Engineered CAR natural killer cells effectively kill tumor cells

Good news! Cancer is history (soon)!

"One of the newest weapons that scientists have developed against cancer is a type of engineered immune cell known as CAR-NK (natural killer) cells. Similar to CAR-T cells, these cells can be programmed to attack cancer cells. ...

researchers have now come up with a new way to engineer CAR-NK cells that makes them much less likely to be rejected by the patient’s immune system, which is a common drawback of this type of treatment. ...

In a study of mice with humanized immune systems, the researchers showed that these CAR-NK cells could destroy most cancer cells while evading the host immune system. ...

The researchers tested these CAR-NK cells in mice with a human-like immune system. These mice were also injected with lymphoma cells.

Mice that received CAR-NK cells with the new construct maintained the NK cell population for at least three weeks, and the NK cells were able to nearly eliminate cancer in those mice. ...

The researchers also found that these engineered CAR-NK cells were much less likely to induce cytokine release syndrome — a common side effect of immunotherapy treatments, which can cause life-threatening complications. ..."

From the abstract:

"Allogeneic cellular immunotherapy exhibits promising efficacy for cancer treatment, but donor cell rejection remains a major barrier.

Here, we systematically evaluate human leukocyte antigens (HLA) and immune checkpoints PD-L1, HLA-E, and CD47 in the rejection of allogeneic NK cells and identify CD8+ T cells as the dominant cell type mediating allorejection. 

We demonstrate that a single gene construct that combines an shRNA that selectively interferes with HLA class I but not HLA-E expression, a chimeric antigen receptor (CAR), and PD-L1 or single-chain HLA-E (SCE) enables the one-step construction of allogeneic CAR-NK cells that evade host-mediated rejection both in vitro and in a xenograft mouse model.

Furthermore, CAR-NK cells overexpressing PD-L1 or SCE effectively kill tumor cells through the upregulation of cytotoxic genes and reduced exhaustion and exhibit a favorable safety profile due to the decreased production of inflammatory cytokines involved in cytokine release syndrome.

Thus, our approach represents a promising strategy in enabling “off-the-shelf” allogeneic cellular immunotherapies."

Engineered “natural killer” cells could help fight cancer | MIT News | Massachusetts Institute of Technology "A new study identifies genetic modifications that make these immune cells, known as CAR-NK cells, more effective at destroying cancer cells."

Selective HLA knockdown and PD-L1 expression prevent allogeneic CAR-NK cell rejection and enhance safety and anti-tumor responses in xenograft mice (open access)

Fig. 5: CD19-CAR and MSLN-CAR NK cells with HLA-ABC knockdown and PD-L1 or SCE expression exhibit enhanced cytotoxicity against tumor cells in vitro.