CAR-NKT

We are developing a wide range of CAR-NKT cell products to treat different types of highly prevalent tumors. The CAR-NKT cell product candidates include both autologous (CMD-501) and allogeneic (CMD-502, CMD-503, CMD-504 and CMD-505) products.

CAR-NKT cells

iNKT cells or type 1 NKT cells are innate-like T lymphocytes that reside preferentially in tissues, including the 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 suggest 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
Autologous CAR-T Cell Challenges
  • Long time required for manufacturing
  • Product-to-product variability due to patient factors
  • Limited success in solid tumours
Cell Medica Off-the-Shelf CAR-NKT Cell Solution
  • Off-the-shelf therapies immediately available
  • Large number of uniform doses manufactured from a single donor
  • NKT cells naturally home to tissues
  • NKT cells modulate immuno-suppressive cells
Allogeneic CAR-T Cell Challenges
  • CAR-T cells cause GvHD
  • Uncertain persistence
Cell Medica Off-the-Shelf CAR-NKT Cell Solution
  • NKT cells do not mediate GvHD
  • Fully functional TCR and no TCR gene editing required
  • Engineered to secrete IL-15 to prolong persistence
  • MHC knock down reduces immunogenicity
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 aGalCer
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 invivo

shRNAs to down-regulate class I and II MHC

  • Reduces recognition by the patients’ T cells
  • Maintaining low level MHC class I prevents elimination by the patient’s NK cells
  • Decreased immunogenicity improves persistence

Future 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
Higher Persistence of CAR-NKT Cells Engineered with IL-15 Correlates with Improved Anti-tumor Efficacy
Allogeneic

We are developing an off-the-shelf CD19 targeted allogeneic CAR-NKT product for the treatment of relapsed, refractory CD19-positive malignancy.

CMD-502: Off-the-Shelf CAR-NKT in relapsed or refractory CD19+ malignancies
CMD-502 CAR-NKT Therapy
  • Allogenic CAR-NKT cells targeting CD19
  • Cell engineering to:
    • Express IL-15 to improve persistence and efficacy
    • Down-regulate MHC modules and diminish allo-reacitvity
CD19 Biology and Tumor Expression
  • Clinically validated target expressed on B cells and related malignancies
  • On target tissue tumor toxicity limited to B cell aplasia
Unmet Medical Need
  • Autologous CAR-T products have complicated logistics which can lead to treatment delays
  • Bridging chemotherapy required during product manufacturing
  • Autologous CAR-T product quality can be highly variable
Clinical Development Plan
  • First patient expected to be treated in Phase 1 trial in 2H 2019
  • Evaluating safety, cell expansion and initial signs of therapeutic activity
Autologous

We are developing a GD2-CAR NKT autologous product (CMD-501) for the treatment of neuroblastoma and small cell lung cancer. A first-in-human study is underway at Baylor College of Medicine (BCM) at Texas Children’s Hospital in Houston, TX

CMD-501: Autologous CAR-NKT in relapsed or refractory High Risk GD2+ Neuroblastoma
CMD-501 CAR-NKT Therapy
  • Autologous CAR-NKT cells targeting GD2
  • Cells engineered to express IL-15 to improve persistence and efficacy
GD2 Biology and Tumor Expression
  • Clinically validated target widely expressed on neuroblastoma cells
  • Limited expression on normal tissue
Unmet Medical Need
  • Neuroblastoma causes almost 15% of childhood cancer related deaths
  • Over half of all children with neuroblastoma have high risk disease
  • No standard therapy for patients with R/R high risk neuroblastoma
  • R/R high risk disease patients have a poor prognosis
    • Median survival of 1-3 years
Clinical Development Plan
  • First patient treated in Baylor College of Medicine sponsored Phase 1 trial in Aug 2018
  • Preclinical evaluation in SCLC, malignant melanoma & other indications
Other targets

Our goal is to expand the off-the-shelf allogeneic CAR NKT platform to treat a wide range of tumor types including both solid and liquid tumors. These includes programs to CAR-NKT cell products to treat liver cancer (CMD-503), triple negative breast cancer (CMD-504), and multiple myeloma (CMD-505). All these programs are currently in pre-clinical development

Additional Allogeneic CAR-NKT Cell Programs
Product Name Target Tumors Target Antigen Upcoming Milestone
CMD-503 Liver cancer, lung cancer, gastric cancer & others GPC3 Preclinical POC 2H 2019
CMD-504 Triple negative breast cancer, glioblastoma & others CSPG4 Preclinical POC 2H 2020
CMD-505 Multiple myeloma BCMA Preclinical POC 2H 2020