Multiple myeloma is a hematologic malignancy characterized by the proliferation of malignant plasma cells. In multiple myeloma, malignant plasma cells accumulate in the bone marrow and produce abnormal antibodies called M proteins, which can cause kidney damage, bone destruction, and impaired immune function. While multiple approved drugs with novel mechanisms have improved disease management over the past decade, multiple myeloma is rarely curable and a significant number of patients are expected to relapse. One such approved drug, daratumumab, is an IgG1 monoclonal antibody targeting CD38, which is overexpressed in multiple myeloma cells and induces cell death through multiple mechanisms, including ADCC. However, because CD38 is also expressed on the surface of activated NK cells, daratumumab treatment can induce NK cell fratricide, which may impair the effectiveness of ADCC-mediated targeting and the destruction of multiple myeloma cells. In addition, NK cell function is often suppressed or absent in patients with multiple myeloma as a result of the cancer itself and/or from cancer therapy, further reducing the effectiveness of daratumumab. Collectively, preclinical and clinical observations suggest a potential therapeutic benefit of maintaining NK cell numbers and function in patients to support daratumumab-mediated ADCC.
We are developing FT538, an investigational, universal, off-the-shelf NK cell cancer immunotherapy derived from a clonal master iPSC line. FT538 incorporates three functional modifications: a novel high-affinity 158V, non-cleavable CD16 (hnCD16) Fc receptor, which has been modified to augment ADCC; an IL-15 receptor fusion (IL-15RF) that promotes enhanced NK cell activity; and the elimination of CD38 expression to mitigate the potential for NK cell fratricide. Together, these features are intended to augment ADCC, enhance cell persistence and prevent anti-CD38 monoclonal antibody-induced fratricide, thereby improving outcomes for patients with multiple myeloma.
FT538 is being investigated in an open-label, multi-dose Phase 1 clinical trial as a monotherapy for the treatment of acute myeloid leukemia and in combination with CD38-directed monoclonal antibody therapy and with SLAMF7-directed monoclonal antibody therapy for the treatment of multiple myeloma.
2019 ASH Abstract
FT538: Preclinical Development of an Off-the-Shelf Adoptive NK Cell Immunotherapy with Targeted Disruption of CD38 to Prevent Anti-CD38 Antibody-Mediated Fratricide and Enhance ADCC in Multiple Myeloma When Combined with Daratumumab