by akronbiotech

Interleukin-2 (IL-2) is a cytokine critical to effector T cell expansion, survival, and function. Importantly, IL-2 is supplemented in the production of T cells for immunotherapy, including CAR-T cell therapies. While IL-2 can improve T cell survival and efficacy, IL-2 provokes a wide range of responses by simultaneously activating and repressing different components of the immune response, which can trigger toxic side effects. For example, systemic IL-2 administration as well has CAR-T cell infusion can lead to cytokine release syndrome, an immune response resulting in elevated levels of inflammatory cytokines that can be life-threatening.

Balancing the therapeutic benefit of IL-2 as an adjuvant to engineered T cells and the dangerous response of IL-2 with the natural immune system is complex. Recently, researchers at Stanford University have developed synthetic IL-2 cytokine-receptor pairs that could improve T cell immunotherapies. The technology works by forcing the engineered cytokine-receptor pair to interact only with one another while ignoring their natural cytokine and receptor counterparts.

The research focused on the murine IL-2/IL-2Rβ interaction so that in vivo characterization could be carried out in mice. First, researchers identified residues in the IL-2Rβ receptor that bind to IL-2. Mutations to these critical residues eliminated binding to the wildtype IL-2, and the resulting mutated IL-2Rβ was termed orthoIL-2Rβ. Using a yeast display-based evolution method, the wildtype IL-2 was mutated to create a molecule that would bind to orthoIL-2Rβ but not wildtype IL-2Rβ.

Schematic overview of orthogonal IL-2/IL-2R pairs, consisting of a mutant IL-2 cytokine and mutant IL-2R that interact specifically with each other but do not cross-react with their wild-type counterparts.

In clinical T cell therapies, patient-derived T cells are engineered and expanded with IL-2 to generate sufficient quantities of therapeutic cells before re-infusion. The engineered T cells must compete with host cells for survival signals such as IL-2. With the orthoIL-2/orthoIL-2Rβ pair, the engineered cells should not compete with the host cells. To test the in vivo activity of orthoIL-2/orthoIL-2Rβ, a mixture of wildtype and orthoIL-2Rβ CD8+ T cells were transferred into mice, and the impact of wildtype IL-2 and orthoIL-2 administration was measured. The orthoIL-2 expanded the number of orthoIL-2Rβ CD8+ T cells comparably to the wildtype IL-2, which acted through the endogenous IL-2Rβ expressed in both wildtype and orthoIL-2Rβ T cells.

In a proof-of-concept study using a mouse model of melanoma, orthoIL-2 in combination with orthoIL-2Rβ T cells delayed tumor growth and conferred a survival advantage that mirrored wildtype T cells with wildtype IL-2.

Reprogramming cytokine specificity may enable the selective expansion of desired T cell subsets in adoptive cell therapies, limiting off-target effects and reducing adverse events. This orthogonality may provide a way to mitigate toxicities associated with cytokines and immunotherapies.

The article titled, “Selective targeting of engineered T cells using orthogonal IL-2 cytokine-receptor complexes,” was published in Science.

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