Background Harnessing both the innate and adaptive immune system could increase the efficiency of current cancer immunotherapies and promote durable anti-tumor immunity. Invariant natural killer T (iNKT) cells are innate-like lymphocytes that bridge innate and adaptive immune responses and promote anti-cancer immunity. iNKT cells are activated and respond rapidly via multiple signals such as recognition of lipid antigens through the invariant T cell receptor (TCR), pro-inflammatory cytokines or recognition of stress ligands. Here we describe, AgenT-797, a novel, allogeneic and ‘off-the shelf’ iNKT cell therapy, designed to promote effective anti-cancer immunity against a wide range of malignancies.
Methods iNKT cells isolated from healthy donors were expanded by stimulation of the invariant TCR with alpha-Galactosylceramide (αGalCer) and cytokines using the AgenTus manufacturing protocol. The phenotype and functional activity of the expanded unmodified iNKT cells, AgenT-797, were characterized by flow cytometry. The cytotoxic potential of AgenT-797 was assessed in tumor co-culture assays against CD1d-expressing cancer cell lines. To further direct anti-tumor responses, iNKT cells were engineered to express Chimeric Antigen Receptors (CARs), and the cytotoxic potential assessed against antigen-expressing cancer cells.
Results iNKT cells were rapidly expanded up to 2 × 1010 cells in 30 days, with over 99% purity. Expanded, unmodified iNKT cells, AgenT-797, were found to secrete both Th1 (IFNγ, TNFa, GM-CSF) and Th2 (IL4, IL13) type cytokines. After rapid expansion, AgenT-797, retained their inherent cytotoxic capacity against CD1d-expressing tumor cell lines. Further, killing of tumor target cells, in vitro, was mediated through their endogenous invariant TCR or engineered CAR receptor.
Conclusions AgenT-797 is an ‘off-the-shelf’ and allogenic cell therapy with effective cancer killing properties. Strategies to engineer iNKT cells using CAR technology further enhance the tumor killing potential of iNKT therapy.
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