The oncology therapeutic landscape has been transformed with the use of checkpoint inhibitor therapy. Despite the clinical benefit conferred by approved checkpoint inhibitor therapy against a variety of tumor types, these therapies are not curative and, in most cases, patients either fail to respond or their disease progresses on these agents. Resistance to checkpoint inhibitor therapy has been linked to impaired immune cell infiltration into the tumor, impaired cytokine response, and deficiencies in antigen presentation including altered expression of major histocompatibility (MHC) class I complex. As a result, there is significant unmet need for novel therapeutic approaches to overcome resistance to checkpoint inhibitor therapy.
One potential strategy to overcome resistance is through the administration of allogeneic NK cells, which have the inherent capability to recognize and directly kill cells with MHC class I down-regulation. The mechanism of killing is through the release of perforins and granzymes, which can lyse tumor cells exposing large amounts of tumor antigens, and the secretion of a number of cytokines and chemokines, both of which can activate and facilitate an adaptive immune response. In addition to direct cytotoxicity, NK cells can also secrete proinflammatory cytokines, which can induce tumor-resident T cells to re-engage and elicit an anti-tumor response, and chemotactic cytokines, which can recruit T cells to the tumor site.
We are developing FT500, an investigational, universal, off-the-shelf NK cell cancer immunotherapy derived from a clonal master iPSC line. To our knowledge, FT500 is the first-ever iPSC-derived cell therapy cleared for clinical investigation in the United States. The product candidate is being investigated in an open-label, multi-dose Phase 1 clinical trial for the treatment of advanced solid tumors (NCT03841110). The study is designed to assess the safety and tolerability of three once-weekly doses of FT500 as a monotherapy and in combination with one of three FDA-approved checkpoint inhibitors – nivolumab, pembrolizumab or atezolizumab – in patients that have failed prior checkpoint inhibitor therapy.