Using cancer's strength to fight against it

Scientists at the UC San Francisco (UCSF) and Northwestern Medicine may have found a way around the limitations of engineered T cells by borrowing a few tricks from cancer itself.

By studying mutations in malignant T cells that cause lymphoma, they zeroed in on one that imparted exceptional potency to engineered T cells.

Inserting a gene encoding this unique mutation into normal human T cells made them more than 100 times more potent at killing cancer cells without any signs of becoming toxic.

While current immunotherapies work only against cancers of the blood and bone marrow, the T cells engineered by Northwestern and UCSF were able to kill tumors derived from skin, lung and stomach in mice.

The team has already begun working toward testing this new approach in people.

"We used nature's roadmap to make better T cell therapies," said Dr. Jaehyuk Choi, an associate professor of dermatology and of biochemistry and molecular genetics at Northwestern University Feinberg School of Medicine.

"The superpower that makes cancer cells so strong can be transferred into T cell therapies to make them powerful enough to eliminate what were once incurable cancers."

"Mutations underlying the resilience and adaptability of cancer cells can super-charge T cells to survive and thrive in the harsh conditions that tumors create," said Kole Roybal, associate professor of microbiology and immunology at UCSF, center director for the Parker Institute for Cancer Immunotherapy Center at UCSF, and a member of the Gladstone Institute of Genomic Immunology.

The study will appear in Nature Feb. 7.

A solution hiding in plain sight

Creating effective immunotherapies has proven difficult against most cancers because the tumor creates an environment focused on sustaining itself, redirecting resources like oxygen and nutrients for its own benefit.

Often, tumors hijack the body's immune system, causing it to defend the cancer, instead of attacking it.

Not only does this impair the ability of regular T cells to target cancer cells, it undermines the effectiveness of the engineered T cells that are used in immunotherapies, which quickly tire against the tumor's defenses.

"For cell-based treatments to work under these conditions," Roybal said, "we need to give healthy T cells abilities that are beyond what they can naturally achieve."

The Northwestern and UCSF teams screened 71 mutations found in patients with T cell lymphoma and identified which ones could enhance engineered T cell therapies in mouse tumor models.

Eventually, they isolated one that proved both potent and non-toxic, subjecting it to a rigorous set of safety tests.

"Our discoveries empower T cells to kill multiple cancer types," said Choi, a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

"This approach performs better than anything we've seen before." Their discoveries can be incorporated into treatments for many types of cancer, the scientists said.

"T cells have the potential to offer cures to people who are heavily pretreated and have a poor prognosis," Choi said.

"Cell therapies are living drugs, because they live and grow inside the patient and can provide long-term immunity against cancer."

In collaboration with the Parker Institute for Cancer Immunotherapy and Venrock, Roybal and Choi are building a new company, Moonlight Bio, to realize the potential of their groundbreaking approach.

They are currently developing a cancer therapy that they hope to begin testing in people within the next few years.

"We see this as the starting point," Roybal said. "There's so much to learn from nature about how we can enhance these cells and tailor them to different types of diseases."

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The fountain of youth is ... a T cell?

The fountain of youth has eluded explorers for ages. It turns out the magic anti-aging elixir might have been inside us all along.

Cold Spring Harbor Laboratory (CSHL) Assistant Professor Corina Amor Vegas and colleagues have discovered that T cells can be reprogrammed to fight aging, so to speak.

Given the right set of genetic modifications, these white blood cells can attack another group of cells known as senescent cells.

These cells are thought to be responsible for many of the diseases we grapple with later in life.

Senescent cells are those that stop replicating. As we age, they build up in our bodies, resulting in harmful inflammation.

While several drugs currently exist that can eliminate these cells, many must be taken repeatedly over time.

As an alternative, Amor Vegas and colleagues turned to a "living" drug called CAR (chimeric antigen receptor) T cells.

They discovered CAR T cells could be manipulated to eliminate senescent cells in mice.

As a result, the mice ended up living healthier lives. They had lower body weight, improved metabolism and glucose tolerance, and increased physical activity.

All benefits came without any tissue damage or toxicity.

"If we give it to aged mice, they rejuvenate. If we give it to young mice, they age slower. No other therapy right now can do this, " says Amor Vegas.

Perhaps the greatest power of CAR T cells is their longevity.

The team found that just one dose at a young age can have lifelong effects.

That single treatment can protect against conditions that commonly occur later in life, like obesity and diabetes.

"T cells have the ability to develop memory and persist in your body for really long periods, which is very different from a chemical drug, " explains Amor Vegas.

"With CAR T cells, you have the potential of getting this one treatment, and then that's it. For chronic pathologies, that's a huge advantage. Think about patients who need treatment multiple times per day versus you get an infusion, and then you're good to go for multiple years."

CAR T cells have been used to treat a variety of blood cancers, receiving FDA approval for this purpose in 2017.

But Amor Vegas is one of the first scientists to show that CAR T cells' medical potential goes even further than cancer.

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How being in space impairs astronauts' immune system

A new study led by researchers at Karolinska Institutet in Sweden has examined how T cells of the immune system are affected by weightlessness. The results, which are published in the journal Science Advances, could explain why astronauts' T cells become less active and less effective at fighting infection.

The next steps in the exploration of space are human missions to the moon and to Mars. Space is an extremely hostile environment that poses threats to human health. One such threat is changes to the immune system that occur in astronauts while in space and that persist after their return to Earth. This immune deficiency can leave them more vulnerable to infection and lead to the reactivation of latent viruses in the body.

"If astronauts are to be able to undergo safe space missions, we need to understand how their immune systems are affected and try to find ways to counter harmful changes to it," says study leader Lisa Westerberg, principal researcher at the Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet. "We've now been able to investigate what happens to T cells, which are a key component of the immune system, when exposed to weightless conditions."

In the study, the researchers have tried to simulate weightlessness in space using a method called dry immersion. This involves a custom-made waterbed that tricks the body into thinking it is in a weightless state. The researchers examined T cells in the blood of eight healthy individuals for three weeks of exposure to simulated weightlessness. Blood analyses were performed before the experiment started, at 7, 14 and 21 days after the start, and at 7 days after the experiment ended.

They found that the T cells significantly changed their gene expression -- that is to say, which genes were active and which were not -- after 7 and 14 days of weightlessness and that the cells became more immature in their genetic programme. The greatest effect was seen after 14 days.

"The T cells began to resemble more so-called naïve T cells, which have not yet encountered any intruders. This could mean that they take longer to be activated and thus become less effective at fighting tumour cells and infections. Our results can pave the way for new treatments that reverse these changes to the immune cells' genetic programme," says Carlos Gallardo Dodd, PhD student at the Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet and shared first author with researchers Christian Oertlin and Julien Record at the same department.

After 21 days, the T cells had "adapted" their gene expression to weightlessness so that it had almost returned to normal, but analyses carried out seven days after the experiment ended showed that the cells had regained some of the changes.

The researchers now plan to use Esrange Space Centre's sounding rocket platform in Kiruna, Sweden, to study how T cells behave in weightless conditions and how their function is affected.

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