Heczey et al. report the safety and antitumor response of a first-in-human phase 1 clinical trial evaluating autologous anti-GD2 CAR-NKT cells expressing IL-15 in relapsed or refractory neuroblastoma patients. The CAR-NKT cells were well tolerated without dose-limiting toxicities. Following infusion, the peripheral NKT cells and CAR-NKT cells expanded in all patients, trafficked to the bone marrow metastases, induced tumor regression in one patient, and decreased the Curie score in 2 out of 3 patients. Single-cell RNAseq revealed that CAR transgene expression was associated with a central memory phenotype, costimulation, and metabolic fitness.
Contributed by Shishir Pant
ABSTRACT: V_24-invariant natural killer T (NKT) cells have shown potent anti-tumor properties in murine tumor models and have been linked to favorable outcomes in patients with cancer. However, low numbers of these cells in humans have hindered their clinical applications. Here we report interim results from all three patients enrolled on dose level 1 in a phase 1 dose-escalation trial of autologous NKT cells engineered to co-express a GD2-specific chimeric antigen receptor (CAR) with interleukin-15 in children with relapsed or resistant neuroblastoma (NCT03294954). Primary and secondary objectives were to assess safety and anti-tumor responses, respectively, with immune response evaluation as an additional objective. We ex vivo expanded highly pure NKT cells (mean ± s.d., 94.7 ± 3.8%) and treated patients with 3 _ 10(6) CAR-NKT cells per square meter of body surface area after lymphodepleting conditioning with cyclophosphamide/fludarabine (Cy/Flu). Cy/Flu conditioning was the probable cause for grade 3-4 hematologic adverse events, as they occurred before CAR-NKT cell infusion, and no dose-limiting toxicities were observed. CAR-NKT cells expanded in vivo, localized to tumors and, in one patient, induced an objective response with regression of bone metastatic lesions. These initial results suggest that CAR-NKT cells can be expanded to clinical scale and safely applied to treat patients with cancer.
Author Info: (1) Department of Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX, USA. axheczey@txch.org. Department of Pathology and Immunology, Baylor Colleg
Author Info: (1) Department of Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX, USA. axheczey@txch.org. Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA. axheczey@txch.org. Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA. axheczey@txch.org. (2) Department of Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX, USA. (3) Immunai Inc., New York, NY, USA. (4) Department of Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX, USA. (5) Department of Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX, USA. (6) Department of Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX, USA. (7) Department of Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX, USA. (8) Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA. (9) Department of Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX, USA. (10) Immunai Inc., New York, NY, USA. (11) Department of Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX, USA. (12) Department of Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX, USA. (13) Department of Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX, USA. (14) Department of Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX, USA. (15) Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. (16) Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. (17) Department of Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX, USA. lsmeteli@txch.org. Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA. lsmeteli@txch.org. Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA. lsmeteli@txch.org.
