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Introduction: Autologous chimeric antigen receptor (CAR) T cells targeting CD19 (CAR19) have been shown to provide significant clinical benefit for patients with relapsed/refractory (R/R) B-cell lymphomas (BCLs), chronic lymphocytic leukemia (CLL), and B-cell acute lymphoblastic leukemia (B-ALL). However, significant barriers remain to their broad application, including dysfunctional starting material, risk of manufacturing failure, lack of product consistency and purity following genetic engineering, and manufacturing delays necessitating the administration of bridging therapy in patients with aggressive disease. Clonal master engineered induced pluripotent stem cell (iPSC) lines can serve as a renewable source for the mass production of immune effector cells, and offer distinct advantages over existing patient- and donor-derived therapeutic approaches, notably off-the-shelf availability enabling on-demand administration and broad patient access. FT819 is the first-ever, iPSC-derived CAR T-cell product candidate. FT819 incorporates the following features designed to improve the safety and efficacy of CAR19 T-cell therapy: a novel 1XX CAR-signaling domain, which has been shown to extend T-cell effector function without eliciting exhaustion; integration of the CAR19 transgene directly into the T-cell receptor alpha constant (TRAC) locus, which has been shown to promote uniform CAR19 expression and enhanced T-cell potency (Feucht et al. 2019); and complete bi-allelic disruption of T-cell receptor (TCR) expression for the prevention of graft-versus-host disease. FT819 exhibits antigen-specific cytolytic activity in vitro against CD19+ leukemia and lymphoma cell lines comparable to that of primary CAR T cells, and persists and maintains tumor clearance in the bone marrow in an in vivo disseminated xenograft model of B-ALL (Valamehr et al. 2020). Methods: This multicenter Phase I study, the first-ever clinical trial of an iPSC-derived CAR T-cell product candidate, is assessing FT819 in patients with R/R BCL, CLL, and B-ALL. Primary objectives of the trial are to assess safety and tolerability and to determine the recommended Phase II dose of FT819. Key secondary objectives include anti-tumor activity and pharmacokinetics. Three FT819 dosing regimens are being assessed in each indication (BCL, CLL, and B-ALL): FT819 administered as a single dose (Regimen A); FT819 administered as a single dose in combination with IL-2 (Regimen A1); and FT819 administered as step-fractionated doses on Days 1, 3, and 5 (Regimen B). FT819 dose levels starting at 90 million cells per treatment cycle are being evaluated. Conditioning chemotherapy consists of 3 consecutive days of fludarabine (30 mg/m2) and cyclophosphamide (500 mg/m2) prior to the first dose of FT819. Key inclusion criteria include R/R disease after at least 2 prior lines of therapies and documented CD19 expression; prior CAR19 therapy is allowed. Results: As of a data cutoff date of 25 June 2022, 12 patients with R/R BCL were treated and evaluable for safety in the first 2 dose levels of Regimen A (90 million cells and 180 million cells; n = 9) and in the first dose level of Regimen B (3 doses at 30 million cells/dose; n = 3). No dose-limiting toxicities, immune effector cell-associated neurotoxicity syndrome (ICANS), graft-versus-host disease (GvHD), or FT819-related Grade ≥3 serious adverse events were observed. Cytokine release syndrome (CRS) events were reported in 3 patients, all of which were Grade ≤2. Conclusions: FT819 is the first-ever, off-the-shelf, iPSC-derived CAR T-cell therapy to be tested in clinical trials. The ongoing Phase I study is designed to assess multiple dosing regimens across a broad range of B-cell malignancies. Interim clinical data, including safety, tolerability, and initial anti-tumor activity from the ongoing Phase I dose-escalation study of FT819, will be presented at the conference. References: Feucht J, Sun J, Eyquem J, et al. Calibration of CAR activation potential directs alternative T cell fates and therapeutic potency. Nat Med. 2019;2582-2588. Valamehr B, Clarke R, van der Stegen et al. FT819 Path to IND: First-of-kind off-the-shelf CAR19 T-cell for B-cell malignancies. Cancer Res. 2020;80(16_Supplement):3245.