CS-1 Is Expressed in Nasal Type NK/T Cell Lymphomas and Angioimmunoblastic T-Cell Lymphomas: Implications for Targeted Therapy with Elotuzumab (HuLuc63).

Background: CS-1 (CRACC, SLAMF7, CD319) is a member of the signaling lymphocyte activating molecule-related receptor family. It is highly and uniformly expressed on the cell surface of benign and malignant plasma cells. We have recently reported the generation of elotuzumab (formerly known as HuLuc63), a humanized antibody targeting CS-1, which is currently in phase 1 trials in relapsed multiple myeloma. Lower levels of CS-1 have also been reported on NK cells and NK-like T-cells (NK/T). CS-1 expression in NK and T-cell lymphomas - aggressive lymphomas for which no effective therapy exists - is unknown. Here, we examined the expression of CS-1 in normal NK/T cells and in a series of NK and peripheral T-cell lymphomas (PTCL).

Methods: CS-1 expression in normal NK and T-cells were assessed by gene expression profiling. Flow cytometry (FACSCalibur, Becton Dickinson) was performed on blood from normal samples using a directly conjugated Alexa-488 elotuzumab. Archival formalin-fixed, paraffin-embedded tissues from PTCLs, including angioimmunoblastic T-cell lymphomas (AITL) and nasal type NK/T cell lymphomas were tested for CS-1 expression using the a paraffin-reactive 1G9 monoclonal antibody and automated immunohistochemistry (IHC, Ventana Medical Systems).

Results: Gene expression profiling showed CS-1 expression in purified NK and NK/T cells. We confirmed cell surface expression of CS-1 protein on normal blood NK and NK/T cells (n=18 samples) by flow cytometry with Alexa-488-HuLuc63. The majority of normal NK and NK/T cells expressed CS-1 (mean% positive and standard deviation of 96% +/− 4% and 71 % +/− 24%, respectively). We then evaluated tumor samples from patients with nasal type NK/T cell lymphoma as well as other peripheral T-cell lymphomas by IHC. Biopsies from 13 patients (5 from the United States, 8 from Korea) with nasal type NK/T cell lymphomas were evaluated by IHC. 12 of 13 (92%) patient samples expressed CS-1 with most cases showing a majority of cells positive. 46 PTCLs were also evaluated (including 9 AITL). Overall, 8/46 (17%) of the PTCL cases expressed CS-1. However, of the AITLs, 4 of 9 (44%) expressed CS-1.

Conclusions: CS-1 is expressed on nearly all nasal type NK/T cell lymphomas and in a substantial proportion of AITLs. These results provide the rationale for exploring elotuzumab in the targeted treatment of NK/T-cell malignancies.