The oncology therapeutic landscape has been transformed with the use of immune checkpoint inhibitors (ICIs). However, more than 60% of subjects treated with ICIs will either not respond or eventually relapse. Resistance to ICI has been linked to impaired immune cell infiltrate into the tumor, impaired cytokine response, and deficiencies in antigen presentation and processing including altered expression of the major histocompatibility complex class I.
Adoptive transfer of NK cells has the intrinsic potential to overcome many of these ICI resistance mechanisms. However, the currently available approaches to NK cell therapy have been limited in part by challenges with product sourcing and dose to dose variability.
To address this opportunity, we are developing FT500, an allogeneic off-the-shelf NK cell cancer immunotherapy derived from a clonal master iPSC line. The use of a clonal master iPSC line for the production of FT500 uniquely provides a large, homogenous population of NK cells that is well-defined and displays potent activity including the ability to synergize with T cells. In addition, FT500 can be cryopreserved and available for repeat clinical dosing.
In preclinical studies, FT500 has displayed multiple potential mechanisms by which it may synergize with T cells to activate the immune system in patients with solid tumors treated with anti-PD1 or anti-PDL-1 therapy. These mechanisms include:
- Release of cytotoxic granules upon NK cell receptor engagement by stress ligands on tumor cells, leading to direct tumor lysis and release of tumor neoantigens
- Secretion of inflammatory cytokines and chemokines for enhanced T cell activity and recruitment to the tumor site
- NK cell recognition and lysis of tumor cells upon downregulation of HLA-1 on tumor cells, a known mechanism for resistance to checkpoint inhibitor therapy