CAR-NKT
We are developing a wide range of CAR-NKT cell products to treat cancers with significant unmet needs. The CAR-NKT cell product candidates include both autologous (KUR-501) and allogeneic (KUR-502 and KUR-503) products.
Type 1 NKT or iNKT cells are innate-like T lymphocytes that reside preferentially in tissues, including the liver and bone marrow. They express a semi-invariant T cell receptor (TCR) that recognizes glycolipid antigens presented by the non-polymorphic MHC class I-like molecule CD1d. Evidence from pre-clinical studies suggests that iNKT cells do not mediate graft-versus-host-disease (GVHD) making them an ideal candidate for off-the-shelf CAR-therapy. In addition to this differentiated cellular biology, we have engineered the innovative CAR construct to:
- Secrete IL-15 to improve their activation, persistence and anti-tumor activity
- Down-regulate MCH class I and II to diminish their alloreactivity and improve persistence in allogeneic recipients
Unique platform for off-the-shelf cell products
- Express an invariant T cell receptor (TCR) that recognizes glycolipids presented by CD1d and does not mediate GvHD
- No TCR gene editing is required
Reside preferentially in tissues and home to tumor sites
- Presence of NKT cells in solid tumors correlates with favorable prognosis
Engage both tumor and immuno-suppressive myeloid cells
- Kills tumor cells through CAR engagement
- Kills or reprograms M2-macrophages and MDSCs through invariant TCR engagement
- Kills CD1d positive tumors (B cell/myeloid origin) through invariant TCR engagement
Homogeneously expanded and manufactured in high numbers
- Invariant TCR facilitates expansion in the presence of glycolipid
- T cells or NKT cells from a same human donor transfected with the identical CAR
- Injected into tumor-bearing hu-NSG mice; analysed after 4-5 weeks for xeno-GvHD
A. Heczey et al, Blood, 2014; 124:2824-33.
Engineered to secrete IL-15:
- Improves activation under hypoxic conditions
- Enhances persistence and anti tumor activity in vivo
shRNAs to down-regulate class I and II MHC
- Reduces recognition by the patients’ immune system
- Maintaining low level MHC class I prevents elimination by the patient’s NK cells
- Decreased immunogenicity improves persistence
- The image panels show luciferase-labeled NKT cells administered to tumor-bearing mice
- The bright red imaging indicates higher numbers of NKT cells, which demonstrates stronger expansion and persistence
- The CAR-NKT cells engineered to express IL-15 show the highest expansion and persistence
