Treating Cancer Without Chemo Or Radiation ?
Synthetic receptor signaling has the potential to endow adoptively transferred T cells with new functions that overcome major barriers in the treatment of solid tumors, including the need for conditioning chemotherapy. They designed chimeric receptors that have an orthogonal IL-2 receptor extracellular domain (ECD) fused with the intracellular domain (ICD) of receptors for common -chain (c) cytokines IL-4, IL-7, IL-9 and IL-21 such that the orthogonal IL-2 cytokine elicits the corresponding c cytokine signal. Of these, T cells that signal through the chimeric orthogonal IL-2R-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. They have superior anti-tumor efficacy in two recalcitrant syngeneic mouse solid tumor models of melanoma and pancreatic cancer and are effective even in the absence of conditioning lymphodepletion. Therefore, by repurposing IL-9R signaling using a chimeric orthogonal cytokine receptor, T cells gain new functions, and this results in improved anti-tumor activity for hard-to-treat solid tumors.