Proof-of-Concept Study of CAR-NK Cell Therapy with Engineered Persistence Shows Potential

A first-of-kind multi-antigen targeted off-the-shelf chimeric antigen receptor (CAR)-natural killer (NK) cell with engineered persistence has the potential to be a readily available treatment option for patients, Robert A. Brodsky, MD, said in a preview of the 61st American Society of Hematology (ASH) Annual Meeting & Exposition.

“As most of you are well aware, CAR T-cell (therapy has) captured the imagination of physician scientists and patients alike, mainly for their incredible efficacy in treating B-cell malignancies like acute lymphocytic leukemia and non-Hodgkin lymphomas,” said Brodsky, who serves as secretary of ASH and is also the director of the division of hematology at Johns Hopkins Medicine.

However, he added, this treatment option does not come without its drawbacks: namely, time, expenses, toxicity.

“Only about two-thirds of patients enrolled in CAR T-cell trials will actually see infusion because often the disease will progress during the time it takes to make a successful product,” Brodsky said.

Therefore, there is a need to develop a more timely infusion that can be associated with lower costs, and hopefully, less toxicity.

At the upcoming ASH Annual Meeting & Exposition, being held from December 7-10 in Orlando, Florida, Jode P. Goodridge, PhD, will present on his team’s proof-of-concept study of induced pluripotent stem cell (iPSC)-derived effector cells.

“iPSC-derived effector cells offer distinct advantages for immune therapy over existing patient- or donor- derived platforms, both in terms of scalable manufacturing from a renewable starting cellular material and precision genetic engineering that is performed at the single-cell level,” the researchers wrote in their abstract. “iPSC derived natural killer (iNK) cells offer the further advantage of innate reactivity to stress ligands and MHC downregulation and the potential to recruit downstream adaptive responses.”

The candidate, called FT596, is consistently manufactured from a master iPSC line engineered to uniformly express an NK cell-calibrated CD19-targeting CAR, an enhanced functioning high-affinity, non-cleavable CD16, and a recombinant fusion of IL-15 and IL-15 receptor alpha for cytokine-autonomous persistence, according to the abstract.

“What the authors here did is take advantage of the use of induced pluripotent stem cells and differentiated them to natural killer cells. Natural killer cells are not T cells but they are another form of lymphocytes that can be very effective in killing cancer cells. What they did is they engineered these pluripotent stem cells to target B cells, and they are specifically targeting the CD19 antigen on B cells and showing that these are very effective in cell line models and animal models,” explained Brodsky.

However, of note, this product has not been tested in humans yet.

“The big advance here is that this offers the potential of having a readily available source of basically CAR-NK cells that wouldn’t need time to grow them up before they would be infused,” Brodsky concluded.

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: 61st ASH Annual Meeting & Exposition Meeting preview; to be presented December 7, 2019; Orlando, Fla. Abstract 301.