Natural killer cells: harnessing Nature’s senolytic

Celularity CEO says senolytic capabilities of placenta-derived NK cells demonstrates potential to ‘change aging biology.’

Earlier this month, regenerative medicine company Celularity presented new preclinical data from its investigational natural killer (NK) cell therapy program, which suggest that the company’s placenta-derived NK cells may serve as selective senolytic agents with the potential to address age-related diseases.

The data, presented at the annual meeting of the American Society of Gene and Cell Therapy, indicates that Celularity’s placenta-derived unmodified CYNK-001 cells, and genetically modified CYNK-201 cells, have the potential to target and selectively eliminate damaged and abnormal cells expressing stress ligands, such as senescent, virally infected and cancer cells.

Longevity.Technology: Senescent cells – the aged, dysfunctional cells that accumulate our bodies as we get older – play a significant role in degenerative diseases, cancer, and the progressive decline in immune function that occurs with age. These cells release chemicals that promote inflammation and hinder the regenerative process necessary for organ and tissue function restoration. Targeting senescent cells therapeutically is the now focus of a host of well-funded longevity biotech companies.

We’ve previously spoken with Celularity about its ongoing work to leverage the human placenta as a “limitless” source of stem cells, as well its work to create cell therapies for a range of age-related diseases, but the company’s work in cellular senescence is a recent development. To find out more, we caught up with Celularity’s founder and CEO, Dr Robert Hariri.

While Celularity’s senescence data may be new, Hariri is quick to point out that the approach behind it is based on the same core science that underpins its other programs.

“This is an extension of the fundamental work we have been doing for over 20 years to explore the unique biological aspects of the placenta, and why some of those fundamental biological processes are relevant clinically,” he says. “One of our programs is to derive natural killer cells from the placenta, which we have been using to treat cancer, but we also have opportunities to use these cells in a variety of indications, including targeting senescent cells.”

Robert Hariri

‘Nature is smarter than we are’

There are many different potential approaches to targeting cellular senescence, but Hariri believes that NK cells present an attractive option that benefits from the process of evolution.

“I always say that nature is smarter than we are,” he says. “Natural killer cells are in all of us, they are part of our innate immune system, they already do the job of clearing out senescent cells, and they do it safely without a lot of collateral damage. From my vantage point, the natural killer cell has stood the test of time in human evolution – the senoablatant activity of NK cells is fundamental to their existence in our immune system.”

The use of the term senoablatant was new to us, but Hariri explains that it’s down to some “nitpicking” on his part. 

“Senolytics means you kill the senescent cell, but it’s not enough to just kill it, you need to get rid of it,” he says. “Because, in addition to the fact that senescent cells make these bad proteins and molecules that stimulate inflammation and cancer, if they’re not cleared out of the tissue, there’s no room for new cells to come in and occupy. So, I prefer the term senoablatant to encompass both destroying the senescent cell and clearing it out of the tissue.”

A versatile approach

Celularity has long been exploring the “biological utility” of NK cells in treating infectious diseases, autoimmune diseases, cancer, and now age-related and degenerative diseases.

“They all follow the same common pathway of leading to cells that express the same targeting molecules – stress ligands – that we first went after in cancer, and that now we can go after in senescent cells,” says Hariri. “And so, it turns out that the same natural killer cells we’ve developed for cancer, and for infectious diseases, including viral infections like COVID, may in fact be a potent natural senoablatant.”

Video showing a red/orange senescent cell being targeted and eventually devoured by green NK cells.
 

The results presented by Celularity at the recent ASGCT meeting may only be in vitro preclinical data, but Hariri says the work is closely linked to the company’s ongoing program in sarcopenia.

“In order to fully exploit this technology, we’re going to have to demonstrate the best way to get the cell to the target,” he says. “However, regardless of the tissue, a senescent cell does in fact express the same common denominator of stress ligands. We’re already doing work to demonstrate in discrete clinical conditions like age-related frailty, where the muscle is populated with a large number of senescent cells, and we think that as long as the NK cell can find its way to the tissue, it will target those same stress ligand-expressing cells.”

If Celularity can demonstrate that its NK therapy works in sarcopenic muscle, Hariri is confident that it can extend those effects into other tissues.

“A couple of places that are of a high degree of interest to me personally, would be seeing if we can have an effect a senoablatant effect in the brain, liver and kidney, and other organs that seem to express the consequences of aging worse than other organs and tissues,” he says.

Potential to change aging biology?

For a company like Celularity, there is an obvious synergy between the clearance of senescent cells and the potential for introducing new cells to replace them.

“Our goal would be to clear out as many senescent or near-senescent cells as possible, make room for young replacement cells, and then augment the reservoir of young replacement cells by introducing an allogeneic off-the-shelf, economical, scalable product, like the cells we produce from the placenta,” says Hariri. “There is clear evidence that the presence of old tissue in a young environment can make it behave like young tissue. And so, if we can do that by simply introducing young cells, after cleaning up all the old cells, maybe we can change the aging biology of an individual.”

When it comes to the next steps for Celularity’s work in cellular senescence, Hariri says the company will be seeking collaborative partners to move things forward.

“We’ve got a lot on our plate right now, so we’re actively talking to academic and industrial collaborators,” he says. “I’ve watched Oppenheimer on every flight I’ve taken across the country for the last the last few months, and I think the time is right for a ‘Manhattan Project’ approach in age-related degenerative changes. I’d love to see some of the big players out there, companies like Regeneron, come together and address this by applying assets from different players to have a higher probability of success in a well-designed clinical development strategy.”

Photographs/video courtesy of Celularity