KITE-222 Demonstrates Manageable Safety but Limited Clinical Activity in Relapsed or Refractory Acute Myeloid Leukemia
Clinical Summary:
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Design/Population: This phase 1 dose-escalation trial evaluated KITE-222, an autologous CLL-1-directed CAR T-cell therapy, in patients with relapsed or refractory acute myeloid leukemia (AML).
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Key Outcomes: KITE-222 demonstrated a manageable safety profile with minimal severe cytokine release syndrome and neurotoxicity. Although CAR T-cell expansion and depletion of CLL-1-positive blasts were observed in some patients, clinically meaningful remissions were not achieved.
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Clinical Relevance: These findings highlight the challenges of CAR T-cell therapy in AML and support further development of strategies to overcome antigen heterogeneity and improve antitumor activity.
Results from a phase 1 dose-escalation trial demonstrated that KITE-222, an autologous CLL-1-directed CAR T-cell therapy, demonstrated a manageable safety profile but limited clinical activity in patients with relapsed or refractory acute myeloid leukemia (AML), highlighting the need for improved approaches to CAR T-cell therapy in this disease.
“CAR T-cell therapy has been a breakthrough in many hematologic malignancies, but success in relapsed/refractory AML has been limited due to underwhelming response rates and high on-target/off-tumor toxicity,” stated Naval Daver, MD, MD Anderson Cancer Center, Houston, Texas, and coauthors. This study “evaluated the safety and efficacy of KITE-222… Predominantly expressed on myeloid cells but absent on normal hematopoietic stem cells and other tissues.”
In this open-label phase 1 trial, 12 adult patients with relapsed or refractory AML received a single infusion of KITE-222 at escalating dose levels of 3 × 10⁷ (n = 3), 1 × 10⁸ (n = 3), or 3 × 10⁸ (n = 6) CAR-positive T cells. The primary end point was the incidence of dose-limiting toxicities. Secondary end points included remission rate, safety, and pharmacokinetic and pharmacodynamic outcomes.
One dose-limiting toxicity was reported in the highest-dose cohort, consisting of prolonged grade 4 neutropenia followed by grade 4 thrombocytopenia after a second course of lymphodepleting chemotherapy. This patient achieved a morphologic leukemia-free state that was confirmed on day 44 following infusion. All patients experienced grade ≥3 adverse events. No grade ≥3 cytokine release syndrome was observed, and 1 patient experienced grade ≥3 immune effector cell-associated neurotoxicity syndrome.
Among the 5 patients in the highest-dose cohort with evidence of CAR T-cell expansion, 2 experienced near-complete depletion of CLL-1-positive bone marrow blasts. However, CLL-1-negative blasts persisted, and meaningful reductions in overall leukemia burden were not observed. Despite detectable CAR T-cell expansion across dose levels, clinically meaningful remissions were not achieved, and the study was terminated before initiation of the planned expansion phase.
These results warrant “future studies that address CLL-1 heterogeneity and focus on improving in vivo expansion and antitumor activity," concluded Dr Daver et al.
Source:
Daver N, Blachly JS, Ghobadi A, et al. Phase 1 study of KITE-222, an autologous CLL-1–directed CAR T-cell therapy in patients with relapsed/refractory acute myeloid leukemia. Clin Can Res. Published online: June 4, 2026. doi:10.1158/1078-0432.CCR-25-374
