Abstract 1550: 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.

Natural killer cells in antitumour adoptive cell immunotherapy

“…Ablation of endogenous receptors allows for combinatorial therapeutic approaches, such as by rendering immune cells resistant to corticosteroid-induced immunosuppression (panel e ), a principle previously established in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-directed cytotoxic T lymphocytes (CTLs) 281 . Knockout of CD38 (panel f ) renders NK cells resistant to CD38-mediated fratricide, which enables combination strategies of NK cells and anti-CD38-targeting monoclonal antibodies in the context of treating multiple myeloma 50 . B reg cell, regulatory B cell; MDSC, myeloid-derived suppressor cell; NKG2A, CD94/NK group 2 member A receptor; TIGIT, T cell immunoreceptor with immunoglobulin and ITIM domains; T reg cell, regulatory T cell.…”

“…4b , e ), for instance, might lead to a multifaceted outcome: boosting CAR NK cell function, hindering signals from suppressive cells in the TME and supporting the function of other immune effector cells 197 – 199 . Lastly, engineering NK cells to become resistant to CD38-mediated fratricide will enable NK cell-based treatment approaches to be combined with anti-CD38 monoclonal antibodies and allow NK cell immunotherapy to move into earlier lines of treatment in the setting of multiple myeloma 50 (Fig. 4f ).…”

Therapeutic approaches to enhance natural killer cell cytotoxicity

“…For example, daratumumab, a mAb targeting CD38 is being tested in multiple myeloma (MM) in combination with FT576, a B cell maturation antigen (BCMA) specific CAR NK with high-affinity, non-cleavable CD16, and a knockout of CD38 (to prevent fratricide) (NCT05182073). In preclinical models, this dual-targeting approach exhibited superior tumor control compared to treatment with CAR T cells, FT576 alone, or daratumumab alone ( 132 ). Early clinical results highlight a lack of dose-limiting toxicities, cytokine release syndrome, neurotoxicity, or GvHD ( 133 ).…”

Multiplexed engineering and precision gene editing in cellular immunotherapy

“…(D) Building on the clinical success of immune checkpoint blockade, efforts are underway to genetically disrupt known negative regulators of immune cell function including, for instance, PD-1, TIGIT and NKG2A as well as TME-sensing receptors which bind immunosuppressive metabolites including adenosine and TGFβ ( 40 – 56 ). (E, F) Deletion of lineage-specific antigens or endogenous receptors may render engineered immune cells resistant to fratricidal killing, which is crucially important when targeting malignancies with an overlapping surfaceome ( 57 , 58 ). For allogeneic CAR-T cells in particular, elimination of the endogenous T cell receptor (TCR) prevents the deleterious effects of alloreactivity and GvHD induction and site-directed engineering strategies now accomplish both simultaneously - deletion of the endogenous TRAC locus and CAR delivery ( 59 , 60 ).…”