Nav: Home

Researchers have unlocked secrets about engineered protein receptor, CAR

November 07, 2018

Cancer remains the second-leading cause of death in the United States. This year, an estimated 1.7 million new cases will be diagnosed, with nearly 610,000 people expected to die from the disease, according to the National Cancer Institute.

Fortunately, several recent cancer treatments show considerable promise. Among them is Chimeric Antigen Receptor (CAR) T cell therapy, which the American Society of Clinical Oncology recently named the "2018 Advance of the Year." Three USC Viterbi School of Engineering researchers - Assistant Professor Stacey Finley, Professor Pin Wang and Assistant Professor Nick Graham - have just published a paper in "Biophysical Journal" that sheds light on how this new treatment works, information that could one day result in better cancer therapies with fewer side effects.

"We're trying to dig into the molecular mechanisms," said Graham, an assistant professor of chemical engineering and materials science. "By understanding how the CAR T cells work, we could try to design better ones."

When the immune system functions normally, immune cells move around the body and look for pathogens that don't belong and kill them. However, cancer cells can mask themselves, making it harder for the good cells, such as T cells, to kill them.

With CAR T cell therapy, a person's T cells are removed, genetically engineered with proteins, and then injected back into the patient. The resulting CAR T cells are much better at fighting cancer cells. That's because these modified CAR T cells have an engineered protein receptor, the CAR, that can bind to cancer cells. When this occurs, a signal from the CAR tells the T cell to begin destroying the cancer by secreting the chemicals perforin and granzyme.

CAR T cell therapies

Earlier this year, the U.S. Food and Drug Administration approved the first CAR T cell therapy for the treatment of some people with advanced leukemia and a form of lymphoma, both blood cancers. Early results have shown great promise. However, in early tests, the CAR-T cell therapies have so far proven much less effective against breast, lung, prostate and other solid-tumor cancers. Additionally, some people undergoing CAR T cell therapy have experienced significant side effects; a few have even died.

The trio of USC researchers hope their work will greatly improve CAR T cell therapies by uncovering the complicated process by which CARs activate cancer fighting cells. Specifically, they are examining a process called phosphorylation, which is a chemical reaction that occurs when the CAR receptor bumps up against a cancer cell and sends a signal to the T cell to attack the bad cells.

"I think what's most exciting is that we're really adding to the field an understanding of which sites on the CAR are becoming phosphorylated, how quickly that happens and the amount of phosphorylation of each site," said Finley, the Gordon S. Marshall Early Career Chair and assistant professor of biomedical engineering, chemical engineering and materials science and biological sciences.

Through their research, Finley, Wang and Graham have learned when and how much phosphorylation occurs on the CAR's six sites, which, in an imperfect analogy, could be imagined as "docking hubs," in Graham's words.

Additionally, they have found that no "gatekeeper" exists, meaning that no single CAR site must be phosphorylated before the others. Until now, scholars only had a general idea about the phosphorylation process, making it difficult to bioengineer CAR T cells that could successfully fight against complex and complicated breast, lung and other solid-tumor cancers.

Better cancer-fighting CARs

Going forward, Finley, Wang and Graham hope to leverage their findings into engineering more effective cancer-fighting CARs with fewer side effects. This could mean having phosphorylation take place quicker and more intensely at certain CAR sites, depending on the complexity of the targeted cancer cells. Alternately, the USC researchers might engineer CARs to phosphorylate less, thereby preventing the cancer-fighting T- and other cells from becoming too aggressive and killing healthy cells - a problem that has cropped up with early CAR T cell cancer treatments.

Already, Finley has built quantitative models that holds great promise.

"Once we have these tools and quantitative models, we should be able to apply them to a variety of different designs of CARs," said Finley, whose research group has an expertise in mathematical models. "Maybe you could use a model, before you do an experiment, to see if this new design would work. Instead of having to do as many tedious experiments in the lab, you could build a predictive mathematical model to screen the best design."

Added Wang, the Zohrab A. Kaprielian Fellow in Engineering and professor of chemical engineering and materials science, and biomedical engineering: "If you want to make the T cells more potent, the question is how best to design the CAR. That's our research's goal, I think."
-end-


University of Southern California

Related Cancer Articles:

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.
Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.
Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.
More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.
New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.
More Cancer News and Cancer Current Events

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Rethinking Anger
Anger is universal and complex: it can be quiet, festering, justified, vengeful, and destructive. This hour, TED speakers explore the many sides of anger, why we need it, and who's allowed to feel it. Guests include psychologists Ryan Martin and Russell Kolts, writer Soraya Chemaly, former talk radio host Lisa Fritsch, and business professor Dan Moshavi.
Now Playing: Science for the People

#537 Science Journalism, Hold the Hype
Everyone's seen a piece of science getting over-exaggerated in the media. Most people would be quick to blame journalists and big media for getting in wrong. In many cases, you'd be right. But there's other sources of hype in science journalism. and one of them can be found in the humble, and little-known press release. We're talking with Chris Chambers about doing science about science journalism, and where the hype creeps in. Related links: The association between exaggeration in health related science news and academic press releases: retrospective observational study Claims of causality in health news: a randomised trial This...