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The Fusion of mRNA and Immunotherapy

Combining these two technologies can make CAR T cell therapy effective, accessible, and affordable for heart disease and cancer.

In a world of fourth generation surgical robots, fifth generation mobile networks, fifth generation fighter aircraft, and soon fourth generation nuclear power, who would possibly get excited about a third generation CAR?

We can, when CAR stands for “chimeric antigen receptor.” Named for a chimera, that militant creature from Greek mythology which is the unnatural-looking fusion of lion, goat, and snake parts, a CAR is a complex, engineered protein used in immunotherapy to weaponize various types of immune cells. Most commonly, the cells are T lymphocytes which are called CAR T cells when they’re fitted with CAR molecules on the outer surfaces of their cell membranes—but there also are other cells modified with CARs. Natural killer (NK) cells, for instance, become CAR NK cells. Acting as a molecular guidance system, CARs are engineered to attach to particular entities that do harm in the body. This brings the immune cell that is fitted with CARs into physical contact with the target entity, so the immune cell can destroy it. 

During the past few years during which CAR technology has developed, the target entities for CAR cell therapies have been mostly various types of leukemia and lymphoma cells. Furthermore, when it comes to using the strategy in clinical settings, the CAR cells—which in a sense are true living drugs—have until now been autologous (made from the self), custom-made from immune cells drawn from the patient, processed, then infused back into the patient as CAR cells. This is costly and takes weeks, during which a desperately ill person could deteriorate or die. And so, a handful of biotech companies, such as Caribou Biosciences in Berkeley, California, have been developing a kind of CAR 2.0—CAR T cells, CAR NK cells, and CAR other types of cells that are allogeneic (made from other, meaning cell lines from donors) and off-the-shelf, so potentially they could be infused as soon as needed. They would be like a typical off-the-shelf product from a blood bank and cost much less than making them to order. The Caribou strategy converges CAR cell technology with another watershed development of our era, CRISPR gene editing, to achieve this efficiency—but that’s hardly the final step.

CAR cells and mRNA therapies are “the two biggest scientific treatment advances in the last 10 years.”

Research published last week in the journal Science goes beyond off-the-shelf to CAR technology 3.0: making CAR cells on demand with mRNA within injected lipid nanoparticles. The same innovation that brought us the Pfizer-BioNTech and Moderna vaccines against COVID-19, the technology can also be applied in the body to teach T lymphocytes to transform into CAR T cells, with no need to harvest them, wait for processing, and then infuse them back.

Remarking to proto.life on how elegantly the newly published study combines CAR T cell immunotherapy with the mRNA vaccine technology, Caleph B. Wilson, an immunologist with CAR T cell expertise, who is unaffiliated with the study, referred to CAR cells and mRNA therapies as “the two biggest scientific treatment [advances] in the last 10 years.”

If that’s not enough to blow your mind, maybe the fact that the research is not even focused on the usual hematology disorder applications of CAR therapy, but on another set of conditions altogether: heart disease. That’s right, CAR T therapy could potentially counter the number one killer in developed countries, and it’s all because of a common type of body cell that can go awry and damage heart tissue: the fibroblast.

“We learned several years ago from other researchers that getting rid of activated fibroblasts actually makes the process of fibrosis reverse, not merely stop,” one of the study’s lead authors, Haig Aghajanian of the University of Pennsylvania Perelman School of Medicine tells proto.life. Conducted in a mouse model of heart failure, the new study is founded on a series of lightbulb-moment ideas that have been striking Aghajanian since he was a postdoctoral fellow at UPenn in the years just prior to the pandemic. 

In 2019, he and various colleagues at and connected with UPenn published another study in Nature demonstrating that heart disease, specifically the activated fibroblasts reacting to heart damage, could be an excellent target for CAR T cells. But sometime in 2020, Aghajanian had another lightbulb moment—the idea to see if a vaccine-style mRNA treatment carrying instructions for a specially designed CAR could get mice to build their own CAR T cells.

It was Aghajanian’s idea, but it didn’t hurt that he was working with one of his now fellow lead authors of the new study, UPenn’s Drew Weissman. Together with Katalin Karikó, who now works for BioNTech, the German company that partners with Pfizer on their coronavirus vaccine, Weissman pioneered the lipid nanoparticle mRNA technology that enables the versatile, genetic molecule to carry life saving treatments. 

As groundbreaking as the new study is, it’s preclinical and conducted in a mouse model, whereas clinical experience with CAR cells comes from their use against malignant cells of blood, bone marrow, and lymphoid tissue in humans. Examples include the abnormal antibody-making plasma cells of multiple myeloma, the disease that indirectly killed former Secretary of State Colin Powell this past October by interfering with his immune system’s ability to respond adequately to vaccination against COVID-19. It was in the world of fighting cancers like the type Powell had, and other clinical scenarios such as amyloidosis (where misfolded proteins accumulate in organs) that the impulse came to move CAR technology beyond the 1.0 version (the autologous, custom-made cells) that would have little chance of confronting disease in millions of people around the world to the 2.0 version (the allogeneic, off-the-shelf cells). And now, introducing CAR 3.0.

 “We are seeing the birth of a field,” notes Richard T. Maziarz, the director of the adult stem cell transplant program at Oregon Health and Science University. “For three decades, cellular immune therapy was based mostly in laboratories and academic centers, but CAR T cell therapy is now approved by the FDA… Many other cell therapy initiatives are in development, the knowledge is being disseminated, and cell therapy is spreading across the world and outside of the traditional academic medical centers.”

One source of Maziarz’s optimism for using biotechnology, including living therapies, to advance the war on cancer relates to his role as OHSU Investigator evaluating a product developed by Cambridge, Massachusetts-based CRISPR Therapeutics called CTX120, which is a CAR T cell product generated from human-donated cells that consists of T lymphocytes engineered with CRISPR genome editing technology to confront refractory multiple myeloma.

But the newly published approach of using mRNA contained in lipid nanoparticles is particularly alluring for the same reasons that it’s appealing for vaccine applications. To change the therapy, which can be given as an intramuscular injection, one need only change the sequence of the mRNA’s building blocks. 

“Potentially, this could expand CAR T cells and other CAR cell therapies to go after any malfunctioning body cell or infectious agent in the body, including the activated fibroblasts that are so important in a multitude of heart conditions that plague humanity,” notes Aghajanian.

“If this model reaches a clinical stage, it would be a game changer in the treatment of heart failure patients.”

Coronary artery disease is one cardiac example, as it leads to infarction in the myocardium, the muscle layer of the heart. Infarction means death of a portion of the heart tissue, surrounded by a region of still living, but damaged, tissue. When this occurs, the heart licks its wounds through the action of fibroblasts. A similar fibrotic process occurs in the heart over the long term in cancer survivors who received radiation therapy to the chest and were unable for whatever reason to benefit from adequate shielding of the heart. Certain anti-cancer drugs provoke heart fibrosis as well, as does hypertrophic cardiomyopathy—a usually inherited disease that tragically causes sudden death, often in young, active people. 

Along with tightening the heart, which prevents it from expanding adequately to receive blood (diastolic heart failure), the pesky fibers from fibroblasts can disturb the heart’s electrical system. This leads to arrhythmias, exacerbating disease and putting the patient at still further risk of sudden, or gradual, death. Attack activated fibroblasts with CAR T cells after an insult to the heart, however, and all of these heart complications should be reduced, at least hypothetically.

“If this model reaches a clinical stage, it would be a game changer in the treatment of heart failure patients,” Sejla Sehovic, an attending cardiologist at the Specialized Cardiac Surgery Clinic and Heart Center in Sarajevo, tells proto.life. “I could envision game-changing applications against left ventricular remodeling, other cardiac remodeling, hypertrophy after aortic valve replacement, and numerous other heart disorders, leading to restored systolic and diastolic function. I cannot wait to see the future studies.”

But attempting CAR T attacks on activated fibroblasts in laboratory animals in their previous studies, the UPenn researchers came up against challenges similar to what hematologist-oncologists face using CAR therapies clinically against cancer cells—a storm of pro-inflammatory immune chemicals called cytokine release syndrome, and effects on the nervous system. An even greater challenge comes from the fact that fibroblasts are not just in the heart, but all over the body, mostly doing beneficial things. 

Along with its reprogrammability, the mRNA tactic offers another advantage particularly beneficial to the cardiac fibrosis application, namely to provide T lymphocytes with their CAR entity just on a temporary basis —for a few days, just like how the mRNA vaccines enable cells to produce spike protein of SARS-CoV-2 only for a couple of days before the mRNA quickly disintegrates. While CAR T cells reverting back to less belligerent T lymphocytes may not be so desirable in cancer settings, where you want long-term surveillance, it works nicely in settings of cardiac fibrosis, where the activated fibroblasts need to be suppressed only for a short time. By limiting the time of suppression, this minimizes effects against the beneficial fibroblasts outside the heart doing beneficial things like healing wounds.

Lipid nanoparticle delivery technology, modified mRNA cargo, plus CAR T technology, and if we consider the Caribou approach, CRISPR editing—with all these biotechnologies converging, it’s reasonable to think that biomedicine is on the verge of accelerations more rapid than we have ever seen, notwithstanding all the work that clearly lies ahead. “We may be in the first inning of a nine inning game,” notes Maziarz. “The full clinical realization of the technologies in the works are still a distance away.”

Even if the fusion of the mRNA approach into the CAR cell world still leaves most of the game ahead of us, perhaps we can wind down the second inning in awe of the simplicity of what the treatment for a multitude of diseases would end up being: mRNA of a certain sequence, contained within lipid nanoparticles, administered by simple injection. Essentially as useful as one of those futuristic injections that the writers of Star Trek imagined 23rd and 24th century physicians whipping out to cure a newly discovered condition, supplying a novel treatment could come down to just changing the mRNA sequence—a simple, affordable, effective, injectable therapy.

“This mouse model has the potential to be rapidly expanded to treat a range of cell-mediated diseases with efficient scalability at a price point less than $20 per dose based on the cost of the SARS-CoV-2 mRNA vaccine dose prices,” says Wilson. “This would be welcomed news for patients, insurance companies, and health care providers.”

Author’s note: As of January 13, 2022, I own a single share of Caribou Biosciences (worth a total of $12.95).

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