Eight pediatric allogeneic HSCT recipients in remission from high-risk CD19+ B cell acute lymphoblastic leukemia were infused without lymphodepleting preconditioning with a low dose of central-memory enriched donor T cells that were modified with a CD19 CAR and had TCRs specific for CMV, EBV, and adenovirus (CD19.CAR-VSTs). CD19.CAR-VSTs persisted long-term and expanded in response to TCR stimulation during viral reactivation (in 3 patients), but not in response to CAR stimulation alone, despite high numbers of circulating normal B cells. No CRS was observed. Five patients remained in remission at 42-60+ months post-infusion.
PURPOSE: Current protocols for CD19 chimeric antigen receptor expressing T cells (CD19.CAR T cells) require recipients to tolerate pre-infusion cytoreductive chemotherapy, and the presence of sufficient target antigen on normal or malignant B cells. EXPERIMENTAL DESIGN: We investigated whether additional stimulation of CD19.CAR T cells through their native receptors can substitute for cytoreductive chemotherapy, inducing expansion and functional persistence of CD19.CAR T even in patients in remission of B-cell acute lymphocytic leukemia (ALL). We infused a low-dose of CD19.CAR-modified virus-specific T cells (CD19.CAR-VST) without prior cytoreductive chemotherapy into 8 patients after allogeneic stem cell transplant. RESULTS: Absent virus reactivation, we saw no CD19.CAR-VST expansion. By contrast, in patients with viral reactivation, up to 30,000-fold expansion of CD19.CAR-VSTs was observed, with depletion of CD19+ B-cells. Five patients remain in remission at 42-60+ months. CONCLUSIONS: Dual TCR and CAR stimulation can thus potentiate effector cell expansion and CAR-target cell killing, even when infusing low numbers of effector cells without cytoreduction.
Author Info: (1) Center for Cell and Gene Therapy, Department of Pathology and Immunology, Baylor College of Medicine. (2) Center for Cell and Gene Therapy, Baylor College of Medicine. (3) Tran
Author Info: (1) Center for Cell and Gene Therapy, Department of Pathology and Immunology, Baylor College of Medicine. (2) Center for Cell and Gene Therapy, Baylor College of Medicine. (3) Translational Immunotherapy, ElevateBio. (4) Center for Cell and Gene Therapy, Department of Pathology and Immunology, Baylor College of Medicine. (5) Baylor College of Medicine. (6) Pediatrics, Baylor College of Medicine. (7) Center for Cell and Gene Therapy, Baylor College of Medicine. (8) CAGT, Baylor College of Medicine. (9) Center for Cell and Gene Therapy, Baylor College of Medicine. (10) Baylor College of Medicine. (11) Texas Children's Cancer Center, Department of Pediatrics/Center for Cell and Gene Therapy, Baylor College of Medicine. (12) Biostatistics Shared Resource, Baylor College of Medicine, Dan L. Duncan Cancer Center. (13) Center for Cell and Gene Therapy, Baylor College of Medicine. (14) Pediatrics- Hematology/Oncology, University of North Carolina at Chapel Hill. (15) Department of Microbiology and Immuniology, University of North Carolina at Chapel Hill. (16) Sheikh Zayed Institute, Children's National Health System. (17) Baylor College of Medicine. (18) Baylor College of Medicine. (19) Baylor College of Medicine. (20) Medicine, Section of Hematology/Oncology, Center for Cell and Gene Therapy, Baylor College of Medicine. (21) Center for Cell & Gene Therapy, Baylor College of Medicine. (22) Center for Cell and Gene Therapy, Baylor College of Medicine. (23) Center for Cell and Gene Therapy, Baylor College of Medicine cmrooney@txch.org. (24) Center for Cell and Gene Therapy, Baylor College of Medicine. (25) Center for Cell and Gene Therapy, Batylor College of Medicine. (26) Baylor College of Medicine. (27) Center for Cell and Gene Therapy, Department of Pathology and Immunology, Baylor College of Medicine.
