FT538

P1, N=0, Withdrawn, Masonic Cancer Center, University of Minnesota | N=34 --> 0

P1, N=33, Suspended, Masonic Cancer Center, University of Minnesota | Recruiting --> Suspended

P1, N=11, Active, not recruiting, Masonic Cancer Center, University of Minnesota | Trial primary completion date: Dec 2025 --> Jan 2024

P1, N=11, Active, not recruiting, Masonic Cancer Center, University of Minnesota | Recruiting --> Active, not recruiting | N=50 --> 11

iPSC-derived NK therapy offers a standardized, off-the-shelf option for NK cell therapies. FT538 iPSC-derived NK cells induce apoptosis in AML cell lines and patient samples in a dose-dependent manner and show a synergistic effect with Venetoclax, Gilteritinib, Azacitidine, and Cytarabine. Therefore, iPSC-derived NK cell therapy may be a promising possibility for AML treatment, particularly for patients resistant to standard therapies.

We hypothesized that the addition of Dara to fludarabine and cyclophosphamide would enhance lymphodepletion and augment ADCC for CD38+ AML leading to better response rates when combined with FT538. FT538 in combination with daratumumab has been tolerated in a highly pre-treated cohort of patients with expected toxicities and a signal of efficacy.

P1, N=16, Terminated, Fate Therapeutics | Trial completion date: Aug 2025 --> Aug 2023 | Active, not recruiting --> Terminated; This study was terminated by the Sponsor.

P1, N=16, Active, not recruiting, Fate Therapeutics | Recruiting --> Active, not recruiting | N=189 --> 16

In Regimen B, conditioning chemotherapy (fludarabine 30 mg/m2 and cyclophosphamide 300 mg/m2) followed by 3 once-weekly doses of FT538 (Days 1, 8, 15 of a 28-d cycle), ranging from 100 million cells/dose up to 1.5 billion cells/dose, are being evaluated using a standard 3 + 3 dose-escalation design. Administration of up to 3 doses of FT538 cells at 100 or 300 million cells/dose in combination with daratumumab is safe and well tolerated without CRS, neurotoxicity, or GvHD. Interim clinical data, including safety and tolerability and initial anti-tumor activity from the ongoing Phase I dose-escalation study of FT538 in combination with daratumumab in R/R MM, will be presented at the conference.

Anti-CD38 therapeutic monoclonal antibodies (mAbs) such as daratumumab (dara) have shown wide application and therapeutic benefit for Multiple Myeloma (MM) patients...To evaluate the effect of anti-CD38 mAb on host lymphocyte reconstitution we used flow cytometry to characterize PBMCs or marrow collected from MM patients after LDC with cytoxan 300 mg/m2 and fludarabine 30 mg/m2 x 3 days either as monotherapy (N = 4) or in combination with dara 16 mg/kg 1 week prior to LDC (Day -11) and weekly thereafter (n = 3) (NCT05182073)...In the presence of anti-CD38 mAb treatment, B2M/CIITA-null FT538 continued to persist while allogeneic NK cells were not detected, while in the study arm that lacked anti-CD38 mAb, B2M/CIITA-null FT538 was eliminated by the persisting allogeneic NK cells (p<0.001). In summary, these data demonstrate the potential to combine off-the-shelf iPSC-derived CD38-null NK cells with anti-CD38 mAb as a novel therapeutic strategy, uniquely demonstrating the potentiating of ADCC while reducing or eliminating the need for LDC in cell therapy.

P1, N=189, Recruiting, Fate Therapeutics | Not yet recruiting --> Recruiting

P1, N=50, Recruiting, Masonic Cancer Center, University of Minnesota | Not yet recruiting --> Recruiting

P1, N=189, Not yet recruiting, Fate Therapeutics

P1, N=50, Not yet recruiting, Masonic Cancer Center, University of Minnesota

The dose‑escalation utilizes a 3+3 design to identify the maximum tolerated dose of three doses of FT538 on Days 1, 8, and 15 as a monotherapy in r/r AML (Regimen A) and in combination with daratumumab (Regimen B) or elotuzumab (Regimen C) in r/r MM. The trial will test up to five FT538 dose levels ranging from 50 million to 1.5 billion cells, and up to 105 patients will be enrolled. The trial is expected to begin patient enrollment in 2020.

To overcome these barriers, we developed a robust genetic editing and manufacturing platform for the uniform engineering and expansion of high-quality NK cells derived from induced pluripotent stem cells (iPSCs)...Previously, we reported on our ability to effectively target multiple myeloma with our FT538 program (the iNK defined below), now FDA approved for clinical trials...Collectively, our results show that utilizing the iNK cell platform to uniformly express hnCD16 and IL15RF combined with complete CD38 KO is an effective strategy to promote effective ADCC against CD38+ cells in the absence of fratricide, and that CD38 KO reprograms NK cells for higher oxidative metabolic fitness for improved persistence and anti-tumor function. Furthermore, we have generated proof-of-concept data supporting triple gene-modified iNK cells combined with dara as a novel AML immunotherapy.

FT538 is an investigational, first-of-kind, multiplexed engineered NK cell therapy generated 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 NK cells for broad patient access...Lympho-conditioning consisting of three consecutive days of fludarabine and cyclophosphamide will be administered prior to the first dose of FT538...Key exclusion criteria include active central nervous system disease, need for systemic immunosuppressive therapy, and prior allograft organ transplant. This trial is expected to begin patient enrollment in 2020.