On December 10, 2022 Fate Therapeutics, Inc. (NASDAQ: FATE), a clinical-stage biopharmaceutical company dedicated to the development of programmed cellular immunotherapies for patients with cancer, reported interim clinical data from the dose-escalation stage of its ongoing Phase 1 study of FT819 for patients with relapsed / refractory B-cell lymphoma (r/r BCL) at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition (Press release, Fate Therapeutics, DEC 10, 2022, View Source [SID1234625019]). The landmark trial is the first-ever clinical investigation of a T-cell product candidate manufactured from a clonal master induced pluripotent stem cell (iPSC) line, a renewable cell source that enables mass production of engineered T-cell therapies with greater product consistency, off-the-shelf availability, and broader patient accessibility. FT819 incorporates several first-of-kind features including the integration of a novel CD19-targeted 1XX chimeric antigen receptor (CAR) construct into the T-cell receptor alpha constant (TRAC) locus, which is intended to promote uniform CAR expression, enhance T-cell potency, and prevent graft-versus-host disease (Eyquem et al. Nature, 543, 113–117, 2017).

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"We are very excited about the early safety and efficacy data emerging from our groundbreaking clinical study of the first-ever iPSC-derived T-cell therapy. Data from the initial dose-escalation cohorts of a single dose of FT819 are indicative of a favorable safety profile and clearly demonstrate activity in heavily pre-treated patients with aggressive large B-cell lymphoma, including in patients that were not eligible for or had previously failed autologous CD19-targeted CAR T-cell therapy," said Scott Wolchko, President and Chief Executive Officer of Fate Therapeutics. "In addition to the rapid responses we observed with a single dose of FT819, the ability to quickly intervene upon the first signs of disease recurrence is a differentiating benefit of off-the-shelf cell therapy and we are also excited by the reinduction of objective response with the administration of a second cycle of FT819 to a patient following disease progression."

Interim Phase 1 Dose-escalation Efficacy Data
The multi-center Phase 1 clinical trial of FT819 is designed to assess its safety and clinical activity in adult patients with r/r BCL and to determine the recommended Phase 2 dose and schedule. As of the September 8, 2022 data cutoff date, 10 patients with aggressive large B-cell lymphoma have been treated with FT819, including 8 patients in Regimen A with a single dose of FT819 and 2 patients in Regimen B with three fractionated doses of FT819 on Days 1, 3, and 5. Patients received standard conditioning chemotherapy consisting of cyclophosphamide (Cy) at 500 mg/m2 and fludarabine (Flu) at 30 mg/m2 for 3 days prior to the initiation of each regimen. Patients were heavily pre-treated having received a median of 4 prior lines of therapy (range 3-7), including 7 of 10 patients (70%) having previously received autologous CD19-targeted CAR T-cell therapy.

In Regimen A, of the 8 patients with aggressive large B-cell lymphoma (median of 4.5 prior lines of therapy [range 3-7]) treated with a single dose of FT819 ranging from 90 million cells to 360 million cells (see Table 1):

1 of 2 patients naïve to CAR T-cell therapy achieved an objective response (1 CR) at Day 30, which was a complete response in a patient with diffuse large B-cell lymphoma (DLBCL) previously treated with 5 prior lines of therapy; and
2 of 6 patients previously treated with CAR T-cell therapy achieved an objective response (1 CR, 1 PR) at Day 30, which included a complete response in a patient with DLBCL previously treated with 7 prior lines of therapy who did not respond to autologous CD19-targeted CAR T-cell therapy.
In Regimen B, 2 patients with aggressive large B-cell lymphoma (each of whom received 3 prior lines of therapy) treated with three fractionated doses at 30 million cells per dose did not respond to therapy at Day 30.

Table 1: Aggressive Large B-cell Lymphoma 1,2,3
FT819 Regimen A: Single Dose (n=8)
CAR T-cell Therapy Naïve Prior CAR T-cell Therapy
Cells 90M 180M 360M 90M 180M 360M
N 1 n/a 1 4 1 1
OR / CR 0 / 0 n/a 1 / 1 2 / 1 0 / 0 0 / 0
FT819 Regimen B: Three Fractionated Doses (n=2)
CAR T-cell Therapy Naïve Prior CAR T-cell Therapy
Cells / Dose 30M 30M
N 1 1
OR / CR 0 / 0 0 / 0
OR = objective response; CR = complete response; M = million
1 As of data cutoff date of September 8, 2022
2 Includes diffuse large B-cell lymphoma (n=8) and high-grade B-cell lymphoma (n=2)
3 Day 30 protocol-defined response assessment per Lugano 2014 criteria
As of the September 8, 2022 data cutoff date, an additional 5 patients with r/r BCL have been treated with FT819. One patient with Grade 3a follicular lymphoma (with 5 prior lines of therapy, including CAR T-cell therapy) treated in Regimen A with a single dose of FT819 at 180 million cells achieved a complete response at Day 30. Four patients with Richter’s Transformation (median of 5.5 prior lines of therapy [range 2-9]) did not respond to therapy at Day 30.

Interim Phase 1 Dose-escalation Safety Data
No dose-limiting toxicities, and no Grade 3 or greater FT819-related adverse events (AEs) or serious AEs, were observed. Of the 15 patients treated in Regimens A and B, three patients (20%) experienced Grade 2 cytokine release syndrome (CRS) characterized by fever, hypotension, and hypoxia, which events resolved with single-dose tocilizumab and supportive care. No treatment-emergent AEs (TEAEs) of any grade of immune effector cell-associated neurotoxicity syndrome (ICANS) or graft-versus-host disease (GvHD) were reported by investigators. The FT819 treatment regimen was well tolerated. Grade 3 or greater TEAEs not related to FT819 primarily included hematologic cytopenias associated with conditioning chemotherapy. There were no study discontinuations or deaths due to TEAEs other than one patient with stable disease who died on Day 38 due to sepsis not considered related to FT819 by the study investigator.

FT819 Patient Case Study: Retreatment to Reinduce Response
The ASH (Free ASH Whitepaper) presentation featured a patient case study demonstrating the potential to safely administer more than one treatment cycle of FT819 and reinduce an objective response following disease progression. The 73 year-old female with DLBCL had previously been treated with 4 prior lines of therapy, including commercial autologous CD19-targeted CAR T-cell therapy with best response of PR, and was refractory to last prior therapy (investigational cord blood-derived NK cell therapy). The patient received a first treatment cycle with a single dose of FT819 at 90 million cells, achieving a PR at Day 30 with 94% reduction in size of target lesions. Continued follow-up through November 8, 2022 was significant for disease progression on Day 72, for which the patient received a second treatment cycle with a single dose of FT819 at 180 million cells on Day 134 with consent from the U.S. Food and Drug Administration and achieved a PR at Day 163 with 61% reduction in size of target lesions. Both treatment cycles were well tolerated with no Grade 3 or greater FT819-related AEs or serious AEs, no reports of any grade of CRS, ICANS, or GvHD, and no evidence of new or worsening toxicity with the second treatment cycle. Following each treatment cycle, FT819 was detected in the peripheral blood with peak level at Day 4 in Cycle 1 and at Day 8 in Cycle 2, with maximum peak level at Day 8 in Cycle 2 at 8,152 transgene copies/μg DNA.

Dose escalation is currently ongoing in Regimen A as a single dose of FT819 at 360 million cells and in Regimen B with three fractionated doses at 60 million cells per dose. The Company has also amended the FT819 study protocol to allow for the use of bendamustine at 90 mg/m2 for 2 days as an alternative to Cy / Flu conditioning chemotherapy.

About Fate Therapeutics’ iPSC Product Platform
The Company’s proprietary induced pluripotent stem cell (iPSC) product platform enables mass production of off-the-shelf, engineered, homogeneous cell products that are designed to be administered with multiple doses to deliver more effective pharmacologic activity, including in combination with other cancer treatments. Human iPSCs possess the unique dual properties of unlimited self-renewal and differentiation potential into all cell types of the body. The Company’s first-of-kind approach involves engineering human iPSCs in a one-time genetic modification event and selecting a single engineered iPSC for maintenance as a clonal master iPSC line. Analogous to master cell lines used to manufacture biopharmaceutical drug products such as monoclonal antibodies, clonal master iPSC lines are a renewable source for manufacturing cell therapy products which are well-defined and uniform in composition, can be mass produced at significant scale in a cost-effective manner, and can be delivered off-the-shelf for patient treatment. As a result, the Company’s platform is uniquely designed to overcome numerous limitations associated with the production of cell therapies using patient- or donor-sourced cells, which is logistically complex and expensive and is subject to batch-to-batch and cell-to-cell variability that can affect clinical safety and efficacy. Fate Therapeutics’ iPSC product platform is supported by an intellectual property portfolio of over 350 issued patents and 150 pending patent applications.

About FT819
FT819 is an investigational, universal, off-the-shelf, T-cell receptor (TCR)-less CD19 chimeric antigen receptor (CAR) T-cell cancer immunotherapy derived from a clonal master induced pluripotent stem cell (iPSC) line, which is engineered with 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; and complete bi-allelic disruption of TCR expression for the prevention of graft-versus-host disease. FT819 demonstrated antigen-specific cytolytic activity in vitro against CD19-expressing leukemia and lymphoma cell lines comparable to that of primary CAR T cells, and persisted and maintained tumor clearance in the bone marrow in an in vivo disseminated xenograft model of lymphoblastic leukemia. FT819 is being investigated in a multicenter Phase 1 clinical trial for the treatment of relapsed / refractory B-cell malignancies, including B-cell lymphoma, chronic lymphocytic leukemia, and acute lymphoblastic leukemia (NCT04629729).