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.