered to a patient.

“Getting rid of the prior day dose prep is one example of the maturation of the field, which we are deploying today to help usher in a new branch of medicine,” Culley said.

At Lineage, “we’re tackling problems that largely were intractable. For dry AMD, there’s nothing approved by the FDA. No one know why the retinal cells die off, so we manufacture brand new retinal cells (OpRegen) and implant them,” Culley said. “We’re seeing very encouraging clinical signs, including the first-ever case of retinal restoration.”

Retinal cells compose a thin layer in the back of the eye, Culley explained.

“They start to die off in one spot, and that area grows outward. When we inject our manufactured cells where the old ones died, we’ve seen the damaged area shrink and the architecture in previously damage areas completely restored,” Culley said. “We’ve treated 20 patients for dry AMD in, ostensibly, safety trials, but you can’t help but notice efficacy when a patient reads five more lines on an eye chart. It’s hard to imagine our intervention wasn’t responsible for that, especially when humans can’t regenerate retinal tissue.”

The spinal injury program (OPC1) may represent an even greater breakthrough. As with dry AMD, there is no FDA-approved therapy.

“We manufacture oligodendrocytes and transport them into the spinal cord, to help produce the myelin coating for axons,” he told BioSpace. Because of the oligodendrocytes, the axons grow, become myelinated, and begin to function. “Small molecule and antibody therapies haven’t been able to do that.”

So far, 25 people have been treated in a Phase I/II trial. Culley reported cases in which a quadriplegic man, after OPC1 therapy, is now typing 30 to 40 words per minute, and another who now can throw a baseball. It’s not unusual for patients who initially were completely paralyzed to now schedule their treatments around college classes, Culley said.

“Humans can have varying degrees of recovery from spinal cord injury, but these are higher than we would expect,” Culley said.

Other cell and gene companies are advancing solutions, too.

“Many companies with induced pluripotent stem cells (iPSCs) are trying to figure out how to get scalability, purity, and reproducibility to work for them. It’s not a quick fix,” he said.

One of the challenges is balancing the clinical and manufacturing aspects of development.

“If you have a technology that’s not yet commercially viable, but you have clinical evidence, it’s tempting to focus on the clinical side,” Culley said.

Too many companies do that, and then find their candidate must be reworked for scale up. Therefore, consider scale up and manufacturing early.

There’s a need for balance at a more granular level, too.  For example, he asked, “How many release criteria do you need? Just because you know a cell expresses a certain surface marker, does that add to your process? I’ve seen companies ruined by trying to be perfect, and others by rushing headlong, seeing evidence where evidence doesn’t exist.”

As Lineage matures its processes to support larger clinical trials, the greatest challenges have been time – “It takes 30 to 40 days to grow cells,” Culley said – and regulatory uncertainty. “Often, there is no regulatory precedence so there are holes to be addressed. For example, cell and gene therapies sometimes have a delivery component – such as a scaffold or delivery encapsulation technology – that also must be considered. Real-time regulatory feedback isn’t available, so you proceed, presuming that what you’re doing will be acceptable to regulators.”

The FDA recognizes that new, disruptive technologies and approaches are being used, and must be used, for cell and gene therapy to reach patients.

“The FDA is responsive and is trying to push guidance out,” Culley said, but it takes time.

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