Evaluating NKp30-Directed Bispecific NK Cell Engagers for Multiple Myeloma Therapy

Description

Immunotherapy with monoclonal antibodies and their use in combination with proteasome inhibitors and immunomodulatory agents have revolutionized treatment of multiple myeloma (MM). Chimeric antigen receptor (CAR) T cells and bispecific T cell engagers (TCE) further improved the outcome of a substantial number of patients. Nevertheless, for relapsed/refractory myeloma (RRMM) patients there is still a high unmet medical need for new treatment options. Especially in later lines of therapy, the sequential use of CAR T cells and TCEs is often suboptimal and the engagement of other immune cells might be a chance to circumvent T cell exhaustion and improve therapy. Natural killer (NK) cells are key elements of the innate immune system and play a crucial role in immune surveillance. Their activity is tightly regulated through the interaction of various inhibitory and activating receptors like the Fc γ receptor IIIa (FcγRIIIa), NKp30, NKp46 or Natural Killer Group 2D. During cancer progression, tumor cells evade NK cell immune surveillance by downregulating the expression or proteolytically cleaving the ligands for activating receptors. NK cell engagers (NKCEs) that bind an activating receptor on the NK cells and a tumor-associated antigen (TAA) might have potential as new immunotherapeutics for MM treatment. Therefore, we designed and characterized new bispecific NKCE that activate NKp30. These NKCE harbor an Fc region to extend their half-life in vivo and either carry a silent or an active Fc to allow for additional effects through binding to FcγR. Functional in vitro and in vivo testing using also myeloma cells of RRMM patients will help to unravel the potential of our novel NKCEs especially after T cell-based treatments. Furthermore, we aim to analyze the impact of different treatments on the expression of activating NK cell receptors on patients’ NK cells and of TAA on patients’ myeloma cells.
Our overarching aim is to identify novel NK cell-based therapeutic options, which can complement the existing therapies and help to further improve myeloma patients’ outcome.