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 (CMD-501) and allogeneic (CMD-502 and CMD-503) products.

CAR-NKT cells

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
NKT Cells are a Distinct Lymphocyte Subset
Advantages of Off-the-Shelf CAR-NKT Cells Over CAR-T Cells
CAR-NKT Cells are Uniquely Positioned for Off-The-Shelf Therapy of Solid Tumors

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
Preclinical Data Suggest That NKT Cells Do Not Cause GvHD
  • 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.

Engineering CAR-NKT Cells to Improve Their Anti-Tumor Activity and Persistence

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

CAR-NKT cell constructs will include a humanized scFv

  • Diminish antigenicity and improve persistence
  • Generated through our proprietary PENTRA™ Body technology
IL-15 Improves Expansion and Persistence of CAR-NKT Cells
  • 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
CAR-NKT Cells Engineered with IL-15 Have Greater Persistence and Correlates with Improved Anti-tumor Efficacy