Ft576 Path To First-Of-Kind Clinical Trial: Translation Of A Versatile Multi-Antigen Specific Off-The-Shelf Nk Cell For Treatment Of Multiple Myeloma.

Abstract Chimeric antigen receptor (CAR) directed therapies have been used successfully to treat a variety of hematological malignancies. With the advent of multi-modal engineering, adoptive cell therapy offers the opportunity to tackle increasingly complex disease settings such as multiple myeloma (MM), where targeting of single tumor associated antigen by CAR or monoclonal antibodies (mAb) is confounded by antigen loss and clonal heterogeneity. Further, expanding treatment options beyond primary T and NK cell based therapies has multiple advantages, including the use of induced pluripotent stem cells (iPSC) to derive effector cells using precision genetic engineering that can be uniformly manufactured at scale from a clonally-derived master cell bank (MCB).FT576 is a multiplex-edited, iPSC-derived CAR-NK (CAR-iNK) cell therapy designed for treatment of Multiple Myeloma. FT576 is engineered 1) to express a recombinant IL-15/IL-15 receptor signaling complex (IL-15RF) for enhanced persistence; 2) to express an enhanced high-affinity, non-cleavable CD16 (hnCD16) ; 3) to disrupt expression of CD38, allowing for enhanced ADCC without NK cell fratricide; and 4) to express a BCMA-targeted CAR with NK-cell optimized signaling.CAR-directed specificity of the FT576 cells for BCMA was demonstrated using a short-term cytotoxicity assay (90.8% cytotoxicity against BCMA+ vs 22.1% BCMA- cells, p<0.0001). Utilizing a long-range tumor clearance assay without exogenous cytokine support, serial restimulation by repeated rounds of exposure to fresh MM target cells showed remarkable persistence and antigen-mediated expansion of FT576 by CAR alone or combined with anti-CD38 mAb. Continuous long-range clearance assays demonstrated levels of BCMA targeting activity of FT576 alone was equivalent to primary BCMA-targeted CAR-T cells against a panel of BCMA+ target cells. BCMA-CAR targeting was tested in combination with multiple therapeutic mAbs to explore breadth of tumor clearance in primary bone marrow samples.In xenograft models, dosing of FT576 as a monotherapy was highly protective against MM progression, resulting in deeper tumor regression and delayed outgrowth. The treatment of MM-bearing mice with both FT576 and daratumumab produced greater myeloma control than either agent alone, demonstrating combined CAR and antibody-directed cytotoxicity. Additionally, FT576 demonstrated enhanced persistence compared to peripheral blood NK cells, suggestive of antigen mediated expansion. Together, these studies demonstrate the versatility of FT576 as a highly effective multi-antigen targeting and cost-effective, off-the-shelf BCMA-CAR iNK cell product and support the rational for a first-of-kind Phase I Study of FT576 as a monotherapy or in combination with therapeutic mAbs targeted to MM-associated surface antigens. Citation Format: Jode P. Goodridge, Ryan Bjordahl, Sajid Mahmood, John Reiser, Svetlana Gaidarova, Robert Blum, Frank Cichocki, Hui-yi Chu, Greg Bonello, Tom Lee, Brian Groff, Miguel Meza, Thomas Daley, Yu-waye Chu, Bruce Walcheck, Karl-Johan Malmberg, Jeffrey S. Miller, Armin Rehm, Bahram Valamehr. FT576 path to first-of-kind clinical trial: translation of a versatile multi-antigen specific off-the-shelf NK cell for treatment of multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1550.