With the goal of safely enhancing CAR T cell efficacy with IL-2, Zhang et al. engineered a highly selective orthogonal human IL-2 (ortho-IL-2)/human IL-2Rβ (ortho-IL-2Rβ) pair that lacked activity on wild-type T cells. In immunodeficient mice with CD19+ Nalm6 xenografts, ortho-IL-2 induced a dose-dependent increase (up to 1000-fold at 2 weeks) in CD19-specific CAR T cells expressing ortho-hIL-2Rβ. In addition, ortho-IL-2 was able to rescue the efficacy of a suboptimal CAR T cell dose, and could rescue a failing anti-leukemic response when started at the time of relapse, highlighting the clinical potential of combining orthogonal cytokines with T cell therapies.
Contributed by Katherine Turner
ABSTRACT: Interleukin-2 (IL-2) is a central T cell cytokine that promotes T cell proliferation and effector function; however, toxicity due to its pluripotency limits its application to enhance CAR T cell immunotherapy. Previously, mouse IL-2 and its cognate receptor were engineered to create an orthogonal (ortho) cytokine-cytokine receptor pair capable of delivering an IL-2 signal without toxicity. Here, we engineered a human orthogonal IL-2 (ortho-hIL-2) and human orthogonal IL-2Rβ (ortho-hIL-2Rβ) pair, containing human-specific mutations. Ortho-hIL-2 is selective toward ortho-hIL-2Rβ–expressing cells with no appreciable signaling on wild-type T cells. Ortho-hIL-2 induces IL-2 receptor signaling and supports proliferation of both an IL-2–dependent cell line and primary T cells transduced to express the ortho-hIL-2Rβ. Using CD19-specific chimeric antigen receptor (CAR) T cells, we show that ortho-hIL-2 induces a dose-dependent increase in ortho-hIL-2Rβ+ CAR T cell expansion in vivo by as much as 1000-fold at 2 weeks after adoptive transfer into immunodeficient mice bearing CD19+ Nalm6 leukemia xenografts. Ortho-hIL-2 can rescue the antileukemic effect of an otherwise suboptimal CAR T cell dose. In addition, ortho-hIL-2 administration initiated at the time of leukemic relapse after CAR T cell therapy can rescue an otherwise failed antileukemic response. These data highlight the potential of combining an orthogonal cytokine approach with T cell–based immunotherapies to augment the antitumor efficacy of engineered T cells.
Author Info: (1) Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (2) Department of Pathology and Lab
Author Info: (1) Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (2) Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (3) Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. (4) Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. (5) Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. (6) Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (7) Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (8) Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104, USA. (9) Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. (10) Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. (11) Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
