Abstract 2216: Combinational strategy targeting B cell malignancy using iPSC engineered CAR-NK (FT596) and CAR-T cell (FT819) platforms with therapeutic antibody to achieve an effective deep and durable response
Authors: Goodridge Jode P. , Reiser John W. , Bjordahl Ryan , Mandal Milli , Chang Chia-wei , Clarck Raedun , Mahmood Sajid , Zhu Huang , Gaidarova Svetlana , Blum Robert , Cichocki Frank , Hsu Hui-ting , Bonello Greg , Lee Tom , Groff Brian , Mamlberg Karl-Johan , Walcheck Bruce , Miller Jeffrey S. , Kaufman Dan , Valamehr Bahram 
Published: September 2020

Abstract
The use of induced pluripotent stem cells (iPSCs) to derive immune effector cells offers distinct advantages for immune therapy over existing patient- or donor- derived platforms, not only in terms of scalable manufacturing and precision genetic engineering at the clonal level, but also in allowing the generation and combinational use of multiple effector cell types each with distinct characteristics. Taking cues from the natural propagation of innate to adaptive effector responses, here we describe the combined use of multi-engineered iPSC derived Natural Killer (iNK) and T (iT) cell platforms in order to exploit the unique properties of each cell type to achieve both depth and durability of response for hematological malignancies. As innate cells, NK cells are characterized by the capacity for spontaneous reactivity, either in response to cell surface antigen or downregulation of class I MHC, and the rapid kinetic under which NK cells operate make them an ideal candidate to achieve a depth of response that outpaces the limiting effects of cytokine support. FT596 was developed as a dual-targeted iNK cell platform engineered to express both a CD19-directed, NK cell-optimized (NKG2D-2B4-CD3ζ) chimeric antigen receptor (CAR) and a high-affinity, non-cleavable Fc receptor (hnCD16), enabling multi-targeting through combination with therapeutic antibodies. The activity of each receptor is further enhanced by the expression of an IL15-IL15Ra fusion receptor, which also allows the cells to expand in the absence of exogenous cytokine support and prolongs cell survival in vitro and in vivo. T cells are exquisitely specific and undergo rapid clonal expansion and differentiation in response to target antigen, and antigen driven persistence has been demonstrated as a key determinant in efficacy in primary CAR-T cell immune therapy. FT819 is an iT cell platform engineered to express a functionally optimized CD19-CAR (1XX) that has been genome edited into the T cell receptor (TCR) alpha constant (TRAC) locus to provide ideal CAR activity and to prevent TCR expression, thereby avoiding the complications of GVH reactivity in an allogeneic setting. In vivo, both FT596 and FT819 showed stable levels of tumor cell clearance against the CD19+ acute lymphoblastic leukemia cell line NALM6, comparable to that of primary CAR19 T cells (p*&lt;0.0001 for FT596, FT819 or Primary CART vs NALM6 alone). FT596 also shows enhanced clearance of CD19+CD20+ Burkitts lymphoma cell line RAJI when used in combination with rituximab (p=0.0002 vs rituximab alone). Collectively, these studies suggest a compounded anti-tumor effect can be achieved utilizing the inherent properties of engineered CAR-iNK cells together with therapeutic antibody combined with engineered CAR-iT cells which will be highlighted in this presentation.
Citation Format: Jode P. Goodridge, John W. Reiser, Ryan Bjordahl, Milli Mandal, Chia-wei Chang, Raedun Clarck, Sajid Mahmood, Huang Zhu, Svetlana Gaidarova, Robert Blum, Frank Cichocki, Hui-ting Hsu, Greg Bonello, Tom Lee, Brian Groff, Karl-Johan Mamlberg, Bruce Walcheck, Jeffrey S. Miller, Dan Kaufman, Bahram Valamehr. Combinational strategy targeting B cell malignancy using iPSC engineered CAR-NK (FT596) and CAR-T cell (FT819) platforms with therapeutic antibody to achieve an effective deep and durable response [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2216.