CD371-targeted CAR T cells secreting interleukin-18 exhibit robust expansion and clear refractory acute myeloid leukemia
Abstract
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.
Article Details
Authors (31)
Mark B. Geyer
Memorial Sloan Kettering Cancer Center
Susan DeWolf
Xiaoli Mi
2Department of Medicine, Cell Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY
Kenyon Weis
3Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY
Brian C. Shaffer
1Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, NY
Briana Cadzin
Memorial Sloan Kettering Cancer Center, New York, New York, United States
Devin McAvoy
Sloan Kettering Institute, New York, New York, United States
Zoe Katsamakis
4Department of Medicine, Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, NY
Rachel Lorenc
7Pharmacology Program, Graduate School of Medical Sciences, Weill Cornell Medical College, New York, NY
Alexander M. Lewis
3Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY
Brianna Gipson
M. Adriana Cuibus
3Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY
Narina N. Girotra
3Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY
Kenton Wu
4Department of Medicine, Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, NY
Natalie Smith
Erin R. Burns
1Department of Medicine, Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY
Jasmine S. Um
1Department of Medicine, Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY
Sarah Yoo
1Department of Medicine, Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY
Behzad Kharabi Masouleh
8Tigen Pharma, Lausanne, Switzerland
Pallavi Galera
9Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
Kinga Hosszu
Memorial Sloan Kettering Cancer Center, New York, New York, United States
Jagrutiben Chaudhari
Memorial Sloan Kettering Cancer Center, New York, New York, United States
Xiuyan Wang
Qianqian Lin
Kevin J. Curran
Jae H. Park
David A. Scheinberg
Marcel R. M. van den Brink
Omar Abdel-Wahab
Molecular Pharmacology Program, Sloan Kettering Institute
Renier J. Brentjens
Roswell Park Comprehensive Cancer Center, Buffalo, New York, United States
Anthony F. Daniyan
1Department of Medicine, Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY