General MM

EBMT 2018 | CD229 is a promising target for MM

The MM Hub were delighted to attend the 44th Annual Meeting of the European Society for Blood and Marrow Transplantation held in Lisbon, Portugal, from 18–21 March 2018. On Monday 19 March 2018 the oral abstract session 2 was held entitled: New drugs and novel cell therapies. The session was moderated by Yngvar Floisand, from the Department of Hematology, Oslo University Hospital, Rikshospitalet, Oslo, Norway and Ahmet Elmaagacli, from the Department of Bone Marrow Transplantation, West German Cancer Center, University Hospital of Essen, Essen, Germany.

The fourth talk in this session was presented by Djordje Atanackovic, from the Huntsman Cancer Institute, the University of Utah, Salt Lake City, Utah, who spoke about CD229 CAR T-cells as an effective treatment for MM. CD229 is a member of the family of signaling lymphocytic activation molecules (SLAM) and is also known as Ly9 or SLAMF3. The key findings of this study are summarized below.

Key findings:
  • CD229 was found to be highly expressed on MM cells from patients and, similar to BCMA, is only expressed in mature plasma cells (PCs), but not on precursor, transitional, and memory B cells
  • Expression is limited to B cells, with some expression on Natural Killer (NK) cells and T cells
  • Phage display was used to generate 23 high-affinity, fully humanized antibodies against CD229
  • Of these 23 clones, 15 showed strong surface expression and antigen binding as CAR constructs
  • None of the clones bound to other SLAM receptors
  • Selection of 2D3 as a lead candidate:
    • Low nanomolar affinity to CD229
    • High CAR surface expression
    • High CAR surface stability (when expressed as a soluble scFv or scFv-Fc)
  • Manufacture of CD229 CAR T-cells based on 2D3
  • Similar in-vitro expansion of CD229-CAR T cells and lack of sustained upregulation of PD-1 was observed in comparison with CD19-specific CAR T-cells
  • In-vitro experiments showed:
    • Previously activated T cells with CD3/CD28 beads are protected against CD229 CAR T-cell killing
    • CD229 CAR T-cells did not kill CD34+ hematopoietic stem cells or NK cells
    • CD229 CAR T-cells efficiently and specifically killed MM cell lines at minimal effector target ratios
  • In-vivo experiments showed:
    • A significant delay in MM progression in mice treated with 1 x 106 CD229 CAR T-cells in comparison with mice treated with CAR T-cells lacking a binding domain (StopX)
    • Complete eradication of MM in animals treated with 3 x 106 CAR T-cells
    • No antigen loss variants emerged
    • Limited activity against normal lymphocytes due to downregulation of CD229

CD229 CAR T-cells were successfully generated and shown to be highly effective against MM, both in-vitro and in-vivo, with limited killing of non-tumor cells. The lack of emergence of antigen loss variants post CAR T-cell treatment is also reassuring. It will be interesting to follow the progress of this construct as it is further developed for possible patient use.

References
  1. Atanackovic Det al. CD229 CAR T cells are an effective treatment for multiple myeloma. #Abstract OS2-4. 44th Annual Meeting of the European Society for Blood and Marrow Transplantation, Lisbon, Portugal.