Healthcare (Commonwealth Union) – Researchers from MIT and Harvard Medical School have developed a new method to engineer CAR-NK cells that are far less likely to be rejected by a patient’s immune system — a common limitation of current cell-based therapies.
This breakthrough could also pave the way for creating “off-the-shelf” CAR-NK cells that can be administered to patients immediately after diagnosis, rather than waiting several weeks as required by traditional CAR-NK or CAR-T cell engineering methods.
Jianzhu Chen, MIT professor of biology and member of the Koch Institute for Integrative Cancer Research indicated that the approach allows them to perform one-step engineering of CAR-NK cells that can evade detection and attack by host T cells and other immune components and they are more effective at killing cancer cells as well as being safe.
In tests involving mice with humanized immune systems, the engineered CAR-NK cells successfully destroyed most cancer cells while avoiding immune rejection.
The study, published today in Nature Communications, was co-led by Rizwan Romee, associate professor of medicine at Harvard Medical School and the Dana-Farber Cancer Institute. The paper’s first author is Fuguo Liu, a postdoctoral researcher at the Koch Institute and research fellow at Dana-Farber.
Natural killer (NK) cells are a vital component of the body’s innate immune system, tasked with detecting and destroying cancerous and virus-infected cells. Like T cells, they use a mechanism known as degranulation to eliminate threats. In this process, NK cells release a protein called perforin, which forms pores in the target cell’s membrane, leading to its death.
To produce CAR-NK cells for cancer therapy, clinicians begin by collecting a blood sample from the patient. The NK cells are obtained from this sample and then genetically modified to bring about a chimeric antigen receptor (CAR), this is a synthetic protein designed for the purpose of identifying specific molecules present on cancer cells.
These engineered cells are then multiplied over several weeks until a sufficient number is available for infusion back into the patient. A comparable method is used to create CAR-T cells, several of which have already been approved for the treatment of blood cancers like leukemia and lymphoma. In contrast, CAR-NK therapies are still undergoing clinical testing.
Because producing enough engineered cells for a single patient takes time — and because patient-derived NK cells may not be as robust as those from a healthy donor — researchers are investigating an alternative: using donor NK cells.
These donor cells could be expanded in large quantities and stored for immediate use, enabling “off-the-shelf” treatments. However, a key challenge is that the recipient’s immune system might recognise these cells as foreign and eliminate them before they can attack the cancer.
In the new study, the MIT researchers aimed to develop a strategy that would allow NK cells to “hide” from a patient’s immune system.
Taking up the exploration of the way immune cells interact, they noted that NK cells could evade detection by T cells if they not have certain surface proteins, which are referred to as HLA class 1 proteins. These proteins are generally seen on NK cell surfaces and assist the immune system mark them as “self,” but when unfamiliar, they may bring about T cells to attack.
For the purpose of making use of this mechanism, the scientists engineered NK cells to produce a type of short interfering RNA (siRNA) that prevents the activity of genes responsible for HLA class 1 proteins. They inserted genes that are responsible for the CAR receptor and either PD-L1 or single-chain HLA-E (SCE). The two proteins—PD-L1 and SCE— improve the NK cell function by initiating pathways that enhance their ability to eliminate cancer cells.
All of these genetic components were packaged onto a single DNA construct, allowing donor NK cells to be easily converted into immune-evasive CAR-NK cells. Using this construct, the scientists created CAR-NK cells designed to target CD-19, a protein commonly found on malignant B cells in lymphoma.
