Finding the recipe for success in cell therapy

Lineage Cell CEO says that cell therapy isn’t about the ‘magic’ of stem cells – it’s about how you control them.

Cell therapy company Lineage Cell Therapeutics (NYSE American: LCTX) recently licensed novel induced pluripotent stem cell (iPSC) lines from Eterna Therapeutics with the intention of finding new treatments for central nervous system (CNS) disorders and other neurology indications. The clinical-stage Californian company is already advancing cell therapy programs across multiple age-related conditions, including both vision and hearing loss.

Longevity.Technology: Back in 2021 Lineage signed a potential $670 million collaboration and license agreement with Roche’s Genentech for the development and commercialization of its OpRegen cell therapy for the treatment of advanced dry age-related macular degeneration (dry AMD). As the company eagerly awaits the results of Genentech’s Phase 2a clinical trial, we caught up with the company’s CEO Brian Culley, to learn why cell therapy may play a key role in improving human longevity.

“We’re trying to help people who are typically older to have better function and quality of life,” says Culley. “For example, our lead program is in advanced dry AMD, a condition where you are essentially outliving the functional utility of specialized retina cells, called retinal pigment epithelial cells, which leads to the loss of vision as you age.”

Limitations of a traditional approach

A traditional biotech approach to a condition like dry AMD would be to identify a pathway that may be responsible for a cell’s dysfunction and develop a drug to change the behavior of that pathway, and, hopefully, the trajectory of the disease.

“Of course, that approach does work in some settings,” says Culley. “But in this particular condition of aging, there are so many things going wrong with these retina cells that trying to tickle just one pathway and achieve a significant clinical outcome is quite challenging.”

Earlier this year, the first ever treatment for advanced dry AMD was approved by the US FDA. Culley says this is a good example of the limitations of a traditional biotech approach to the condition.

“All it does is slow the disease progression a little bit, something like 20% less per year,” he says of the approved drug. “So, you have a wound in the back of your eye, which will constantly get larger, and they found a way to make it grow a little bit slower. It tells you how low the bar is that even just slowing the expansion of the wound by 20% per year was enough to get approved.”

The replacement parts business

Lineage’s approach is very different from that of a traditional biotech company.

“The approach that we utilize could be thought of as ‘replacement parts’ – being able to manufacture brand new replacement RPE cells and transplant them into the body to take over the role of the cells that are either no longer there or have become dysfunctional,” explains Culley.

From its early clinical trials in patients, Lineage’s dry AMD cell therapy was shown to not only transplant cells permanently (without cases of rejection) but also, in some cases, was able to stop the progression of the of the disease and even make the area of atrophy smaller.

“That never happens naturally,” says Culley. “In the history of time, no one has ever been able to regenerate their retinal tissue – it’s just not an ability that human beings have. So, we’ve been able to show a much larger clinical benefit via a transplant of these retinal cells.”

Another key point is that the patients treated by Lineage to date also tend to improve their vision.

“That might seem self-evident – you’re making the wound smaller, you’re adding functional cells to the body, and you’re getting activity and improving vision,” says Culley, “But it never happens with these other treatments – they have gotten approved on anatomical changes but without improving a patient’s vision.”

These results ultimately led to the Genentech deal, which included a $50 million upfront payment.

“We’re one of a vanishingly small number of cell therapy companies that have been able to land a major pharma partnership,” says Culley. “While there have been many attempts to use cell therapy to try to treat all sorts of diseases and conditions, there hasn’t been a lot of success yet, so we appreciate the interest and support that Genentech has provided.”

Stem cell ‘magic’ is exaggerated

The limited success of cell therapy to date is, according to Culley, in part due to a misguided belief in the “magic” of stem cells, from which almost every other cell in our bodies is created.

“People had this view that these magical cells with all these wonderful properties could cure all sorts of diseases – that was your Time Magazine cover from 20 years ago,” he says. “The reality is, those are undifferentiated stem cells, which harbor a lot of potential but don’t really have a specific function. And nobody has been able to provide the kind of rigorous evidence in a major clinical trial that is needed for FDA approval. For example, we know that people have tried putting stem cells in the eye and tried to harness the secretions and trophic factors that come from those cells, but it hasn’t really worked.”

Even today, efforts continue to demonstrate that undifferentiated stem cells have a therapeutic capacity. But Lineage is doing things differently.

“At Lineage, we start with those same undifferentiated cells, but importantly, we then fully differentiate them into retinal epithelial cells – they are no longer stem cells,” says Culley. “We direct them like shepherds – we’re directing them to become pure populations of RPE cells, because that’s the cell that’s broken and which we want to replace.”

Nailing down the process

While this may sound like a straightforward solution, the reality is that “shepherding” stem cells in this way is far from easy.

“It’s actually quite difficult to come up with the recipe for how to control these cells because you can’t just make a cell, put it in the clinic, get an effect and have a product,” says Culley. “You have to be able to control that process. You have to be able to scale that process. It has to be reproducible. It has to meet all these other criteria that people never talk about in order to actually get past the FDA and become a useful product.”

Culley says that Lineage spent “a lot of time and a lot of money” working on solving those challenges.

“What’s really key here is we’re not using the magic of stem cells – we’re just using the fact that stem cells can replicate and become other cell types. So, we can make a retina cell. And now we can make a certain kind of spinal cord cell, and we can also make an auditory neuron for hearing loss.  We have five programs now, where we have been able to figure out the recipe for a specific cell type, and I think that’s the main reason we’re seeing success.”

Photo credit: Lineage Cell Therapeutics

For Lineage disclaimer and notice of forward-looking statements, please click here.