Demonstrating a Senolytic Chimeric Antigen Receptor T Cell Therapy

Chimeric antigen receptor (CAR) T cell therapies target specific surface features on other cells by providing T cells with a way to recognize that feature - the CAR. T cells so equipped will selectively destroy other cells with the target surface feature. To produce a CAR T cell therapy, a patient's T cells are taken, genetically engineered to introduce the CAR, expanded, and then reintroduced. This is presently used as a form of cancer therapy. Given a surface feature sufficiently specific to senescent cells, CAR T cell immunotherapy can be turned into a senolytic treatment, however. Senescent cell accumulation is one of the important causes of degenerative aging, and effective clearance of senescent cells is a form of rejuvenation. Researchers here claim to have identified a suitably specific surface marker of senescence, and use it to demonstrate benefits in mice via CAR T cell therapy. It will be interesting to see how this develops.

Cellular senescence is characterized by stable cell-cycle arrest and a secretory program that modulates the tissue microenvironment. Physiologically, senescence serves as a tumour-suppressive mechanism that prevents the expansion of premalignant cells and has a beneficial role in wound-healing responses. Pathologically, the aberrant accumulation of senescent cells generates an inflammatory milieu that leads to chronic tissue damage and contributes to diseases such as liver and lung fibrosis, atherosclerosis, diabetes, and osteoarthritis. Accordingly, eliminating senescent cells from damaged tissues in mice ameliorates the symptoms of these pathologies and even promotes longevity.

Here we test the therapeutic concept that chimeric antigen receptor (CAR) T cells that target senescent cells can be effective senolytic agents. We identify the urokinase-type plasminogen activator receptor (uPAR) as a cell-surface protein that is broadly induced during senescence and show that uPAR-specific CAR T cells efficiently ablate senescent cells in vitro and in vivo. CAR T cells that target uPAR extend the survival of mice with lung adenocarcinoma that are treated with a senescence-inducing combination of drugs, and restore tissue homeostasis in mice in which liver fibrosis is induced chemically or by diet. These results establish the therapeutic potential of senolytic CAR T cells for senescence-associated diseases.

Link: https://doi.org/10.1038/s41586-020-2403-9

Comments

OT: Good news - neuronal replacement technique successful in mouse model of PD:
https://medicalxpress.com/news/2020-06-one-time-treatment-neurons-parkinson-disease.html

"The researchers administered the PTB antisense oligonucleotide treatment directly to the mouse's midbrain ...
In the treated mice, a small subset of astrocytes converted to neurons, increasing the number of neurons by approximately 30 percent. Dopamine levels were restored to a level comparable to that in normal mice. What's more, the neurons grew and sent their processes into other parts of brain...
By two different measures of limb movement and response, the treated mice returned to normal within three months after a single treatment ... "

Posted by: CD at June 25th, 2020 12:30 PM

With Car-T therapies costing up to a million $$ an administration, plus the side effects profile, including Cytokine release syndrome, this is an example of nonsensical anti-aging research

Posted by: Daniel Permisov at June 25th, 2020 2:56 PM

@Daniel Permisov
I agree that this is not the most likely b research to bring clinical applications. There's also the question of permanent destruction of senecent cells. We need some of them to, as long as they don't linger around

Posted by: Cuberat at June 25th, 2020 7:20 PM

It's not nonsensical at all. It's simply a technology that is in its beginnings. Most new medical technologies are costly and unreliable at the beginning. Another example is in vivo gene therapy, and nobody says that it's nonsensical and must be abandoned.

Posted by: Antonio at June 26th, 2020 2:42 AM

@Antonio

You are living in longevity fantasy world if you think CAR-T, or gene therapy for that matter, will ever become legitimate therapeutic tools (reimbursed at scale) for the anti-aging masses

These are not biologic tools that just get cheaper per scale economies

One only need to look at monoclonal market - from niche products to wide spread use in targeted segments, and they more expensive than ever with severe pharmaco-economic baggage

We need common sense anti-aging drug development - not fantasy

Posted by: Daniel Permisov at June 26th, 2020 3:47 AM

"You are living in longevity fantasy world if you think CAR-T, or gene therapy for that matter, will ever become legitimate therapeutic tools (reimbursed at scale) for the anti-aging masses"

And you are basing that on....?

Posted by: Antonio at June 26th, 2020 7:15 AM

@Antonio

Based on my long history in the health insurance market

Just because products get approved by FDA, doesn't mean they will get reimbursed and until there is a valid anti-aging product with real documented pharamco-economic benefit, "million $$ a shot" biologics like Car-T and gene therapy are dead on arrival for longevity purposes (with the exception a of a few billionaires that can cover out-of-pocket costs)

To think otherwise is a fallacy promulgated by too many people that have never spent a day in the healthcare space

Posted by: Daniel Permisov at June 26th, 2020 10:36 AM

@Daniel Permisov
But the huge cost is due to the treatment being unique and one of the kind which a small research project.

If it gets streamlined and optimized eventually will become orders of magnitude cheaper.

If it really works and is much better than others Senolytics then it might be worth it. However, I am skeptical that an immune approach is any better than a cocktail of senolytics drugs.

Posted by: Cuberat at June 26th, 2020 1:06 PM

@Daniel Permisov:

That's not what we were discussing, but your statement that CAR T-cells and in vivo gene therapy are nonsensical antiaging research because they will never get cheaper.

Posted by: Antonio at June 26th, 2020 2:24 PM

@David Permisov: What we need are technologies that expedite the manufacture of biologics; small molecule approaches are great where they work, but not every medical problem has a small molecule solution, or it requires you to keep taking a drug for your entire life. This problem isn't just a matter of economies of scale, that's true, but that doesn't make it intractable; what's needed are new technologies that reduce the cost of production.

For antibodies, that might entail genetically engineering strains of e.coli or yeast to produce antibodies the same way we do insulin instead of using hybridoma cell lines with vastly lower protein yields; that's what makes synthetic biology so attractive. Incidentally recombinant insulin for diabetics is an example of mass market biologic.

A similar approach could be applied to gene therapies; engineer fast growing organisms to produce large quantities of the vector, if we're talking about viral vectors. With non-viral vectors, they're already fairly cheap, the problem is the ability to target them, which doesn't matter as much for RNA and plasmid based systems that don't attempt to stably transduce the cells.

When it comes to

Posted by: Dylan Mah at June 26th, 2020 3:39 PM

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