Abstract
Natural killer (NK) cells are a noteworthy lymphocyte subset in cancer adoptive cell therapy. NK cells initiate innate immune responses against infections and malignancies with natural cytotoxicity, which is independent of foreign antigen recognition. Based on these substantive features, genetically modifying NK cells is among the prime goals in immunotherapy but is currently difficult to achieve. Recently, we reported a fully human CAR19 construct (huCAR19) with remarkable function in gene-modified T-cells. Here, we show efficient and stable gene delivery of huCAR19 to primary human NK cells using lentiviral vectors with transduction efficiencies comparable to those achieved with NK cell lines. These huCAR19 NK cells display specific and potent cytotoxic activity against target cells. To improve homing of NK cells to the bone marrow, we augmented huCAR19 NK cells with the human CXCR4 gene, resulting in transgenically augmented CAR NK cells (TRACKs). Compared to conventional CAR NK cells, TRACKs exhibit enhanced migration capacity in response to recombinant SDF-1 or bone marrow stromal cells while retaining functional and cytolytic activity against target cells. Based on these promising findings, TRACKs may become a novel candidate for immunotherapeutic strategies in clinical applications.
Highlights
Cancer immunotherapy using CD19-specific chimeric antigen receptor (CAR) modified T-cells (CAR T-cells) has shown remarkable clinical benefit in patients with relapsed or refractory B-cell malignancies
A fully human, second-generation CD19-specific CAR construct as well as the human CAR19 construct (huCAR19) construct linked to the human CXCR4 sequence via a P2A site were used to produce CAR natural killer (NK) cells by lentiviral transduction
CAR gene delivery to the NK cell lines NKL and NK-92 was analyzed by applying polybrene as a transduction enhancer, revealing very efficient gene transfer (Figures 1B,C). 3 days after transduction, nearly 100% of the NKL and NK-92 cells were transduced by huCAR19-Lentiviral vectors (LVs)
Summary
Cancer immunotherapy using CD19-specific chimeric antigen receptor (CAR) modified T-cells (CAR T-cells) has shown remarkable clinical benefit in patients with relapsed or refractory B-cell malignancies. The first CAR T-cell products, tisagenlecleucel (Kymriah, Novartis) and axicabtagene ciloleucel (Yescarta, Gilead), were approved in the United States in 2017 and Europe in 2018 This success has not been translated to other hematological indications, such as huCD19-CAR NK Cells Augmented With CXCR4 acute myeloid leukemia (AML) or even solid tumors. CAR T-cell therapies can be associated with severe, sometimes even life-threatening adverse events, such as cytokine release syndrome (CRS), neurotoxicity, B-cell aplasia, and/or graftversus-host disease (GvHD) [1]. Another immune cell type that can recognize and destroy cancer cells is natural killer (NK) cells. The transfer of ex vivo expanded autologous and allogeneic NK cells has been found to be safe and well tolerated in a range of clinical trials with no signs of GvHD, CRS, or neurotoxicity, but the effect on tumor suppression appears to be low for autologous NK cell infusions or highly dependent on the type of cancer for allogeneic NK cell infusions [2]
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