Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction

Senescent cells accumulate in organisms over time because of tissue damage and impaired immune surveillance and contribute to age-related tissue decline1,2. In agreement, genetic ablation studies reveal that elimination of senescent cells from aged tissues can ameliorate various age-related pathologies, including metabolic dysfunction and decreased physical fitness3-7. While small-molecule drugs capable of eliminating senescent cells (known as ‘senolytics’) partially replicate these phenotypes, many have undefined mechanisms of action and all require continuous administration to be effective. As an alternative approach, we have developed a cell-based senolytic therapy based on chimeric antigen receptor (CAR) T cells targeting uPAR, a cell-surface protein upregulated on senescent cells, and previously showed these can safely and efficiently eliminate senescent cells in young animals and reverse liver fibrosis8. We now show that uPAR-positive senescent cells accumulate during physiological aging and that they can be safely targeted with senolytic CAR T cells. Treatment with anti uPAR CAR T cells ameliorates metabolic dysfunction by improving glucose tolerance and exercise capacity in physiological aging as well as in a model of metabolic syndrome. Importantly, a single administration of a low dose of these senolytic CAR T cells is sufficient to achieve long-term therapeutic and preventive effects.

Open Access Research Paper:

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How many can afford the cost?

“CAR T-cell therapy, which harnesses a patient’s genetically-modified immune cells to fight disease, can cost as much as $375,000 for a one-time treatment, depending on the cancer type and treatment regimen.3 Hospitals may charge as much as $1.5 million or more to avoid losing money when factoring in all the costs associated with chimeric antigen receptor T-cell therapy.1 The total cost of care during the initial CAR T-cell therapy period ranged from $350,000 to more than $2 million, with the cost for CAR T treatment medication alone being $527,000 on average. The wholesale acquisition cost of CAR T-cell therapies to treat B-cell lymphoma is $373,000, but a new study by Prime Therapeutics found that the total cost averages more than $700,000 and can exceed $1 million in some cases.0 The cost of CAR T-cell therapy is one of the biggest challenges, with financial implications for patients, payers, and providers.”

The above quoted paragraph is from

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Another story on this research:

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I think this will also be the future of cancer treatment. Its like having loads of biological nanobots inside you targeting whatever they’re trained to eliminate. Genius.

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I agree :+1:

Ideally what you need is a cell (that you can pick off the shelf) with a ‘plug and play’ system, so that you can with ease insert a targeting sequence and a payload sequence, that can be injected into anybody. After it’s done it’s job you can take an innocuous drug which would activate the cells self-destruct mechanism so it can be cleared from the body

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Think this could be use even more broadly for other viruses and other things we want the immune system to get rid of beyond senescent cells and beyond cancer.

What are the risks / side effects?

Does anyone know to what extent the costs of this treatment could fall with more experience, larger adoption (and outside of lethal cancer), more automation?

And/or if the labor intensive steps of processing the CAR-T cells for each individual eg were done in a place with well educated staff like India instead of in the US?

Wonder if it perhaps could “covid / long covid proof” us and perhaps get rid of EBV, CMV and other viruses that the majority of the population has in dormant form, but they still be creating issues over decades of time?

In the long term this seems more promising than small molecule senolytics, but for now it suffers from the same lack of understanding of the diversity and role of senescent cells in the aging organism. This is compounded by the fact that, as far as I know, there is no way to remove the modified cells if they turn out to be harmful.

Hopefully by the time there is a turn-key solution for targeting these to cancers there will also be more answers to the science re. cellular senescence.

Before getting in line for the next trial, I took a cursory look at CAR T cells as cancer therapy - their current use. This could turn out be really something, but it may be pretty early in its development. In cancer treatment, the risk of the side effects listed below might be acceptable - life or death: choose one. For a chance at healthy aging or rejuvenation, the specter of nervous system damage and the other side effects might not.

Definitely something to keep an eye on, but the first website I looked at set out all this:

"A serious complication of CAR T cell therapy is cytokine release syndrome (CRS). CAR T cells may release chemicals called cytokines, which causes a reaction from the immune system. Your care team has specialized treatments to manage this complication. Signs and symptoms may include:

  • Fever and chills
  • Dizziness, lightheadedness or headaches
  • Fatigue
  • Pain in the muscles or joints
  • Nausea, vomiting or diarrhea
  • Rapid heartbeat
  • Low blood pressure
  • Difficulty breathing

CAR T therapy may also cause negative effects on the nervous system. Your care team can manage these complications with specialized treatments. These signs and symptoms may include:

  • Confusion
  • Tremors (shaking) or seizures
  • Trouble speaking or understanding
  • Loss of balance or consciousness

Other serious side effects that may require medical attention include:

  • Abnormal levels of important minerals in the blood
  • Allergic reactions
  • Risk of infections, bruising or bleeding"

Much would depend on whether these are temporary or permanent side effects, but the warning didn’t say.

The actual published paper is now out.

Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction

www.nature.com/articles/s43587-023-00560-5

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Seems like auto immune disease is an area where this could grow and drive costs (also of course solve a lot of issues in those big categories of diseases):

Nature: CAR-T therapy for multiple sclerosis enters US trials for first time

Hopes are high that engineered immune cells, which are already in use to treat blood cancer, will halt the progression of a degenerative autoimmune disorder.

“I don’t want to get ahead of myself, but there’s a prospect here for a one-and-done therapy, which is pretty incredible,” says Dunn. “It could be an enormous paradigm shift.”

There are also practical challenges ahead. CAR-T therapy is gentler than autologous stem-cell transplant, but still requires a harsh ‘preconditioning’ chemotherapy to make room for the bespoke cells. Price is an issue, too: the hard-to-manufacture therapies currently cost up to US$500,000. But researchers are working on next-generation CAR T cells that could be easier and cheaper to use, says Chung, and successes in autoimmune diseases are likely to spur on these efforts.

https://www.nature.com/articles/d41586-024-00470-5