Scientists from National University of Singapore found that expression of erythropoietin receptor or of a functionally more potent mutant (EpoRm) promote T-cell survival and proliferation. EpoRm expression endows CAR-T cells with superior anti-tumor activity, an approach that could be applied to other adoptive T-cell therapies. This research has been published in Blood recently.
In adoptive T-cell immunotherapy of cancer, expansion and persistence of effector cells is a key determinant of response. Scientists tested whether T lymphocytes could be rendered sensitive to erythropoietin (Epo) through ectopic expression of its wild-type receptor, or a truncated form (EpoRm) which augments Epo signaling in erythrocyte progenitors.
Both receptors could be expressed in human T lymphocytes; Epo ligation induced STAT5 phosphorylation, which was abrogated by non-toxic concentrations of the JAK1/2 inhibitor ruxolitinib. EpoRm had higher expression and triggered more potent stimulation than its wild-type counterpart, including superior T-cell survival and proliferation.
Using a bicistronic vector, scientists expressed EpoRm together with an anti-CD19-41BB-CD3z chimeric antigen receptor (CAR), while maintaining the functions of each receptor. In the presence of Epo, EpoRm-CAR-T cells had greater ex vivo expansion than CAR-T cells, and killed CD19+ leukemic cells more effectively in long-term cultures. In immunodeficient mice, physiologic levels of murine Epo were sufficient to preferentially expand EpoRm-CAR-T cells, yielding a significantly higher anti-leukemic activity.
Thus, outfitting adoptive T cells with EpoRm should yield greater effector-to-target ratios with a smaller number of infused cells; Epo or ruxolitinib administration could be used to adjust their levels post-infusion, maximizing anti-tumor activity and minimizing toxicity.
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