A new approach to cancer immunotherapy, developed by researchers at MIT and Harvard Medical School, offers a potential breakthrough in overcoming one of the biggest hurdles in cell-based therapies: immune rejection. The team has engineered natural killer (NK) cells – a type of immune cell that naturally targets and destroys cancerous cells – to evade detection by the patient’s own immune system, paving the way for “off-the-shelf” treatments that could be readily available at diagnosis. This innovation in cancer immunotherapy could dramatically expand access to these powerful therapies and potentially improve outcomes for a wider range of patients.
Traditional cancer treatments like chemotherapy and radiation can damage healthy cells alongside cancerous ones. Immunotherapy, however, harnesses the power of the body’s own immune system to fight cancer. Chimeric antigen receptor (CAR) T-cell therapy, a form of immunotherapy already approved for certain blood cancers, has shown remarkable success, but it’s a complex and time-consuming process. It requires extracting a patient’s T cells, genetically modifying them to recognize cancer cells, and then infusing them back into the patient. This personalized approach is expensive and can accept weeks, and the infused cells can sometimes trigger a dangerous immune response. CAR-NK cell therapy offers a promising alternative, utilizing NK cells which possess inherent anti-cancer activity and a potentially safer profile.
The key challenge with donor-derived CAR-NK cells has been rejection. When NK cells are sourced from a donor, the recipient’s immune system recognizes them as foreign and attacks them, diminishing their effectiveness. The MIT team, led by Jianzhu Chen, a professor of biology at MIT and member of the Koch Institute for Integrative Cancer Research, and Rizwan Romee, an associate professor of medicine at Harvard Medical School and Dana-Farber Cancer Institute, tackled this problem by essentially cloaking the NK cells. Their research, published in Nature Communications, details a method to remove surface proteins, specifically HLA class 1 molecules, that identify the cells as non-self.
“Stealth” Cells and Enhanced Cancer Killing
HLA class 1 molecules are present on nearly all cells in the body and act as “identity markers” for the immune system. By silencing the genes responsible for producing these proteins using short interfering RNA (siRNA), the researchers were able to create NK cells that largely evaded detection by the host’s T cells. This “invisibility cloak” allowed the engineered CAR-NK cells to persist longer in the body and more effectively target and destroy cancer cells. Fuguo Liu, a postdoctoral researcher at the Koch Institute and a research fellow at Dana-Farber, is the lead author of the study.
The team didn’t stop at simply hiding the NK cells. They also incorporated genes that enhance their cancer-fighting abilities. These included genes encoding for PD-L1 or single-chain HLA-E (SCE), both of which bolster the NK cells’ ability to recognize and kill cancer cells. All of these genetic modifications were combined into a single DNA construct, streamlining the engineering process and making it more efficient. The engineered cells were designed to target CD-19, a protein commonly found on malignant B cells in lymphoma patients.
Promising Results in Preclinical Trials
To test their approach, the researchers used mice with humanized immune systems – mice engineered to have immune systems that closely resemble those of humans. These mice were injected with lymphoma cells, and then treated with the newly engineered CAR-NK cells. The results were striking. Mice treated with the “stealth” 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 that received either unmodified NK cells or NK cells with only the CAR gene saw their donor cells quickly attacked and eliminated by their own immune systems, and the cancer continued to progress unchecked. Importantly, the engineered CAR-NK cells also demonstrated a lower risk of inducing cytokine release syndrome (CRS), a potentially life-threatening side effect common in some immunotherapies. Cytokine release syndrome occurs when the immune system becomes overactivated, releasing a flood of inflammatory molecules.
The Potential for “Off-the-Shelf” Therapies and Beyond
The ability to create donor-derived CAR-NK cells that evade immune rejection opens the door to “off-the-shelf” therapies. Currently, CAR-T cell therapy requires a personalized approach, meaning cells must be extracted from each patient, engineered, and then infused back into the same patient – a process that can take weeks. “Off-the-shelf” therapies, using cells from healthy donors, could be manufactured in advance and stored, allowing for immediate treatment upon diagnosis. Here’s particularly crucial in aggressive cancers where time is of the essence.
“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,” said Jianzhu Chen. He anticipates that the new approach could eventually replace CAR-T cell therapy in some cases, given the potentially improved safety profile of CAR-NK cells. The researchers are now planning a clinical trial, in collaboration with Dana-Farber Cancer Institute, to test the safety and efficacy of this approach in humans.
Beyond lymphoma, the team is also exploring the employ of these engineered CAR-NK cells to treat autoimmune disorders like lupus, where the immune system mistakenly attacks healthy tissues. They are collaborating with a local biotech company to investigate this potential application. The research was supported by funding from Skyline Therapeutics, the Koch Institute Frontier Research Program, the Claudia Adams Barr Foundation, and the National Cancer Institute.
Disclaimer: This article provides information for general knowledge and informational purposes only, and does not constitute medical advice. This proves essential to consult with a qualified healthcare professional for any health concerns or before making any decisions related to your health or treatment.
The next step for this promising research is the initiation of clinical trials, which will be critical in determining the safety and effectiveness of this new approach in humans. The researchers are actively preparing for these trials and anticipate beginning patient enrollment in the near future. Share this article with others who may be interested in learning more about this exciting development in cancer immunotherapy, and join the conversation in the comments below.
