MIT’s ‘hidden’ immune cells could change cancer treatment forever
Scientists have created a new, more advanced form of immune-based cancer treatment using engineered cells known as CAR-NK (natural killer) cells. Like CAR-T cells, these modified immune cells can be programmed to recognize and attack cancer, but they rely on a different type of immune cell that normally targets abnormal or infected cells.
A team from MIT and Harvard Medical School has now developed a more effective way to engineer CAR-NK cells that significantly reduces the chance of rejection by the body’s immune system. Immune rejection has been one of the biggest limitations of cell-based therapies, often impairing their effectiveness.
This innovation may also make it possible to produce “off-the-shelf” CAR-NK therapies that are available immediately after diagnosis, rather than waiting weeks for specially designed cells. Traditional CAR-NK and CAR-T manufacturing methods typically require several weeks to complete before patients can begin treatment.
“This enables us to single-step engineer CAR-NK cells that can avoid rejection by host T cells and other immune cells,” says Jianzhou Chen, a professor of biology at MIT, a member of the Koch Institute for Integrative Cancer Research, and one of the study’s senior authors. “They kill cancer cells better and are safer.”
In tests on mice with humanized immune systems, the newly engineered cells successfully destroyed most cancer cells while avoiding attack by the host’s immune defenses.
Radwan Roumi, MD, associate professor of medicine at Harvard Medical School and Dana-Farber Cancer Institute, is also a senior author of the paper published in Nature Communications. The study’s lead author is Fugu Liu, a postdoctoral researcher at the Koch Institute and a research fellow at Dana-Farber.
Evasion of the immune system
Natural killer (NK) cells are a vital part of the body’s built-in immune defense and are responsible for identifying and destroying cancerous and virus-infected cells. They remove 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 usually collect a blood sample from a patient. The 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 laboratory for several weeks before there are enough to inject them back into the patient. The same general process is used in CAR-T cell therapies, some of which are already approved to treat blood cancers such as lymphoma and leukemia. However, CAR-NK therapies are still being tested in clinical trials.
Because growing enough personalized CAR-NK cells takes time, and a 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 can be produced in large quantities and stored for rapid use. But the challenge is that the recipient’s immune system often identifies the donor cells as foreign and destroys them before they can attack the cancer.
In their latest research, the MIT team aims to solve this problem by helping natural killer cells “hide” from immune detection. Their experiments showed that removing surface proteins known as HLA class 1 molecules allowed NK cells to avoid attack by T cells in the host’s immune system. These proteins usually act as identity markers that tell the immune system whether a cell belongs to the body.
To take advantage of this insight, the researchers added a sequence of siRNA (short interfering RNA) that silences the genes responsible for producing HLA class I proteins. Along with this genetic modification, 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, allowing the team to efficiently convert donated NK cells into immune-evasive CAR-NK cells. Using this method, they engineered cells that target CD-19, a protein normally found on malignant B cells in lymphoma patients.
Unleashing NK cells
The researchers tested these CAR-NK cells in mice that have a human-like immune system. These mice were also injected with lymphoma cells.
Mice that received CAR-NK cells with the new construct maintained their NK cell counts for at least three weeks, and the NK cells were able to nearly eliminate the cancer in those mice. In mice that received either NK cells without genetic modifications or NK cells containing only the CAR gene, host immune cells attacked the donor NK cells. In these mice, the natural killer cells died within two weeks, and the cancer spread unchecked.
The researchers also found that the engineered CAR-NK cells were less likely to induce cytokine release syndrome, a common side effect of immunotherapies, which can cause life-threatening complications.
Given the better safety properties of CAR-NK cells, Chen expects they could eventually be used instead of CAR-T cells. He says that for any CAR-NK cells 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.
The researchers now hope to conduct a clinical trial of this approach, working with their 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 Frontier Research Program of the Koch Institute through the Kathy and Curt Marble Cancer Research Fund, the Elisa Rah Memorial Fund, the Claudia Adams Barr Foundation, and a Support (core) grant to the Koch Institute from the National Cancer Institute.
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