We report the results of an investigator initiated phase I study designed to evaluate the safety of FT596 with rituximab for relapse prevention in patients who have undergone auto-HSCT for B-cell lymphoma. FT596 is an allogeneic NK cell therapy derived from induced pluripotent stem cells, with three gene edits: a high-affinity 158V non-cleavable CD16 Fc receptor to enhance antibody-dependent cellular cytotoxicity (ADCC), an IL-15 receptor fusion to promote intrinsic survival, and a CAR19 targeting CD19 for anti-tumor activity.

This 2 component dose-escalation study involved a single dose of FT596 in combination with rituximab given 2 days prior to FT596. Component 1 aimed to establish the maximum tolerated dose (MTD) of FT596 when administered 30 days post-auto-HSCT; Component 2 aimed to assess safety when FT596 administered at MTD on Day 7 post-auto-HSCT.

Eight patients were enrolled in Component 1 with all patients in complete remission 30 days after autoHSCT. We treated patients at 3 cell dose levels: 9 x 10^7 (n=3), 3 x 10^8 (n=3) and 9 x 10^8 (n=2). No dose-limiting toxicities or serious adverse events (SAEs) were observed. Additionally, no patients experienced infusion reactions greater than grade 1. There were no immune effector-associated toxicities (e.g., CRS or ICANS), graft-versus-host disease, or non-engraftment.

Pharmacokinetic (PK) analysis revealed that FT596 cells were undetectable in patients’ blood by PCR or flow cytometry after infusion. We hypothesize that the lack of persistence after auto-HSCT may be due to the absence of targets in this minimal residual disease setting. Other potential factors include intrinsic survival limitations or more potent allogeneic rejection. The trial was terminated by the sponsor before advancing to Component 2.

In conclusion, the strategy to prevent relapse of B-cell lymphoma with iPSC CAR-NK therapy after autoHSCT should focus on immediate post-transplant period and enhanced resistance to allo-rejection induced by host immunity.