Posted on 02/02/2022 1:14:43 PM PST by libh8er
mRNA technology is making waves with the success of the COVID-19 vaccines by Pfizer-BioNTech and Moderna. CAR-T cell therapy, a type of immunotherapy that engineers a patient’s own cells, have transformed the treatment of certain blood cancers. Now, scientists at the University of Pennsylvania have harnessed the power of both approaches in a promising experimental therapy to treat heart disease.
The Penn team designed mRNAs that could turn regular T cells into therapeutic CAR-T cells inside the body to target heart fibrosis, a scarring from cardiac injury that impairs heart function. In a mouse model of heart failure, an injection of the therapy removed cells called activated fibroblasts, leading to a significant reduction of fibrosis and improvement in heart function. The researchers published the results in the journal Science.
Existing CAR-T therapies—including Novartis’ Kymriah, which researchers at Penn helped develop—need to draw patients’ blood to modify T cells outside the body. But the new mRNA therapy temporarily turns the body itself into a factory of chimeric antigen receptors (CARs), selectively reprogramming T cells to recognize and attack fibrotic cells.
The ability to transiently express the CARs significantly increases the safety profile of the therapy, Haig Aghajanian, Ph.D., a co-corresponding author of the study, told Fierce Biotech Research via email. Famed mRNA researcher Drew Weissman, M.D., Ph.D., whose earlier work fed the design of mRNA COVID vaccines, and T cell therapy pioneer Carl June, M.D., are also authors on the study.
Fixing a safety risk
Back in 2019, Aghajanian and lab leader Jonathan Epstein, M.D., co-led a Nature study, showing that CAR-T cells targeting fibroblast activation protein (FAP) expressed on the surface of some fibroblasts could reduce cardiac fibrosis and restore heart function in mice with high blood pressure.
Despite the strong efficacy, that earlier approach has one problem. In that study, T cells were integrated outside the body with CAR-encoding gene through a retroviral vector, leading to long-time CAR expression, Aghajanian explained. In fact, real-world experience with CAR-T therapy has found CAR-T cells lasting years in some patients, he said.
In cancer treatment, that long persistence of the T cells represents an advantage as they offer durable efficacy. However, fibroblast activation is part of the normal wound-healing process. Therefore, continuous suppressing of fibroblast could pose a safety risk if the patient experiences an injury.
To solve the problem, Aghajanian and colleagues turned to mRNA, this time for a more controllable CAR-T therapy. They modified mRNA to encode CAR that can recognize FAP and packaged the mRNA within lipid nanoparticles, just as how available mRNA COVID-19 vaccines are delivered. The nanoparticles themselves were designed to target CD5, which is naturally expressed by T cells.
Once injected into mice, the encapsulated mRNA molecules were taken up by T cells, which got reprogrammed to FAP-targeted CAR-T cells. As mRNA molecules are inherently unstable, the modification was only temporary. The researchers observed consistent anti-FAP CAR T-cells two days after the injection, while the population declined to undetectable levels in about a week.
In terms of efficacy, the mRNA therapy removed large numbers of fibrotic cells in mice of heart failure. The animals also showed better heart function on multiple markers including ejection fraction and heart weight, consistent with what was observed in the 2019 study that used CAR T-cells modified outside the body.
Why mRNA could be better
Conventional CAR-T therapies like Kymriah require extensive manufacturing infrastructure and high-cost reagents. Without the need to expand the T cells outside the body, a nanoparticle-based mRNA therapy could offer a more scalable and affordable alternative, two scientists at the University of California, Los Angeles, wrote in an accompanying editorial.
In the current study, the Penn team observed almost 20% of the T cells in the spleen were FAPCAR-positive after the treatment, Aghajanian said. “If this were the same case in humans, that would translate to an order or orders of magnitude more CAR-T cells per mRNA LNP treatment even after full expansion of adoptively transferred CAR-T cells.”
What’s more, an mRNA-turned-CAR therapy forgoes the need for toxic lymphodepleting chemotherapy before adoptive transfer, the two UCLA researchers noted. In addition, the use of lipid nanoparticles allows scientists to decorate the vehicles with antibodies to increase target specificity, they said.
“We do think that there may need to be some optimization to limit uptake in other organs like the liver and are currently working on that through modifications to the composition of the LNP,” Aghajanian said.
Canadian biotech Acuitas Therapeutics, which is behind the nanoparticle used in Pfizer and BioNTech’s COVID shot Comirnaty, helped with the nanoparticle component in the Penn study.
Room for improvement
There’s one caveat to the Penn team’s current approach, though. Despite an improvement in interstitial fibrosis, the mRNA treatment still left behind some persistent FAP-negative perivascular fibrosis, the researchers noted.
The interstitial fibrosis contributes to the stiffness of the heart, which impairs both the pump function and the relaxation, resulting in cardiac dysfunction, Aghajanian explained. Perivascular fibrosis can affect oxygen and nutrient exchange that may worsen heart disease.
The lack of effect on perivascular fibrosis at least showed the specificity of the mRNA therapy on FAP-expressing fibroblasts, Aghajanian said. The team is currently searching for specific target antigens on the cells responsible for this type of fibrosis to design a CAR against, he added.
(RELATED: Gene therapy repairs cardiac tissue after heart attack in animal models )
Still, the current study “provides a strong rationale for the broadening of immunotherapies into disease areas with unmet needs,” the UCLA scientists wrote in the editorial. “This work represents an exciting step toward translating personalized immunotherapies into accessible and affordable 'off-the-shelf' immunotherapies.”
The FAPCAR-T cells may have application in other fibrotic diseases beyond heart failure, they noted.
Aghajanian currently also serves as the vice president of research at a startup called Capstan Therapeutics. The young biotech remains in stealth mode, but Aghajanian said the firm is working on off-the-shelf immunotherapies based on targeted lipid nanoparticles originating from Penn for a broad range of diseases including oncology, fibrosis and inflammatory diseases and blood monogenic disorders.
I have worked in IT departments where the motto was “We fix more things than we break.” I am not comfortable with a medical superstructure that imposes the same mindset.
It also cures myocarditis, hemorrhagic strokes, and cancer! Influenza killed itself off thinking about mRNA shots!
“mRNA technology is making waves with the success of the COVID-19 vaccines”
They don’t wor
For Car-T use of Il-12 or other cytokines is more direct and safe.
It’s ludicrous to think mRNA would be used for this in vino.
There are anti-FAP cells?
“mRNA technology is making waves with the success of the COVID-19 vaccines by Pfizer-BioNTech and Moderna. “
Welcome to Earth.
Moderna ? Pfizer ?
No thanks. I’ve learned my lesson.
Shot #5 to fix what shot #4 broke, which was to fix what shot #3 broke
lovely world — the only one making $$$ is Big Pharma
“Success” = “$$$$$$”
Doesn’t matter if the patient died as long as you get the money.
“It’s ludicrous to think mRNA would be used for this in vino.”
In vino, veritas.
“... with the success of the COVID-19 vaccines by Pfizer-BioNTech and Moderna.”
pure bs.
Not sure how the medical community can ever win back the trust they have lost over the past two years.
That's basicaly how they sold us CV19 mRNA jabs imo.
Hee hee. True lol.
I think it changed vivo to vino. Or I mistyped it.
Hic calix
And:
The interstitial fibrosis contributes to the stiffness of the heart, which impairs both the pump function and the relaxation, resulting in cardiac dysfunction, Aghajanian explained. Perivascular fibrosis can affect oxygen and nutrient exchange that may worsen heart disease."
What I can't gleam from this is if the mRNA jab was found to cause the perivascular fibrosis when trying to eradicate the interstitial fibrosis, or if the perivascular fibrosis was always there and the mRNA treatment didn't get it all out.
great but couldnt they have done this without forced experimentation on the world population?
“… What I can’t gleam from this is if the mRNA jab was found to cause the perivascular fibrosis when trying to eradicate the interstitial fibrosis, or if the perivascular fibrosis was always there and the mRNA treatment didn’t get it all out.
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I’m fairly certain it’s the latter.
Genetic manipulation … mad scientists get to play.
It’s absurd.
The whole premise is that mRNA vaccine side effects - properties they tried to minimize - will activate the innate immune system via RNA activation of Toll like receptors. This is RNA that is not supposed to ever be free in the blood.
They could use dead bacteria to do the same thing or bacterial proteins like flagella, or lipopolysaccarides. They could use straight DNA.
All of these will activate an innate immune response and release cytokines, but the types and amount can vary greatly depending on a person’s cellular and molecular physiology at the time.
They can more safely get their effect with interleukin-12 or interferon-alpha.
And the shots are all the same - it’s not like it’s a different shot like it is for the flu (reformulated every year). Each shot / booster is just more of the same original shot.
And looking at Israel’s Covid death stats right now, they are as high as they’ve ever been, and they are on shot #4 (so far).
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