Preclinical Evidence Generates Buzz Around Novel Off-the-Shelf CAR NK Therapy

Bob Valamehr, PhD

A multi-antigen off-the-shelf chimeric antigen receptor (CAR) natural killer (NK) cell therapy has been included in the ASH annual meeting spotlight due to exciting preclinical evidence. An investigational new drug application was approved in September 2019 for the therapy, labeled as FT596, developed by Fate Therapeutics, and human trials are scheduled to start in the first quater of 2020.

In preclinical in vitro experiments using the Raji lymphoma cell lines that were presented at the ASH meeting,¹the investigational NK cell therapy with or without the CD20 inhibitor rituximab (Rituxan) lowered cancerous cell counts more effectively than rituximab alone or available CAR T cells. Moreover, the agent showed indications of better prevention of antigen escape compared with other treatment methods.

"NK cells are multifaceted and can be viewed as a ‘jack-of-all-trades’ when it comes to protecting the host, whereas T cells can act in only one way,” Bob Valamehr, PhD, from Fate Therapeutics, said during a presentation of the data at a press briefing.

The primary desire driving the creation of an off-the-shelf therapy is accessibility; moreover, there could be potential cost savings, as it skips the arduous manufacturing process required for autologous therapies. In his presentation, Valamehr suggested that FT596 could be administered at a price of just $2,500 per dose.

"Eliminating the high production cost, weeks of manufacturing time, and complex manufacturing process required for CAR T-cell therapy and replacing it with a mass-produced, off-the-shelf product promises to expand access to effective cell-based cancer immunotherapy to many more patients who may benefit from it," said Valamehr.

FT596 is engineered from induced pluripotent stem cells (iPSC), which have been narrowed down to a single clonal cell line. The therapy is engineered to include a NKG2D transmembrane domain with a 2B4 co-stimulatory domain and a CD3-zeta signaling domain. The therapy targets 3 anti-tumor modalities, namely CD19, CD16, and IL-15. The multi-pronged approach is meant to drive deeper, more durable responses, Valamehr said.

Fate has developed other off-the-shelf NK cell therapies, including FT516 and FT500, for which clinical findings are available from human studies.²In a patient treated with refractory acute myeloid leukemia (AML), the iPSC-derived NK cell therapy FT516 induced hematologic recovery and resulted in no morphologic evidence of disease in bone marrow biopsy. There were no signs of circulating leukemia cells, according to the company. Other patients with AML and those with advanced B-cell lymphoma are still being enrolled in the study (NCT04023071).

The iPSC-derived NK cell therapy FT500 has also shown promising clinical findings, in a phase I study that included 12 patients with solid tumors. This therapy was given alone or in combination with immune checkpoint inhibition, with signs of activity seen in approximately half to two-thirds of patients. There were no cases of cytokine release syndrome (CRS), graft-versus-host disease, or neurotoxicity across the 12 patients analyzed. This study also remains ongoing (NCT03841110).

“The safety, tolerability, and immunogenicity data from the phase I dose-escalation stage of FT500, the first-ever cell therapy derived from a clonal master induced pluripotent stem cell line to undergo clinical investigation in the United States, provide compelling evidence that multiple doses of iPSC-derived NK cells can be delivered off-the-shelf and administered without patient matching,” Wayne Chu, MD, vice president of clinical development at Fate Therapeutics, said in a statement. “Additionally, initial clinical observations with FT516 are very encouraging, as an assessment of the first AML patient’s bone marrow at day 42 following 3 once-weekly doses of FT516 demonstrated anti-leukemia activity and hematopoietic recovery.”

The field of cellular therapy has advanced significantly in recent years, particularly with the FDA approval of the CAR T cells tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta). These therapies require the collection of autologous cells, off-site manufacturing, and then administration. Although progress is being made toward outpatient administration, the risk of CRS and neurotoxicity with these agents currently calls for hospitalization, often for longer durations. Each of these steps adds time and costs, according to Gary Schiller, MD, from UCLA Health, the moderator of the press briefing.

"An off-the-shelf product is attractive because of feasibility issues but it all depends on durability," said Schiller. "For a clinician who needs to take care of a patient with a desperate disease, tolerability is secondary to access and feasibility. Whatever product we have access to tomorrow will be better and easier for us to use."

References:

1. Goodridge JP, Mahmood S, Zhu H, et al. FT596: Translation of First-of-Kind Multi-Antigen Targeted Off-the-Shelf CAR-NK Cell with Engineered Persistence for the Treatment of B Cell Malignancies. Presented at: 2019 ASH Annual Meeting, Orlando, FL, December 7-10, 2019.Abstract 301.
2. Fate Therapeutics Announces Clinical Data from Landmark Phase 1 Studies of First-ever Universal, Off-the-shelf, iPSC-derived NK Cell Cancer Immunotherapy Programs. Fate Therapeutics. Published December 7, 2019. https://bit.ly/2LuA3HC. Accessed December 7, 2019.