A Phase I Study of FT819, a First-of-Kind, Off-the-Shelf, iPSC‑Derived TCR‑Less CD19 CAR T Cell Therapy for the Treatment of Relapsed/Refractory B-Cell Malignancies

Background: Autologous T cells engineered to express a chimeric antigen receptor (CAR) targeting the B-cell lineage antigen CD19 (CAR19) in patients with relapsed/refractory (r/r) aggressive B-cell lymphomas (BCL) and pre-B acute lymphoblastic leukemia (B-ALL) have resulted in transformative improvements in clinical outcomes. However, there remain significant limitations concerning autologous CAR19 T cell manufacturing, including dysfunctional starting material, lack of product consistency and purity following genetic engineering, manufacturing timelines that necessitate the administration of bridging therapy in patients with aggressive disease, and insufficient quantities of CAR19 T cells, especially in severely cytopenic patients, to allow for more than single‑dose administration routinely. The ability to consistently administer more than a single dose of CAR19 T cells enables dosing schedules that may reduce the risk of potentially life-threatening toxicities such as cytokine release syndrome and neurotoxicity, while maintaining or improving the depth and durability of anti-tumor responses.

FT819 is a first-of-kind, off-the-shelf CAR19 T cell product candidate derived from a clonal master engineered induced pluripotent stem cell (iPSC) line, which can be used as a renewable source for the mass production of off-the-shelf CAR T cells for broad patient access. FT819 is engineered with the following features designed to improve the safety and efficacy of CAR 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 CAR transgene directly into the T cell receptor alpha constant (TRAC) locus, which has been shown to promote uniform CAR expression and enhanced T cell potency; and complete bi-allelic disruption of T cell receptor (TCR) expression for the prevention of graft-versus-host disease (GVHD). FT819 has demonstrated antigen-specific cytolytic activity in vitro against CD19-expressing leukemia and lymphoma cell lines comparable to that of donor-derived CAR T cells, and persists and maintains tumor clearance in the bone marrow in an in vivo disseminated xenograft model of lymphoblastic leukemia (Mandal et al. 2020). The properties of FT819 and its ability to improve outcomes of patients with B-cell malignancies warrants further clinical investigation.

Study Design and Methods: This study is a multicenter, Phase I clinical trial of FT819 in patients with r/r B-cell malignancies, including BCL, chronic lymphocytic leukemia (CLL), and B-ALL. The primary objective of the trial is to determine the recommended Phase II dose of FT819. Key secondary objectives include evaluation of FT819 safety and tolerability, anti-tumor activity, and pharmacokinetics (PK). Exploratory objectives include characterization of FT819 pharmacodynamics as assessed by peripheral blood biomarkers, and by phenotypic and genetic characterization of the tumor microenvironment from paired pre- and post-treatment tumor biopsies.

The dose‑escalation part of the trial utilizes a 3+3 dose‑escalation design to identify the maximum tolerated dose for BCL, CLL, and B-ALL. The dose‑expansion part of the trial is designed to further characterize the safety, efficacy, and PK of FT819 in multiple indications. Up to a maximum of 300 patients will be enrolled. The trial will test up to four FT819 dose levels ranging from 30 to 900 million cells. Three FT819 dosing regimens each will be tested for BCL, CLL, and B-ALL: Regimen A, FT819 administered as a single dose; Regimen A1, FT819 administered as a single dose in combination with interleukin (IL)-2; and Regimen B, FT819 administered as fractionated doses on Days 1, 3, and 5. Lympho-conditioning will consist of three consecutive days of fludarabine and cyclophosphamide administered prior to the first dose of FT819. Key inclusion criteria include r/r disease after standard approved therapies, documented CD19 expression, and adequate organ function. Key exclusion criteria include ongoing immunosuppression such as systemic GVHD therapy, prior allograft organ transplant, active central nervous system involvement of disease, and known allergy to FT819 components. The trial is expected to begin patient recruitment in 2020.