NK Cell (Natural Killer Cell) Attacking a Cancer Cell
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A team of researchers at the University of Texas MD Anderson Cancer Center say they have developed a novel approach to the engineering of natural killer (NK) cells that improves tumor specificity and anti-tumor activity. The newly developed cells overcome NK cell dysfunction and tumor relapse via the addition of a second chimeric antigen receptor (CAR) to act as a logic gate to require two signals in order to eliminate a cell.

The study, published in Nature Medicine shows that a normal physiological process called trogocytosis contributes to tumor escape and poor responses after CAR NK cell therapy by causing tumor antigen loss, NK cell exhaustion, and fratricide. During trogocytosis, surface proteins from a target cell are transferred to the surface of an immune cell, such as an NK cell or T cell, in order to regulate their activity.

“We identified a novel mechanism of relapse following CAR NK cell therapy, and we also have developed a strategy to mitigate this process,” said corresponding author Katy Rezvani, M.D., Ph.D., professor of Stem Cell Transplantation & Cellular Therapy. “We engineered CAR NK cells with dual-targeting CARs that are able to ignore tumor antigens on the surface of their sibling NK cells acquired as a result of trogocytosis and selectively eliminate tumor cells.”

Using multiple in vivo tumor models and clinical data, the MD Anderson investigators showed  that CAR activation in NK cells promoted transfer of the CAR cognate antigen from tumor to NK cells via trogocytosis. This antigen transfer both lowered tumor antigen density, impairing the ability of CAR-NK cells to engage with their target; and induced self-recognition and continuous CAR-mediated engagement, resulting in fratricide of trogocytic antigen-expressing NK cells and NK cell hyporesponsiveness.

The team used clinical samples from patients with lymphoid malignancies treated with anti-CD19 CAR NK cells in a clinical trial to confirm that higher levels of the CD19 antigen on CAR NK cells were associated with lower levels of CD19 on tumor cells and a higher probability of relapse.

As a method to prevent this NK cell fratricide, the researchers then added an inhibitory CAR designed to recognize a marker unique to NK cells, one that signaled “don’t kill me” to CAR NK cells when they are interacting with their siblings, even if they had the tumor antigen on their surface. Applied against pre-clinical tumor models these next-generation CAR NK cells showed improved ability to find and attack only tumor cells, while reducing NK cell exhaustion and fratricide. The result was improved antitumor activity.

“It’s important to prevent tumor escape following CAR NK therapy because that has led to relapse in some patients,” noted Rezvani. “By preventing exhaustion and fratricide in CAR NK cells, we can further improve their activity and function.”

The new study was built on earlier work from the Rezvani lab which focuses on improving CAR NK cell therapy and has included a clinical trial in leukemia and lymphoma. The research team has also conducted preclinical work to design CAR NK cells to overcome immune suppression in glioblastoma.

The lab will now turn its attention to translating these latest findings to clinical care with broad implications for its use as the technology has the potential to be applied to any CAR NK cell therapy.

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