Scientists have made a significant stride in the fight against cancer with a novel approach to engineering CAR-NK (chimeric antigen receptor natural killer) cells. This breakthrough, developed by researchers at MIT and Harvard Medical School, aims to overcome a common challenge in immunotherapy: the patient’s immune system rejecting the therapeutic cells. The innovation could pave the way for readily available, "off-the-shelf" cancer treatments.
Traditional methods for developing CAR-T or CAR-NK cells typically involve a lengthy process of several weeks to engineer and proliferate a patient’s own immune cells. However, this new technique allows for a one-step engineering process that produces CAR-NK cells capable of avoiding rejection by the host’s T cells and other immune components. These advanced cells are also designed to be more effective at targeting cancer and safer for the patient.
Jianzhu Chen, an MIT professor of biology and a member of the Koch Institute for Integrative Cancer Research, emphasized the multi-faceted benefits: "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.”
In a study involving mice with humanized immune systems, these specially engineered CAR-NK cells demonstrated a remarkable ability to eliminate most cancer cells while successfully evading the host’s immune response. The findings of this research were published today in Nature Communications. Rizwan Romee, an associate professor of medicine at Harvard Medical School and Dana-Farber Cancer Institute, also served as a senior author, with Fuguo Liu, a postdoc at the Koch Institute and a research fellow at Dana-Farber, as the lead author.
The Strategy for Immune Evasion
NK cells are vital components of the body’s natural defense system, primarily tasked with identifying and destroying cancer cells and those infected by viruses. One of their key killing mechanisms, shared with T cells, is degranulation, where they release perforin to create holes in target cells, leading to cell death.
Currently, creating CAR-NK cells involves extracting NK cells from a patient’s blood, modifying them to express a Chimeric Antigen Receptor (CAR) that targets specific cancer cell proteins, and then culturing them for several weeks to reach sufficient numbers for reinfusion. While CAR-T cell therapies have found success in treating blood cancers, CAR-NK treatments are still undergoing clinical trials.
The lengthy production time and potential limitations of using a patient’s own cells have led researchers to explore donor-derived NK cells. These "off-the-shelf" cells could be mass-produced and readily available, but they face the significant hurdle of being recognized as foreign by the recipient’s immune system, leading to rejection.
The MIT team’s solution involves making NK cells "invisible" to the patient’s immune system. Their research revealed that NK cells could evade T-cell responses if they lacked surface proteins called HLA class 1 proteins. These proteins, normally found on NK cell surfaces, can trigger T cells to attack if they are not recognized as "self."
To achieve this, the scientists engineered the NK cells to express short interfering RNA (siRNA) that silences the genes responsible for HLA class 1 expression. Simultaneously, they introduced the CAR gene and a gene for either PD-L1 or single-chain HLA-E (SCE). PD-L1 and SCE are proteins that enhance the NK cells’ cancer-killing effectiveness by upregulating genes involved in cell destruction.
All these genetic modifications are integrated into a single DNA construct, simplifying the process of transforming donor NK cells into these immune-evasive CAR-NK cells. The researchers specifically created CAR-NK cells targeting CD-19, a protein commonly found on cancerous B cells in lymphoma patients.
Unleashing the NK Cells
Testing these engineered CAR-NK cells in mice with human-like immune systems and lymphoma cells yielded promising results. Mice receiving the new CAR-NK cells maintained a stable NK cell population for at least three weeks, resulting in the near elimination of cancer. In contrast, mice receiving unmodified NK cells or those with only the CAR gene experienced donor NK cell rejection by the host immune system, leading to the rapid spread of cancer.
A significant finding was that these engineered CAR-NK cells were far less likely to cause cytokine release syndrome, a dangerous side effect often associated with immunotherapy treatments.
Given the improved safety profile of CAR-NK cells, Chen foresees their potential to eventually replace CAR-T cells in certain applications. He believes that existing CAR-NK cell therapies under development for lymphoma and other cancers could be enhanced by incorporating the new construct.
The research team is now planning a clinical trial for this innovative approach, collaborating with colleagues at Dana-Farber. They are also exploring the use of CAR-NK cells to treat lupus, an autoimmune disorder, in partnership with a local biotech company.
The study received funding from various sources, including Skyline Therapeutics, the Koch Institute Frontier Research Program, the Claudia Adams Barr Foundation, and the Koch Institute Support (core) Grant from the National Cancer Institute.
