On April 25, Nkarta, a biopharmaceutical company developing off-the-shelf engineered natural killer (NK) cell therapies, announced highly promising results from two Phase I trials. The trials were investigating Nkarta’s two lead chimeric antigen receptor (CAR) NK cell therapy candidates, NKX101 and NKX019.
In the first trial, NKX101, which is engineered to target the NKG2D ligand on cancer cells, was administered to 21 patients, 17 with relapsed/refractory acute myeloid leukaemia (AML), and four with myelodysplastic syndrome (MDS). Three of the five patients with heavily pretreated AML, who received the three-dose regimen of 1-1.5 billion cells, achieved a complete response (CR), with two of these responses being minimal residual disease negative, a good predictor for a durable response. Neither of the two MDS patients who received this dose level had any response. There were responses in AML patients treated with lower dosing regimens; however, no complete responses were reported. The overall response rate (ORR) for AML patients across dosing levels was 47%.
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In the second trial, NKX019, which is engineered to target the B-cell antigen CD19, was administered to ten patients with heavily pretreated non-Hodgkin lymphoma (NHL), and three patients with relapsed/refractory B-cell acute lymphoblastic leukaemia (B-ALL). Three of the six NHL patients who received three doses of 1 billion cells achieved a CR, and the ORR was 83%. The ORR across dosing levels for NHL patients was 70%. No responses were reported in the three patients with B-ALL.
CAR T-cells are the first class of engineered immune cells to have received regulatory approval. CAR T-cell therapies, both marketed and in development for the treatment of haematological malignancies, have demonstrated very impressive response rates. While this class of therapeutics has provided a cure for some patients, significant challenges of utilising CAR T-cells remain. The toxicities associated with CAR T-cell treatment are serious and sometimes fatal, including cytokine release syndrome, graft-versus-host disease (GvHD) and neurotoxicity. The cost associated with CAR T-cell treatment is also significant, with the expansion and engineering of autologous cells required for each patient. The autologous nature of these products also means that it takes several weeks from T-cell collection until the product is ready for infusion, with this delay increasing the risk of disease progression. The drawbacks associated with CAR T-cells have driven the development of CAR NK-cells, with no dose-limiting toxicities reported for either NKX101 or NKX019. No cases of cytokine release syndrome, neurotoxicity or GvHD occurred in either trial. With no human leukocyte antigen (HLA)-matching restrictions, CAR-NK therapies can be off-the-shelf products, reducing the cost of therapy and enabling rapid treatment initiation.
The findings reported by Nkarta demonstrate the potential of this novel therapy class. However, it remains to be seen whether the responses are durable and provide curative treatment, as has been observed with CAR T-cell therapies. Nkarta will face competition from other biotech companies developing CAR-NK cells, including Fate Therapeutics, Affimed and Asclepius Technology. Breakthroughs in the development of allogeneic CAR T-cells mean that off-the-shelf CAR T therapies with reduced toxicity may also enter this treatment landscape.
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