The first patient has received treatment in a first-in-human Phase 1 trial of NKX101, Nkarta‘s investigational cell therapy for the treatment of relapsed/refractory acute myeloid leukemia (AML) or higher-risk myelodysplastic syndromes.

NKX101 uses natural killer cells — immune cells that kill virally infected cells — that are engineered to express up to 10 times the level of a key receptor.

“Despite recent treatment breakthroughs, AML patients who relapse after front-line therapy still have poor outcomes, underscoring the need for new treatment options for this aggressive and lethal blood cancer,” Carlos Bachier, MD, director of cellular therapy research at TriStar Centennial Medical Center in Nashville, Tenn., said in a press release. TriStar, one of the trial’s four U.S. study sites, is where the first patient was treated.

The trial’s design was presented in a scientific poster, titled “A Phase 1 Study of NKX101, an Allogeneic CAR Natural Killer (NK) Cell Therapy, in Subjects with Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML) or Higher-Risk Myelodysplastic Syndrome (MDS),” at the 2020 American Society of Hematology Annual Meeting. The 62nd ASH Annual Meeting is being held all-virtually Dec. 5-8.

The study (NCT04623944) is designed to evaluate NKX101’s safety, pharmacokinetics — how the medication moves through the body — and preliminary anti-tumor activity. Its goal is to find the appropriate dose for a later Phase 2 trial.

Nkarta is seeking approximately 27 participants, ages 18 and older, with previously treated relapsed/refractory (resistant) AML. More information on enrollment is available here.

The trial consists of two parts: a dose-finding portion followed by a second dose-expansion phase to further evaluate the safety, tolerability, and other clinical measures of the doses identified in part one.

Participants will receive fludarabine/cyclophosphamide lymphodepletion — used to destroy certain white blood cells — followed by three weekly doses of NKX101. All patients will be monitored for harmful side effects, known as adverse events, for 30 days and for dose-limiting toxicities for 28 days.

Secondary trial goals include establishing the treatment’s half-life, or the time it takes for 50% of the medication to remain in a patient’s body, and how long overall NKX101 persists in the body. This last measure will include two years’ worth of blood samples, taken every three months after dosing.

NKX101 consists of natural killer (NK) cells — cells of the innate or natural immune system best known for killing virally infected cells — engineered to express increased levels of the NKG2D receptor fused to the co-stimulatory and signaling domains of other proteins. The levels of NKG2D are engineered to be 10 times higher in these cells. This type of hybrid protein is called a chimeric antigen receptor (CAR).

CAR therapy has shown some success in treating leukemias. Past CAR products involving T-cells have had limited success, however, in treating AML, which offers few specific cellular targets and provides a hostile microenvironment for T cell-based therapy.

NKG2D is a receptor found on naturally occurring NK cells that, when activated, triggers a cell-killing response through the detection of certain broadly cancer cell-specific molecules. The added co-stimulatory and signaling domains enhance the intrinsic anti-AML activity of the NK cells.

“An extensive body of academic research has already shown increased expression of NKG2D targets in AML and other cancers, and demonstrated clinical responses in relapsed/refractory AML patients who received non-engineered allogeneic [donor] NK cells in single center academic studies as treatment,” said Kanya Rajangam, MD, PhD, Nkarta’s chief medical officer. Of note, allogeneic cells come from donors and are not the patients’ own cells.

Pre-clinical studies have shown the cell-killing activity of NKX101 is four-to-eight times greater than that of non-engineered NK cells. NKX101 also expresses membrane-bound IL-15, a signaling molecule with proven anti-tumor activity that enhanced NKX101’s activity and persistence.

“With its amplified NKG2D targeting and enhanced NK cell engineering, NKX101 has the potential to improve upon this earlier clinical experience with non-engineered NK cells and to activate a deep and robust immune response in AML patients,” Rajangam added.