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Initiation of the first-in-human trial of allogeneic NKG2D-directed CAR NK-cell therapy to treat R/R AML or high-risk R/R MDS

Mar 25, 2021
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Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are hematologic diseases with very limited curative therapy options. The use of chimeric antigen receptor (CAR) T-cells to treat patients with relapsed/refractory (R/R) AML/MDS has had limited clinical success due to the absence of AML-specific target antigens.1

Recently, natural killer (NK)-cell therapy has gained significant attention. Naturally, NK cells maintain a balance between activation and inhibition of their receptors to balance the cytolytic activity. NK cells induce an apoptotic immune response by identifying stress ligands on cancer cells through their unique NKG2D receptors. Recent studies have revealed that increased expression of NKG2D receptors results in better clinical responses in patients with R/R AML/MDS who received non-engineered haploidentical NK cells.2

A recent study has described the development of CAR NK-cells termed NKX101 for treating patients with MDS or AML.3 The NKX101 product is manufactured from donor NK cells expressing a genetically modified NKG2D receptor containing OX40 and CD3ζ domains that increase tumor recognition and antileukemic activity. NKX101 also contains membrane-bound interleukin-15, which increases persistence compared with the non-engineered versions by serving as an autocrine growth factor of NK cells. Tests on xenograft models indicated four- to eight-fold greater cytotoxicity, superior intrinsic longevity, and enhanced antitumor activity of these CAR NK-cells compared with the non-engineered version.

The first patient has reportedly been treated in an ongoing clinical trial exploring the safety of NKX101 in patients with R/R AML or intermediate, high, or very high risk R/R MDS (NCT04623944).4 This trial is designed to assess the safety, pharmacokinetics, and preliminary antitumor activity of the allogeneic cell therapy NKX101.

  1. Epperly R, Gottschalk S, Velasquez MP. A bump in the road: How the hostile AML microenvironment affects CAR T cell therapy. Front Oncol. 2020;10:262. DOI: 3389/fonc.2020.00262
  2. Romee R, Rosario M, Berrien-Elliott MM, et al. Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia. Sci Transl Med. 2016;8(357):357ra123. DOI: 1126/scitranslmed.aaf2341
  3. Bachier C, Borthakur G, Hosing C, et al. 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). 2020;136(Supplement 1):42-42. DOI: 10.1182/blood-2020-134625
  4. Clinicaltrials.gov. Safety of intravenous allogeneic engineered natural killer cells in adults with AML or MDS. https://clinicaltrials.gov/ct2/show/NCT04623944. Updated Nov 10, 2020. Accessed Mar 19, 2021.

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