Safety and Efficacy of FT522, a First-in-Class, Multi-Antigen Targeted, Off-the-Shelf, iPSC-Derived CD19 CAR NK Cell Therapy with Alloimmune Defense Receptor (ADR) in Relapsed/Refractory B-Cell Lymphoma
Authors: Bachanova Veronika , Deol Abhinav , Al-Juhaishi Taha Mahdi Salih , Lulla Premal D. , Byrne Michael T. , Wong Carol , Bickers Cara , Greene Trever , Wong Lilly , Villa Bertha , Patel Deepa , Valamehr Bahram Bob , Elstrom Rebecca , Lunning Matthew 
Published: December 2024

Background: While conditioning chemotherapy supports CAR T-cell expansion and persistence, it is associated with significant toxicities, including prolonged cytopenias, poor immune reconstitution, and severe infections. Reducing or eliminating the need for conditioning chemotherapy, while maintaining anti-tumor activity, could significantly improve tolerability and reduce non-relapse mortality.
FT522 is an iPSC-derived, off -the-shelf, natural killer (iNK) cell therapy that expresses a novel alloimmune defense receptor (ADR), which is designed to target activated host immune cells expressing 4-1BB and uniquely enable effector cell proliferation and functional persistence in an allogeneic host immune system (Mamonkin et al., 2020). In nonclinical alloreactivity models, ADR+ antiCD19 CAR NK cells expand, persist, and maintain anti-tumor activity in the presence of activated T cells from an unmatched donor, indicating the potential to overcome the requirement for patient lympho-conditioning (Williams et al., 2022). In addition to ADR-arming, FT522 incorporates 4 additional genetic edits: a CAR targeting CD19; a novel high-affinity, non-cleavable CD16 Fc receptor that enhances antibody-dependent cell cytotoxicity in combination with a therapeutic monoclonal antibody (mAb); IL-15/IL-15 receptor fusion promoting cytokine-autonomous persistence; and CD38 knock out that increases mitochondrial respiratory capacity and resistance to oxidative stress.
Methods: FT522 is being investigated in a Phase I clinical trial in patients (pts) with relapsed/refractory (R/R) B-cell lymphomas (BCL) (ClinicalTrials.gov: NCT05950334). Three doses of FT522 are administered in Regimen A following conditioning chemotherapy (fludarabine 30 mg/m2 and cyclophosphamide 500 mg/m2 Days -5 to -3, or bendamustine 90 mg/m2 Days -5 and -4) with rituximab (R) 375 mg/m2 (Day -4) or in Regimen B with no conditioning chemotherapy and rituximab (R) 375 mg/m2 (Day -4). Observation for dose limiting toxicity continues for 28 days. Pts experiencing clinical benefit may receive a second cycle of their assigned regimen. Primary objectives are to determine the recommended Phase II dose of FT522, and to evaluate safety and tolerability of each regimen. Additional key objectives include preliminary anti-tumor activity, pharmacokinetics, and anti-product immunogenicity.
Results: As of the data cutoff, the first dose level (DL1) in Regimen A of 300 million cells/dose has been fully evaluated and found to be tolerable. Three pts with R/R BCL were enrolled to this dose escalation cohort and completed at least one treatment cycle. Pts had received a median of 3 prior therapies. Two of the 3 pts had primary refractory disease, with no response to first line chemoimmunotherapy.
No dose-limiting toxicities were reported. No cytokine release syndrome, graft-versus-host disease or immune effector cell-associated neurotoxicity syndrome were observed. Most common treatment-emergent adverse events of any grade were neutrophil count decreased, nausea, arthralgia and peripheral edema (N=2 each). Grade 3 or higher adverse events included neutrophil count decreased (N=2), lymphocyte count decreased, and white blood cell count decreased (N=1 each).
Two of the 3 pts (one with Grade 3A follicular lymphoma and one with marginal zone lymphoma) achieved a complete response after the first FT522 treatment cycle, while the third pt (triple hit diffuse large B cell lymphoma) experienced progressive disease. Enrollment has been initiated in Regimen A, DL2 (900 million cells/dose) and Regimen B, DL1.
Pharmacokinetics analysis for pts treated in Regimen A, DL1 showed detectable FT522 up to Day 15, with improved AUC compared to a prior generation CD19-targeted CAR NK cell product candidate without ADR arming. Preliminary peripheral blood T cell subset analysis demonstrated delayed recovery of T cells with a differential rate of reduction of CD4+ and CD8+ subsets coinciding with expression of 4-1BB, suggesting potential interaction with ADR. No B- or T-cell mediated anti-product responses were observed.
Conclusions: ADR-armed FT522 was well-tolerated, demonstrated complete responses in pts with R/R BCL in the first cohort studied, and delayed emergence of 4-1BB+ T cells. Dose escalation of FT522 is ongoing, including in Regimen B without conditioning chemotherapy. Updated clinical and translational data will be presented.