To regulate CAR T cell activity in vivo, Aspuria et al. engineered the human IL-2 receptor to bind a modified and PEGylated IL-2 ligand (STK-009), but not WT IL-2. CD19-directed CAR T cells expressing this receptor (SYNCARs), but not PBMCs, proliferated in response to STK-009. STK-009 showed no toxicity in non-human primates. In NSG mice with CD19+ lymphoma, STK-009 expanded SYNCAR numbers without increasing exhaustion, regressed tumors even in a s.c. (typically CAR-refractory) model, and induced SYNCAR proliferation months after tumor elimination, but also led to weight loss and cytokine production while tumor antigen was present.
Contributed by Alex Najibi
ABSTRACT: Chimeric antigen receptor (CAR) T cells induce durable responses in patients with refractory hematological tumors. However, low CAR T cell activity, poor engraftment, or short in-patient persistence can lead to tumor progression or relapse. Furthermore, excessive CAR T cell expansion and activation can result in life-threatening cytokine release syndrome (CRS). Thus, in-patient control of the CAR T cell population is essential. Interleukin-2 (IL-2) is a critical cytokine for T cell proliferation and effector function, but its clinical use is limited by immune-mediated toxicity. Here, we report on an orthogonal IL-2 receptor and ligand system that enables specific in vivo control of CAR T cell expansion and activation, wherein an orthogonal human IL-2 (STK-009) selectively pairs with an orthogonal human IL-2Rβ (hoRb) expressed on CAR T cells. STK-009 expands hoRb-expressing CAR T cells in the presence and absence of tumor antigen and maintains the presence of stem cell memory T cells (TSCM) and effector T cells. In preclinical models of human CAR-refractory lymphoma, STK-009 treatment resulted in systemic and intratumoral expansion and activation of hoRb-expressing anti–CD19-CD28ζ CAR T cells (SYNCAR). The orthogonal IL-2 receptor/ligand system delivers complete responses in large subcutaneous lymphomas, even with substantially reduced CAR T cell doses, by selectively expanding and activating CAR T cells in vivo. STK-009 withdrawal allowed normal CAR T cell contraction, thereby limiting CRS induced by tumor antigen–specific T cell activation. These data suggest that the orthogonal IL-2 receptor/ligand system provides the in vivo control necessary to maximize efficacy of CAR T therapies.
Author Info: (1) Synthekine, Menlo Park, CA 94025, USA. (2) Synthekine, Menlo Park, CA 94025, USA. (3) Synthekine, Menlo Park, CA 94025, USA. (4) Synthekine, Menlo Park, CA 94025, USA. (5) Synt
Author Info: (1) Synthekine, Menlo Park, CA 94025, USA. (2) Synthekine, Menlo Park, CA 94025, USA. (3) Synthekine, Menlo Park, CA 94025, USA. (4) Synthekine, Menlo Park, CA 94025, USA. (5) Synthekine, Menlo Park, CA 94025, USA. (6) Synthekine, Menlo Park, CA 94025, USA. (7) Synthekine, Menlo Park, CA 94025, USA. (8) Synthekine, Menlo Park, CA 94025, USA. (9) Synthekine, Menlo Park, CA 94025, USA. (10) Synthekine, Menlo Park, CA 94025, USA. (11) Synthekine, Menlo Park, CA 94025, USA. (12) Synthekine, Menlo Park, CA 94025, USA. (13) Synthekine, Menlo Park, CA 94025, USA.
