Technology

Technology

We are developing an approach for human natural killer (NK) cell immunotherapy that involves an off-the-shelf CAR NK cell that enables the cell to recognize specific proteins or antigens that are present on the surface of tumor cells. Our NK cell engineering platform builds on Drs. Caligiuri’s and Yu’s 54 years of collective laboratory investigation of NK cells, their treatment of over 1,000 patients with therapies modulating NK cells in man, and their prior success in engineering T cells.

Our current platform includes proprietary technologies that enable us to (1) generate an abundant supply of potent human CAR NK cells to treat multiple patients from a single umbilical cord blood product, (2) highly effective transduction efficiency of the CAR into the human NK cells, (3) improved the persistence of these CAR NK cells for sustained activity once infused into the body, (4) an ability to freeze, store and thaw our engineered NK cells for infusion into unmatched cancer patient recipients for an off-the-shelf treatment of cancer.

As noted above, each of our CAR NK cell product candidates are designed to be allogeneic, meaning in this case that they are produced from the umbilical cord blood of an unrelated donor and can be expanded, frozen, shipped and subsequently infused into any cancer patient without delay resulting from autologous collection or collection from an HLA-matched related or unrelated donor as currently occurs in approved therapies.

The first (and only) published study on the clinical use of CAR NK cells in cancer patients was recently performed at MD Anderson Cancer Center. In that study partially HLA-matched and unmatched CAR NK cells were infused into 11 patients with minimal toxicities and some impressive anti-tumor responses. We believe that engineered CAR NK cells can be well tolerated and avoid the most serious toxicities sometimes observed in patients treated with autologous or HLA-matched CAR T cell therapies. Collectively, these four advances should substantially lower the cost and availability of these therapies for cancer patients.

The Opportunity for Engineered NK Cells in Treating Cancer

The development of chimeric antigen receptor (CAR) NK 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.

We are developing an approach for human natural killer (NK) cell immunotherapy that involves an off-the-shelf CAR NK cell that enables the cell to recognize specific proteins or antigens that are present on the surface of tumor cells. Our NK cell engineering platform builds on Drs. Caligiuri’s and Yu’s 55 years of collective laboratory investigation of NK cells, their treatment of over 1,000 patients with therapies modulating NK cells in man, and their prior success in engineering T cells.

Our current platform includes proprietary technologies that enable us to: (1) generate an abundant supply of potent human CAR NK cells to treat multiple patients from a single umbilical cord blood product, (2) highly effective proprietary transduction efficiency of the CAR into the human NK cells, (3) improve the persistence of these CAR NK cells for sustained activity once infused into the body, (4) an ability to freeze, store and thaw our CAR NK cells for infusion into HLA-unmatched cancer patient recipients for an off-the-shelf treatment of cancer.

As noted above, each of our CAR NK cell product candidates are designed to be allogeneic, meaning in this case that they are produced from the umbilical cord blood of an unrelated donor and can be expanded, frozen, shipped and subsequently infused into any cancer patient without delay that typically results from autologous collection or collection from an HLA-matched related or unrelated donor as currently occurs in approved therapies.

The first (and only) published study on the clinical use of CAR NK cells in cancer patients was recently performed at MD Anderson Cancer Center. In that study partially HLA-matched and unmatched CAR NK cells were infused into 11 cancer patients with minimal toxicities and some impressive anti-tumor responses. We believe that engineered CAR NK cells can be well tolerated and avoid the most serious toxicities sometimes observed in patients treated with autologous or HLA-matched CAR T cell therapies. Collectively, these advances should substantially lower the cost and increase the availability of these therapies for cancer patients.

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.