分泌白介素-18 的 CD371 靶向 CAR-T 细胞展现强劲扩增并清除难治性急性髓系白血病

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 (IL-18) secretion to enhance immune function (CD371/SAVVY/IL-18 CAR).

We initiated a phase 1 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 3 104 or 3 105 CAR T cells per kg; 3 patients refractory to 5 lines of therapy and postallogeneic transplant exhibited AML clearance and no evidence of graft-versus-host disease. Dose-limiting toxicity in the 2 patients treated with 3 105 CAR T cells per kg dose (prolonged cytopenias with marrow hypoplasia; severe cytokine release syndrome) led to dose reduction to 3 104 CAR T cells per kg in the following 3 patients.

Single-cell analyses revealed that circulating CAR T cells in responders included predominantly cytotoxic CD8+ effector T cells 2 weeks after infusion while coexisting natural killer (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 antitumor immunity. This trial was registered at www. ClinicalTrials. gov as #NCT06017258.