CD147-CAR-NK Cells for Hepatocellular Carcinoma Treatment

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Project Summary: This project will pursue an ‘off-the-shelf’ immunotherapy liver cancer “living drug” by re- engineering human primary Natural killer (NK) cells derived from a third-party cord blood or peripheral blood to home-in on a specific hepatocellular carcinoma cancer antigen (CD147). Recent clinical trials testing cancer immunotherapies have shown promising results for the treatment of various cancers. One such therapy involves engineering immune cells to express chimeric antigen receptors (CAR), which combine tumor antigen specificity with immune cell activation in a single receptor. The adoptive transfer of these CAR-modified immune cells (especially T cells, CAR T) into patients has shown remarkable success in treating multiple refractory blood cancers. However, CAR T therapy is often associated with significant toxicity, high cost, marginal effects on solid tumors. In order to achieve the promise of CAR cell therapy in treating solid tumor cancers, further advances will be required. One key challenge is identifying a safe and effective solid tumor antigen, as well as development of ‘off-the-shelf’ cell products. We recently devised a novel strategy for targeting hepatocellular carcinoma (HCC, one of the deadliest solid tumor cancers in humans). We report that T and NK cells transduced with a CAR that targets the HCC surface marker, CD147, also known as Basigin (BSG) or extracellular matrix metalloproteinase inducer (EMMPRIN), can effectively kill multiple malignant HCC cell lines (including SK-Hep1 and HepG2 cell lines), primary HCC in vitro and tumors in xenograft and patient-derived xenograft (PDX) mouse models of liver cancer (Tseng, HC., D. et al., Nature Communications., 2020,). Critical gaps in our current knowledge of this immunotherapeutic strategy include the exact mechanism(s) by which the CD147-CAR-NK cells derived from a third-party peripheral or cord blood (CD147-CAR-NKprimary) can control HCC and whether the CD147-CAR-NK cells are safe in vivo. We propose to test the hypothesis that the CD147-CAR-NKprimary targeting HCC is effective and safe. The long- term goal of this project is to develop a novel immunotherapeutic strategy for the treatment of HCC. The objective of this application is to assess the efficacy CD147-CAR-NKprimary in vitro using HCC cell lines and in vivo using a newly created human CD147 transgenic (hCD147TG) mouse model. The proposed work will characterize the biology of CD147-CAR-NKprimary by analyzing surface marker profile, cytokine production, and cellular proliferation (Aim 1), test the efficacy of CD147-CAR-NKprimary both in vitro and in vivo (including severe combined immunodeficiency [SCID], patient-derived xenograft (PDX), and DEN/PB and HDF-induced orthotopic HCC in hCD147TG mouse model) and investigate the molecular mechanisms with a focus on immunological synapse (Aim 2), Future plan includes characterization of the CD147-CAR-NKprimary toxicity in the hCD147TG HCC mouse model. The results of these studies will streamline the path to clinical trials of ‘off- the-shelf’ CD147-CAR-NKprimary cells for adoptive cell therapy for the treatment of HCC.