“This enables us to do one-step engineering of CAR-NK cells that can avoid rejection by host T cells and other immune cells. And, they kill cancer cells better and they’re safer,” says Jianzhu Chen, an MIT professor of biology, a member of the Koch Institute for Integrative Cancer Research, and one of the senior authors of the study. 

In tests using mice with humanized immune systems, the newly engineered cells successfully destroyed most cancer cells while avoiding attack from the host’s own immune defenses.

Rizwan Romee, an associate professor of medicine at Harvard Medical School and Dana-Farber Cancer Institute, is also a senior author of the paper, which was published in Nature Communications. The study’s lead author is Fuguo Liu, a postdoctoral researcher at the Koch Institute and a research fellow at Dana-Farber.

Evading the immune system

Natural killer (NK) cells are a vital part of the body’s built-in immune defense, responsible for identifying and destroying cancerous and virus-infected cells. They eliminate these threats through a process called degranulation, which releases a protein known as perforin. This protein punctures the membrane of target cells, leading to their death.

To produce CAR-NK cells for treatment, doctors typically collect a blood sample from the patient. NK cells are then extracted and engineered to express a specialized protein called a chimeric antigen receptor (CAR), which is designed to target specific markers found on cancer cells.

Once modified, the cells must multiply in the lab for several weeks before there are enough to be infused back into the patient. The same general process is used for CAR-T cell therapies, some of which have already been approved to treat blood cancers like lymphoma and leukemia. CAR-NK therapies, however, are still being tested in clinical trials.

Because growing enough personalized CAR-NK cells takes time and the patient’s cells may not always be healthy enough for reliable use, scientists have been exploring an alternative: creating NK cells from healthy donors. These donor-derived cells could be mass-produced and stored for rapid use. The challenge, however, is that the recipient’s immune system often identifies donor cells as foreign and destroys them before they can attack the cancer.

In their latest research, the MIT team aimed to solve this problem by helping NK cells “hide” from immune detection. Their experiments showed that removing surface proteins known as HLA class 1 molecules allowed NK cells to avoid attack from T cells in the host’s immune system. These proteins normally act as identity markers that tell the immune system whether a cell belongs to the body.

To make use of this insight, the researchers added a sequence of siRNA (short interfering RNA) that silences the genes responsible for producing HLA class 1 proteins. Along with this genetic tweak, they introduced the CAR gene itself and another gene that encodes either PD-L1 or single-chain HLA-E (SCE), both of which help strengthen the NK cells’ cancer-fighting abilities.

All of these genetic components were combined into a single DNA construct, which allowed the team to efficiently convert donor NK cells into immune-evasive CAR-NK cells. Using this method, they engineered cells that target CD-19, a protein commonly found on malignant B cells in lymphoma patients.

NK cells unleashed

The researchers tested these CAR-NK cells in mice with a human-like immune system. These mice were also injected with lymphoma cells.

Mice that received CAR-NK cells with the new construct maintained the NK cell population for at least three weeks, and the NK cells were able to nearly eliminate cancer in those mice. In mice that received either NK cells with no genetic modifications or NK cells with only the CAR gene, the host immune cells attacked the donor NK cells. In these mice, the NK cells died out within two weeks, and the cancer spread unchecked.

The researchers also found that these engineered CAR-NK cells were much less likely to induce cytokine release syndrome — a common side effect of immunotherapy treatments, which can cause life-threatening complications.

Because of CAR-NK cells’ potentially better safety profile, Chen anticipates that they could eventually be used in place of CAR-T cells. For any CAR-NK cells that are now in development to target lymphoma or other types of cancer, it should be possible to adapt them by adding the construct developed in this study, he says.

The researchers now hope to run a clinical trial of this approach, working with colleagues at Dana-Farber. They are also working with a local biotech company to test CAR-NK cells to treat lupus, an autoimmune disorder that causes the immune system to attack healthy tissues and organs.

The research was funded, in part, by Skyline Therapeutics, the Koch Institute Frontier Research Program through the Kathy and Curt Marble Cancer Research Fund and the Elisa Rah Memorial Fund, the Claudia Adams Barr Foundation, and the Koch Institute Support (core) Grant from the National Cancer Institute.

The Alzheimer's-cancer paradox

For years, researchers noticed something odd in population data: people diagnosed with Alzheimer’s disease appeared to have a much lower risk of developing cancer. This unusual pattern intrigued Besim Ogretmen, Ph.D., associate director of Basic Science at Hollings, who set out with his team to uncover the biological explanation behind it.

Epidemiologist Kalyani Sonawane, Ph.D., led the effort to verify this correlation. Her group examined five years of nationally representative survey data and found striking evidence—adults over age 59 with Alzheimer’s were 21 times less likely to develop cancer than those without it.

Although the connection was clear, the underlying reason was not. What biological mechanism could explain why the two diseases seem to work in opposite directions?

A biological trade-off

Through a series of experiments, the researchers traced the connection to a familiar culprit: amyloid beta, the protein known for forming harmful plaques in the brains of Alzheimer’s patients. They discovered that amyloid beta has a dual personality, depending on where it acts. In the brain, it damages neurons, but in the immune system, it appears to make immune cells stronger.

Amyloid beta interferes with a cellular recycling process called mitophagy, which normally removes damaged mitochondria—the energy-producing parts of cells. In the brain, blocking this cleanup leads to a buildup of faulty mitochondria that release toxins and trigger neuron death, worsening memory loss and cognitive decline.

In contrast, when amyloid beta affects immune cells called T-cells, the outcome flips. By limiting mitophagy, it allows more mitochondria to stay functional, giving T-cells extra energy to power their cancer-fighting activity.

"What we found is that the same amyloid peptide that is harmful for neurons in Alzheimer's is actually beneficial for T-cells in the immune system," Ogretmen said. "It rejuvenates the T-cells, making them more protective against tumors."

Rejuvenating the immune system

To explore this further, the team transplanted mitochondria from T-cells of Alzheimer’s patients into aging T-cells from individuals without the disease. The change was remarkable.

"Older T-cells began functioning like young, active T-cells again. That was an incredible finding because it suggests a whole new way to think about rejuvenating the immune system."

The results also revealed that amyloid beta contributes to cancer in another way - by depleting fumarate, a small molecule made inside mitochondria during energy production. Fumarate acts like a brake, keeping mitophagy from running out of control. When fumarate levels drop, cells recycle too many of their healthy mitochondria, resulting in a loss of strength.

"When you deplete fumarate, you increase mitophagy much more," Ogretmen explained. "Fumarate no longer binds proteins involved in that process, so the proteins become more active and induce more mitophagy. It's like a reinforcing feedback loop."

In T-cells, fumarate helps to regulate this balance. When the researchers administered fumarate to aging T-cells in mice and human tissue, they found lower levels of mitophagy. By preserving their mitochondria, fumarate gave the immune cells more energy to fight cancer. The discovery that fumarate rescues aging T-cells from excessive mitochondrial loss and enhances their anti-tumor activity suggests another way to protect immune health.

Broad implications for cancer and aging

Together, these findings shed light on why people with Alzheimer's disease are less likely to develop cancer - and how that protection might be harnessed. Rather than attacking tumors directly, this research points to a new generation of therapies that recharge the immune system itself.

One approach is mitochondrial transplantation, giving older T-cells fresh, healthy "power plants" to revitalize their disease-fighting protection. Another strategy is to maintain or restore fumarate levels to preserve mitochondria and boost T-cells' anti-tumor activity.

The potential applications for cancer are wide-ranging. Revitalizing T-cells by transplanting healthy mitochondria could strengthen existing treatments like CAR-T cell therapy. Ogretmen's group has already filed a patent for this discovery, underscoring its potential as a new class of therapy. Fumarate-based drugs or supplements might further extend the life and energy of older immune cells by preserving their mitochondria. These could be used in conjunction with immunotherapy to maintain T-cells' strength during treatment.

Beyond cancer, these approaches could help to slow immune aging more generally. As mitochondria naturally wear down over time, protecting them could help older adults to fight infections and stay healthier. Further delving into the double-edged impact of amyloid beta could also inform future treatments for neurodegenerative diseases, like Alzheimer's, by finding ways to isolate its protective immune effects without harming the brain.

For Ogretmen, the novel findings highlight the power of teamwork, noting the collaboration across Hollings' research programs in cancer biology, immunology and prevention.

"This was a true team effort," he emphasized. "We're proud of the different areas of expertise that came together to make these discoveries. The research exemplifies how discoveries in one area can open unexpected doors in another."