NKR-2 is an investigational cell-based cancer therapy being developed by Celyad. It is currently in a clinical study as a potential treatment of several solid cancers and hematological malignancies (cancers of the blood).

Celyad obtained approval from the U.S. Food and Drug Administration (FDA) in March 2017 to initiate a Phase 1b clinical trial (NCT03018405), called THINK, testing the safety and activity of NKR-2 in people with five types of solid cancers (colorectal, ovarian, bladder, triple-negative breast, and pancreatic cancers) and two hematological malignancies (acute myeloid leukemia and multiple myeloma).

How NKR-2 works

NKR-2 consists of a patient’s own T-cells that have been genetically engineered to produce a receptor normally present on natural killer (NK) cells (another type of immune cell) called NKG2D, which activates NK cell function when bound to its ligands. It is a type of CAR T-cell therapy, because the engineered cell expresses what is known as a chimeric antigen receptor — or CAR — on its surface.

Since NKG2D can bind to eight naturally occurring ligands (MIC-A, MIC-B, and the ULBPs 1 to 6) that are known to be overproduced by more than 80 percent of tumors, it allows the T-cells to recognize and attach to antigens on cancer cells. This could make NKR-2 therapy useful in a wide range of solid and blood cancers.

The modified T-cells are allowed to multiply in the laboratory and then administered into the bloodstream of the patients. The engineered T-cells further multiply in the patient’s body, with the intent of recognizing and killing cancer cells.

Preclinical studies have shown that NKR-2 works through several mechanisms to elicit an immune response against cancer cells by decreasing the number of regulatory T-cells that suppress immune function, recruiting other immune cells, and targeting tumor blood vessels.

NKR-2 in clinical trials

A dose-escalation Phase 1 trial (NCT02203825) evaluated the safety and tolerability of NKR-2 therapy in 12 patients with acute myeloid leukemia (AML) and multiple myeloma (MM), who were treated with low but escalating doses of NKR-2 cells. Results demonstrated that NKR-2 is safe and well-tolerated, with no serious treatment-related side effects. They also showed evidence of potential efficacy for NKR-2, including prolonged survival in both AML and MM patients.

The open-label Phase 1b THINK study (NCT03018405) now aims to evaluate the safety and efficacy of NKR-2 T-cells in five solid tumors and two hematological malignancies. The trial consists of two parts: the dose escalation part that will enroll up to 24 patients, and the extension part that will enroll 86 additional patients. The trial will test three doses of NKR-2 cells. Patients will receive three successive administrations of each dose of NKR-2 cells, one every two weeks. The study, expected to be completed by 2020, is currently recruiting patients at three sites in the U.S. and three in Belgium. More information is available by clicking on the trial’s identification number.

Another open-label, Phase 1 study (NCT03310008), called SHRINK, aims to evaluate the safety and clinical activity of NKR-2 administered concurrently with a standard chemotherapy (FOLFOX) in up to 36 patients whose colorectal cancer has spread to the liver, but potentially can be removed from that organ with surgery. The trial will test three dose levels of NKR-2, administered three times with each dose given every two weeks. The study is recruiting patients in Belgium and is expected to finish in 2021.


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