Phase 1 Study of KITE-222, an Autologous CLL-1–directed CAR T-cell Therapy in Patients With Relapsed/Refractory Acute Myeloid Leukemia

PURPOSE: Chimeric antigen receptor (CAR) T-cell therapy has been a breakthrough in many hematological malignancies but success in relapsed/refractory (R/R) acute myeloid leukemia (AML) has been limited due to underwhelming response rates and high on-target/off-tumor toxicity. This Phase 1 dose-escalation trial evaluated the safety and efficacy of KITE-222, an autologous CAR T-cell therapy that recognizes C-type lectin-like molecule 1 (CLL-1) predominantly expressed on myeloid cells but absent on normal hematopoietic stem cells and other tissues. METHODS: Patients with R/R AML (≥50 kg) received a single intravenous infusion of 3×107 (Cohort 1), 1×108 (Cohort 2), or 3×108 (Cohort 3) KITE-222 CAR+ T cells. The primary endpoint was incidence of dose-limiting toxicities (DLTs). Key secondary endpoints included overall remission rate, incidence of adverse events (AEs), and pharmacokinetics/pharmacodynamics. RESULTS: Twelve patients received KITE-222. One patient in Cohort 3, who was the only patient to receive 2 courses of lymphodepleting chemotherapy, experienced a DLT (prolonged Grade 4 neutropenia/thrombocytopenia) but achieved a best response of morphologic leukemia-free state on Day 14 following infusion (confirmed on Day 44). All patients experienced Grade ≥3 AEs, none had Grade ≥3 cytokine release syndrome, and 1 had Grade ≥3 immune effector cell-associated neurotoxicity syndrome. Clinically meaningful responses were lacking across dose levels despite detectable CAR T-cell expansion. Although 2 of 5 Cohort 3 patients with clear expansion had near complete depletion of CLL-1+ bone marrow blasts after infusion, CLL-1- blasts persisted, and reductions in total blasts were not observed. CONCLUSIONS: Despite successful manufacturing and acceptable safety, KITE-222 lacked preliminary efficacy, warranting future studies that address CLL-1 heterogeneity and focus on improving in vivo expansion and antitumor activity.