CD371-Targeted CAR T cells Secreting Interleukin-18 Exhibit Robust Expansion and Clear Refractory Acute Myeloid Leukemia.

Success of chimeric antigen receptor (CAR) T-cell therapy in lymphoid malignancies has not yet been recapitulated in acute myeloid leukemia (AML). We developed CAR T-cells targeting CD371 with a mutated CD28 costimulatory domain to limit T-cell exhaustion, and constitutive interleukin-18 secretion to enhance immune function (CD371/SAVVY/IL-18 CAR). We initiated a phase I trial (NCT06017258), successfully manufactured and administered CD371/SAVVY/IL-18 CAR T-cells in 5 patients with relapsed/refractory AML and observed expansion following a single infusion of 3x104 or 3x105 CAR T-cells/kg; three patients refractory to ≥5 lines of therapy and post-allogeneic transplant exhibited AML clearance and no evidence of graft-versus-host disease. Dose-limiting toxicity in the two patients treated with 3x105 CAR T-cells/kg dose (prolonged cytopenias with marrow hypoplasia; severe cytokine release syndrome) led to dose reduction to 3x104 CAR T-cells/kg in the following three patients. Single-cell analyses revealed that circulating CAR T-cells in responders included predominantly cytotoxic CD8+ effector T-cells 2 weeks post-infusion while co-existing NK-cells expressed markers of activation. This pilot study highlights the activity of low-dose IL-18 "armored" CAR T-cells against refractory AML and their potential to promote CAR T-cell cytotoxicity and innate endogenous anti-tumor immunity. NCT06017258.