CD371-targeted CAR T cells secreting interleukin-18 exhibit robust expansion and clear refractory acute myeloid leukemia.
| Publication Type | Academic Article |
| Authors | Geyer M, DeWolf S, Mi X, Weis K, Shaffer B, Cadzin B, McAvoy D, Katsamakis Z, Lorenc R, Lewis A, Gipson B, Cuibus M, Girotra N, Wu K, Smith N, Burns E, Um J, Yoo S, Masouleh B, Galera P, Hosszu K, Chaudhari J, Wang X, Lin Q, Curran K, Park J, Scheinberg D, van den Brink M, Abdel-Wahab O, Brentjens R, Daniyan A |
| Journal | Blood |
| Volume | 146 |
| Issue | 26 |
| Pagination | 3163-3174 |
| Date Published | 12/25/2025 |
| ISSN | 1528-0020 |
| Keywords | Leukemia, Myeloid, Acute, Interleukin-18, Immunotherapy, Adoptive, Receptors, Chimeric Antigen, T-Lymphocytes |
| Abstract | 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. |
| DOI | 10.1182/blood.2025029532 |
| PubMed ID | 40864984 |