Heczey et al. assessed autologous NKT cells engineered to express a GD2-specific CAR and IL-15 in 12 pediatric cases of relapsed/resistant neuroblastoma. No dose-limiting toxicities were detected at 4 tested dose levels. After infusion, 4/12 had stable disease and 3/12 had partial response (PR). A second infusion in 4 patients resulted in 1 complete response, and maintained 1 PR. CAR-NKTs expanded and persisted in the periphery and trafficked to tumors. BTG1 expression was associated with exhaustion in CAR-NKT (and naive T) cells after chronic exposure. In a murine model, BTG1 knockdown in CAR-NKTs prevented exhaustion and improved efficacy.
Contributed by Maartje Wouters
ABSTRACT: Vα24-invariant natural killer T cells (NKTs) have anti-tumor properties that can be enhanced by chimeric antigen receptors (CARs). Here we report updated interim results from the first-in-human phase 1 evaluation of autologous NKTs co-expressing a GD2-specific CAR with interleukin 15 (IL15) (GD2-CAR.15) in 12 children with neuroblastoma (NB). The primary objectives were safety and determination of maximum tolerated dose (MTD). The anti-tumor activity of GD2-CAR.15 NKTs was assessed as a secondary objective. Immune response evaluation was an additional objective. No dose-limiting toxicities occurred; one patient experienced grade 2 cytokine release syndrome that was resolved by tocilizumab. The MTD was not reached. The objective response rate was 25% (3/12), including two partial responses and one complete response. The frequency of CD62L+NKTs in products correlated with CAR-NKT expansion in patients and was higher in responders (n = 5; objective response or stable disease with reduction in tumor burden) than non-responders (n = 7). BTG1 (BTG anti-proliferation factor 1) expression was upregulated in peripheral GD2-CAR.15 NKTs and is a key driver of hyporesponsiveness in exhausted NKT and T cells. GD2-CAR.15 NKTs with BTG1 knockdown eliminated metastatic NB in a mouse model. We conclude that GD2-CAR.15 NKTs are safe and can mediate objective responses in patients with NB. Additionally, their anti-tumor activity may be enhanced by targeting BTG1. ClinicalTrials.gov registration: NCT03294954 .
Author Info: (1) Department of Pediatrics, Center for Advanced Innate Cell Therapy, Baylor College of Medicine, Houston, TX, USA. heczey@bcm.edu. Department of Medicine, Center for Cell and Gen
Author Info: (1) Department of Pediatrics, Center for Advanced Innate Cell Therapy, Baylor College of Medicine, Houston, TX, USA. heczey@bcm.edu. Department of Medicine, Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA. heczey@bcm.edu. (2) Department of Pediatrics, Center for Advanced Innate Cell Therapy, Baylor College of Medicine, Houston, TX, USA. (3) Department of Pediatrics, Center for Advanced Innate Cell Therapy, Baylor College of Medicine, Houston, TX, USA. (4) Department of Pediatrics, Center for Advanced Innate Cell Therapy, Baylor College of Medicine, Houston, TX, USA. (5) Department of Pediatrics, Center for Advanced Innate Cell Therapy, Baylor College of Medicine, Houston, TX, USA. (6) Department of Pediatrics, Center for Advanced Innate Cell Therapy, Baylor College of Medicine, Houston, TX, USA. (7) Department of Pediatrics, Center for Advanced Innate Cell Therapy, Baylor College of Medicine, Houston, TX, USA. (8) Department of Pediatrics, Center for Advanced Innate Cell Therapy, Baylor College of Medicine, Houston, TX, USA. (9) Department of Pediatrics, Center for Advanced Innate Cell Therapy, Baylor College of Medicine, Houston, TX, USA. (10) Department of Pediatrics, Center for Advanced Innate Cell Therapy, Baylor College of Medicine, Houston, TX, USA. (11) Department of Pediatrics, Center for Advanced Innate Cell Therapy, Baylor College of Medicine, Houston, TX, USA. (12) Department of Pediatrics, Center for Advanced Innate Cell Therapy, Baylor College of Medicine, Houston, TX, USA. (13) Department of Pediatrics, Center for Advanced Innate Cell Therapy, Baylor College of Medicine, Houston, TX, USA. (14) Department of Pediatrics, Center for Advanced Innate Cell Therapy, Baylor College of Medicine, Houston, TX, USA. (15) Department of Radiology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA. (16) Department of Medicine, Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA. (17) Department of Medicine, Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA. (18) Department of Medicine, Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA. (19) Department of Medicine, Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA. (20) Biostatistics and Data Management Resource, Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA. (21) Department of Pediatrics, Cincinnati Children's Hospital, Cincinnati, OH, USA. (22) Immunai, Inc., New York, NY, USA. (23) Immunai, Inc., New York, NY, USA. (24) Immunai, Inc., New York, NY, USA. (25) Immunai, Inc., New York, NY, USA. (26) Immunai, Inc., New York, NY, USA. (27) Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. (28) Department of Pediatrics, Center for Advanced Innate Cell Therapy, Baylor College of Medicine, Houston, TX, USA. lsmeteli@txch.org. Department of Medicine, Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA. lsmeteli@txch.org.
