Engineered CAR-NK Cells Show Promise for Universal Cancer Therapy | MIT & Harvard Breakthrough

A new approach to engineering immune cells, developed by researchers at MIT and Harvard Medical School, offers a potential breakthrough in cancer treatment by significantly reducing the risk of the body rejecting these cells. This innovation centers on CAR-NK (chimeric antigen receptor natural killer) cells, a type of engineered immune cell designed to target and destroy cancer. The challenge with these therapies and similar CAR-T cell treatments, has long been the immune system’s tendency to recognize and eliminate the infused cells before they can effectively fight the disease. This new work, published in Nature Communications, aims to overcome that hurdle, potentially paving the way for more readily available and effective cancer immunotherapies.

How CAR-NK Cells Differ from CAR-T Cells

Both CAR-NK and CAR-T cell therapies involve modifying a patient’s immune cells to recognize and attack cancer cells. Still, they utilize different types of immune cells. CAR-T cells rely on T cells, while CAR-NK cells utilize natural killer (NK) cells. NK cells are a crucial part of the body’s innate immune system, naturally equipped to identify and eliminate abnormal cells, including those infected with viruses or those that have become cancerous. They work by releasing proteins that puncture the membranes of target cells, leading to their destruction – a process called degranulation. MIT News explains this fundamental difference, highlighting the potential advantages of leveraging the NK cell’s existing anti-cancer capabilities.

The Challenge of Immune Rejection and the “Stealth” Solution

Traditionally, creating CAR-NK or CAR-T cells involves extracting immune cells from a patient, genetically engineering them to express a chimeric antigen receptor (CAR) – a protein designed to target specific cancer cell markers – and then growing these modified cells in the lab before infusing them back into the patient. This process can take several weeks. A significant obstacle, particularly when considering using donor NK cells to create “off-the-shelf” treatments, is immune rejection. The recipient’s immune system often identifies the donor cells as foreign and attacks them.

To address this, the MIT team focused on helping the NK cells evade immune detection. Their research revealed that removing surface proteins known as HLA class 1 molecules allowed the NK cells to avoid attack from the host’s T cells. These HLA class 1 molecules normally act as identity markers, signaling to the immune system that a cell belongs to the body. By silencing the genes responsible for producing these proteins using short interfering RNA (siRNA), the researchers effectively created “stealth” NK cells. ScienceDaily details this key innovation, emphasizing its potential to unlock the promise of readily available, donor-derived CAR-NK therapies.

Enhancing Cancer-Fighting Power

The researchers didn’t stop at simply evading immune detection. They as well incorporated genetic modifications to enhance the NK cells’ ability to kill cancer cells. Along with the siRNA to silence HLA class 1, they introduced the CAR gene itself and another gene encoding either PD-L1 or single-chain HLA-E (SCE). These additions are designed to strengthen the NK cells’ cancer-fighting capabilities. This combined approach allowed for efficient, one-step engineering of CAR-NK cells capable of avoiding rejection and effectively targeting cancer.

Promising Results in Preclinical Trials

The engineered CAR-NK cells were tested in mice with human-like immune systems that had been injected with lymphoma cells. The results were encouraging. Mice treated with the new CAR-NK cells maintained a robust population of the engineered cells for at least three weeks and experienced near-complete elimination of the cancer. In contrast, mice receiving unmodified NK cells or NK cells with only the CAR gene saw their donor cells attacked and eliminated by the host immune system, leading to unchecked cancer growth. The engineered cells were less likely to trigger cytokine release syndrome, a potentially life-threatening side effect sometimes associated with immunotherapy. SciTechDaily reports on these findings, highlighting the successful cancer elimination and reduced risk of adverse effects.

Study Details and Limitations

The study, led by Fuguo Liu, Rizwan Romee, and Jianzhu Chen, involved a specific type of lymphoma and a humanized mouse model. While these results are promising, it’s crucial to remember that preclinical findings don’t always translate directly to humans. The mouse immune system, while engineered to resemble the human system, is not identical. Further research, including clinical trials, is necessary to determine the safety and efficacy of this approach in human patients. The researchers acknowledge that the long-term effects of silencing HLA class 1 expression also require further investigation.

What’s Next for CAR-NK Cell Therapy?

The research team is now preparing to launch a clinical trial at Dana-Farber Cancer Institute to evaluate the safety and effectiveness of this engineered CAR-NK cell therapy in humans. They are also collaborating with a local biotechnology company to explore the potential of these cells in treating lupus, an autoimmune disorder. Jianzhu Chen, an MIT professor of biology, anticipates that this construct could be adapted for apply with other CAR-NK cells currently in development for various cancer types. The team is also exploring the potential of this technology for other applications beyond cancer, such as treating infectious diseases.

The development of these “stealth” CAR-NK cells represents a significant step forward in the field of cancer immunotherapy. By overcoming the challenge of immune rejection, this innovation could unlock the potential of readily available, off-the-shelf cancer treatments, offering hope for more effective and accessible therapies for patients in the future. The ongoing clinical trials will be critical in determining whether these promising preclinical results translate into tangible benefits for individuals battling cancer.