Potentiating adoptive cell therapy using synthetic IL-9 receptors

Abstract

Synthetic receptor signalling has the potential to endow adoptively transferred T cells with new functions that overcome major barriers in the treatment of solid tumours, including the need for conditioning chemotherapy1,2. Here we designed chimeric receptors that have an orthogonal IL-2 receptor extracellular domain (ECD) fused with the intracellular domain (ICD) of receptors for common γ-chain (γc) cytokines IL-4, IL-7, IL-9 and IL-21 such that the orthogonal IL-2 cytokine elicits the corresponding γc cytokine signal. Of these, T cells that signal through the chimeric orthogonal IL-2Rβ-ECD–IL-9R-ICD (o9R) are distinguished by the concomitant activation of STAT1, STAT3 and STAT5 and assume characteristics of stem cell memory and effector T cells. Compared to o2R T cells, o9R T cells have superior anti-tumour efficacy in two recalcitrant syngeneic mouse solid tumour models of melanoma and pancreatic cancer and are effective even in the absence of conditioning lymphodepletion. Therefore, by repurposing IL-9R signalling using a chimeric orthogonal cytokine receptor, T cells gain new functions, and this results in improved anti-tumour activity for hard-to-treat solid tumours.

Enhanced STAT5a activation rewires exhausted CD8 T cells during chronic stimulation to acquire a hybrid durable effector like state

“…In particular, the ortho IL-2 approach 47 may control for previous limitations by delivering Stat5 inducing signals only to the cells of interest. 61…”

“…In particular, the orthoIL-2 approach 47 may control for previous limitations by delivering Stat5 inducing signals only to the cells of interest. 61 Since the discovery of the distinct epigenetic wiring of TEX that limits re-differentiation upon PD-1 blockade, 25,40 developing approaches to reprogram the epigenetics of TEX has been a major goal. Identifying such strategies, however, has proven challenging.…”

Therapeutic perspectives for adult soft tissue sarcoma—updates from the 2022 ASCO annual meeting

“…Among them, prolonged cytopenia due to lymphodepletion chemotherapy before T-cell infusion is a critical concern. Furthermore, previous trials have indicated that different lymphodepletion conditions might affect treatment efficacy 25 . Recently, new CAR-T cells designed with synthetic chimeric receptors with an orthogonal IL-2r extracellular domain fused with an IL-9r intracellular domain have been described, which can also be expanded in the absence of conditioning lymphodepletion 25 .…”

Cancer Resistance to Immunotherapy: Molecular Mechanisms and Tackling Strategies

“…Although CAR T therapy demonstrates remarkable efficacy in patients with hematological malignancies, the outcomes are limited by the tumor microenvironment (TME), particularly in solid tumors [ 22 ]. However, by repurposing IL-9R signaling using a chimeric orthogonal cytokine receptor, T cells gain new functions including characteristics of stem cell memory and effector T cells leading to augmented anti-tumor activity against solid tumors [ 23 ]. CAR-NK cell therapy has started to gain attraction as an alternative to CAR-T approach.…”