In this preclinical study, Prodigy-produced (PROD)-CAR-NK cells showed a similar functionality compared to small-scale-produced (SS)-CAR-NK cells from the same donor in vitro and in an OCI-AML2 NSG-SGM3-xenograft mouse model after a multiple-hour transportation in cooled formulation solution. While use of a CliniMACS Prodigy ® device was already shown for the generation of CAR-T and for the expansion of untransduced NK cells, this is the first report on the automated generation of CD33-CAR-NK cells using the CliniMACS Prodigy ® platform resulting in a proof-of-concept evaluation in a xenograft AML model in vivo.

In previous work, we were able to show the generation of effective CD33-targeting CAR-NK cells for the treatment of acute myeloid leukemia (AML), a disease for which no CAR-T cell therapy is available yet, and which demonstrates dismal overall survival rates especially for elderly patients. Hence, one crucial step to enable the generation of clinical CAR-NK cell products is to establish robust methods for the generation of high numbers of primary CAR-NK cells under Good Manufacturing Practice (GMP)-conditions. Therefore, the usage of primary peripheral blood-derived NK cells in patients is highly desirable. Yet, their generation still remains challenging as primary NK cells proliferate slower and possess a shorter lifetime compared to primary T cells ex vivo. The generation of CAR-modified NK cell lines such as CAR-NK-92 cells appears feasible but possesses problems such as the necessity to irradiate CAR-NK-92 cells prior to infusion which can limit proliferation and functionality of these cells in vivo. Therefore, CAR-NK cells might be suited to treat CAR-T cell resistant malignancies and offer the potential to be applied as a so-called off-the-shelf product, which could drastically reduce costs and enable fast availability of a CAR-immune cell therapy. Natural killer (NK) cells on the other hand do not cause graft-versus-host-disease and recognize malignant cells in an antigen-independent manner through an intrinsic killing capacity which is orchestrated by a broad range of activating and inhibitory cell-surface receptors. Furthermore, CAR-T cells might possess limited efficacy against T cell resistant malignancies, which lack cancer-exclusive antigens. However, CAR-T cells still face major limitations such as the necessity to be applied in an autologous manner, since allogeneic T cells might carry the risk for major side effects such as graft-versus-host-disease. Food & Drug Administration (FDA) as well as the European Medicines Agency (EMA). This technology might be well suited for the generation of primary CAR-modified NK cells for a broad range of targets and could facilitate clinical transition.Ĭhimeric antigen receptor (CAR)-modified T cells already demonstrated outstanding results for the treatment of B cell neoplasms such as CD19 + B cell acute lymphoblastic leukemia as well as B cell maturation antigen (BCMA) + multiple myeloma which led to the approval of multiple drugs by the U.S. Automated-produced CD33-CAR-NK cells showed similar phenotype and cytotoxicity compared to small-scale-produced CD33-CAR-NK cells in vitro and were able to strongly reduce leukemic burden in an OCI-AML2 NSG-SGM3 xenograft mouse model in vivo following a cross-site shipment of the cell product. Here we report on the automated generation of high numbers of primary CD33-targeting CAR-NK cells using the CliniMACS Prodigy ® platform. Therefore, robust systems for the generation of high numbers of CAR-NK cells under GMP conditions are required. However, the generation of primary CAR-NK cells can be difficult and time consuming. Natural killer (NK) cells possess a high intrinsic killing capacity against AML and might be well suited for the treatment of this disease.

Chimeric antigen receptor (CAR)-modified T cells struggle to target AML partly due to a lack of true AML-exclusive antigens and heterogeneity of the disease. Acute myeloid leukemia (AML) still constitutes a dreadful disease with limited therapeutic options.

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