General MM

Success for SLAMF7-directed CAR T-cells: MM-specific pre-clinical study

Chimeric Antigen Receptor (CAR) T-cells hold promise as a future treatment option for Multiple Myeloma (MM). To read more about CAR T-cells see our MM Hub article: Original Review: Driving forward with CAR-T Therapy - what does this mean for MM? One of the biggest factors in the success of a given CAR T-cell is whether the target antigen is specific and has limited off-target effects. One of the targets under investigation is SLAMF7 (signaling lymphocytic activation molecule), also known as CD319, CS-1 and CRACC. SLAMF7 has a receptor tyrosine switch motif (ITSM), through which it modulates the function of immune cells. It is expressed on pro-B cells and plasma cells, and high expression is retained on malignant plasma cells, as well as the precursor states of monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SM). This expression is also retained following intensive therapy, and importantly expression appears to be limited to hematological cells only.

A SLAMF7-CAR construct has been developed by Tea Gogishvili and Sophia Danhof, led by Michael Hudecek, and in collaboration with Hermann Einsele, all from the University of Wurzburg, Germany,  and the findings from their initial pre-clinical study to test the resulting CAR T-cells were published in Blood on 1st November 2017.

Key Highlights:
  • CAR-T construct: lentiviral vector containing a targeting domain derived from the monoclonal antibody targeting SLAM7, huLuc63 (elotuzumab), fused to an IgG4-Fc Hinge-CH2-CH3 spacer (with 4/2NQ modification to prevent binding of Fc-receptors), a CD28/CD3zeta signaling module in cis with a T2A element and truncated epidermal growth factor receptor (EGFRt)
  • SLAMF7 CAR T-cells were successfully prepared using CD4+ and CD8+ T-cells from 7 myeloma patients (pts) and four healthy donors with the following activity functional activity:
    • Effective anti-myeloma activity was observed in vitro, using SLAMF7 myeloma cell lines (MM.1S, OPM2, NCI-H929 and K-562 transduced with SLAMF7); 80% and 90% lysis was observed after 4hrs and 20hrs, respectively (for CD8+ CAR T-cells), as well as productive proliferation
    • Near complete cytolysis of primary CD38+/CD138+ malignant plasma cells isolated from either newly diagnosed (ND) MM patients (n=3) or Relapsed/Refractory (RR) MM patients (n=4) within 4 hrs; no differences observed between NDMM and RRMM
    • Systemic myeloma was eradicated in a xenograft mouse model; complete elimination of the MM.1S bioluminescent cells was observed along with survival of all 8 mice
  • Co-culture experiments with CD8+/SLAMF7 CAR T-cells and cells from the ‘normal’ lymphocyte compartment (T-cells, NK-cells and B-cells) indicated selective fratricide of SLAMF7+/high cells, leaving a viable and functional SLAMF7-/low cell subset

This well-designed pre-clinical study reveals highly promising data for the SLAMF7 CAR-T construct developed with the aim of targeting MM. The resultant SLAMF7 CAR T-cells were highly functional against cell lines, patient cells and in a xenograft model. In addition, whilst they led to some degree of depletion of the normal lymphocyte compartment, selective fratricide of only a fraction of normal cells was observed, leaving a functional immune compartment with efficient anti-viral capacity. We eagerly await this construct entering into early phase clinical trials.

 
References
  1. Gogishvili T., Danhof S. et al. SLAMF7-CAR T-cells eliminate myeloma and confer selective fratricide of SLAMF7+ normal lymphocytes. Blood. 2017 Oct 31. pii: blood-2017-04-778423. DOI:10.1182/blood-2017-04-778423
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