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

AbstractPurpose: Chimeric antigen receptor (CAR) T-cell therapy has been a breakthrough in many hematologic 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. Patients and 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 the incidence of dose-limiting toxicities (DLT). Key secondary endpoints included overall remission rate, incidence of adverse events (AE), and pharmacokinetics/pharmacodynamics. Results: Twelve patients received KITE-222. One patient in cohort 3, who was the only patient to receive two 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 one had grade ≥3 immune effector cell–associated neurotoxicity syndrome. Clinically meaningful responses were lacking across dose levels despite detectable CAR T-cell expansion. Although two of five 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.