The development of CAR NK cell therapies can capitalize on the knowledge and experience gained from decades of CAR T research. Furthermore, the inherent biology of NK cells offers a number of potential advantages as the starting cell type for allogeneic, off-the-shelf engineered cell therapy. These advantages include:
Inherent anticancer activity. In a systematic literature review of published clinical trial results of allogeneic NK cells in cancer, a 34% response rate was observed amongst 103 patients with relapsed or refractory acute myeloid leukemia (AML) that were treated with non-engineered NK cells across six academic clinical studies. These data demonstrate the inherent anticancer activity of the body’s NK cells, and support the opportunity for increasing the activity of NK cells through the addition of a CAR that specifically targets the tumor, and secretory IL-15 that sustains NK cell survival in the body.
Allogeneic and off-the-shelf without gene editing. Unlike T cells NK cells are not generally activated following an encounter with “non-self” cells. Thus, further modification of NK cells via gene editing is not necessary to avoid the risk of a potentially serious toxicity sometimes found with allogeneic T cell therapies called “graft-versus-host” disease. This could allow for a potentially safer allogeneic, off-the-shelf engineered NK cell therapy.
Modest clonal expansion lowers the risk for cytokine release syndrome (CRS). While T cells can undergo exponential growth when activated by a matching target antigen in the body, NK cells expand only modestly. The explosive growth of T cells is believed to be the basis of the risk of a serious toxicity known as CRS following CAR T cell therapy. However, a significant incidence of CRS has not been reported in the medical literature for NK cell therapy.
Balance of “on” and “off” switches. The activity of NK cells is tightly regulated by a common set of activating receptors that serve to recognize and kill cancerous or virally infected cells, as well as a set of inhibitory receptors that prevent death of healthy cells from the same individual. Thus, the fundamental biology of NK cells enhances their ability to discriminate between tumor cells and healthy cells.
Ability to overcome tumor evasion of the immune system. In addition to expressing a CAR that is inserted into the NK cell, NK cells already have “built in” receptors that recognize tumors. All NK cells express a receptor called NKG2D, and that NK receptor recognizes a set of molecules commonly expressed on solid tumors such as lung cancer and pancreatic cancer. Thus, CAR NK cells have at least two different receptors on their surface to combat the tumor and better prevent the tumor from escaping recognition and destruction by the NK cell. In addition, activated NK cells express a molecule called PD-L1 which, when exposed to an FDA-approved antibody called atezolizumab, the NK cell is further activated to kill tumors more efficiently. Thus, there are multiple avenues to harness and even boost the NK cell’s anti-tumor activity.
Platform and Programs
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CytoImmune Operates a Fully Integrated CAR-NK Manufacturing Facility
In-house Manufacturing in Puerto Rico
- 37,000 ft2 cGMP production footprint in Toa Baja Puerto Rico
- Cell and virus manufacturing in PR
- Locked-in cord blood supply
- Capacity adequate for all planned trials
- Team of 40+ employees in manufacturing; 50%+ relocated from mainland
- First GMP lots completed in 1H2022