Abstract
Orthogonal IL2/IL2Rβ pairs allow selective targeting of engineered autologously transferred T cells.
Major finding: Orthogonal IL2/IL2Rβ pairs allow selective targeting of engineered autologously transferred T cells.
Concept: IL2/IL2Rβ pairs limit toxicity and enhance expansion of autologously transferred T cells in vivo.
Impact: Engineering T cells for selective IL2Rβ activation may enhance the efficacy of autologous T-cell transfer.
Adoptive T-cell transfer therapies induce antitumor immunity in some patients with cancer, but their efficacy is limited by the need to produce sufficient quantities of cells for infusion and for the T cells to persist and remain functional in vivo. The cytokine IL2 is required for effector T-cell expansion, survival, and function, and concomitant administration improves the antitumor activity of transplanted T cells. However, IL2 has pleiotropic effects, promoting both immune stimulatory and immune suppressive T-cell responses, and can induce systemic toxicity. To overcome these limitations, Sockolosky and colleagues developed an orthogonal receptor–ligand system in which engineered mutant IL2 (orthoIL2) binds specifically to an engineered mutant IL2Rβ receptor (orthoIL2Rβ), but not to the endogenous wild-type IL2Rβ. Primary mouse CD8+ T cells were engineered to express fluorescently labeled orthoIL2Rβ. As expected, orthoIL2 potently activated STAT5 on orthoIL2Rβ-transduced cells but did not activate STAT5 through wild-type IL2Rβ. In wild-type mice adoptive transfer of orthoIL2Rβ T cells with administration of orthoIL2 resulted in specific expansion of orthoIL2Rβ T cells with negligible toxicity. Further, orthoIL2Rβ T cells expanded in orthoIL2 produced more IFNγ than IL2 expanded cells. In a mouse model of melanoma, lymphocyte depletion with adoptive transfer of orthoIL2Rβ T cells expressing the melanoma antigen pmel1 and orthoIL2 administration delayed tumor growth and extended survival. Taken together, these findings demonstrate that engineered orthogonal IL2/IL2Rβ pairs may allow for selective expansion of desired T-cell subsets to improve the efficacy of adoptive T-cell transfer with minimal toxicity and off-target activity. Further, this orthogonalization strategy may be applied to other ligand–receptor interactions in other biological systems.
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